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DRUGS & SUPPLEMENTS
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Celemin-10 Plus
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Celemin-10 Plus uses
Celemin-10 Plus consists of Acetate, Asparagine, Chloride, DL-Lysine Monohydrochloride, Glycine, L-Alanine, L-Arginine, L-Aspartic Acid, L-Cysteine Hydrochloride, L-Glutamic Acid, L-Histidine, L-Isoleucine, L-Leucine, L-Malate, L-Methionine, L-Phenylalanine, L-Proline, L-Serine, L-Threonine, L-Tryptophan, L-Valine, Magnesium, Magnesium Acetate, Malic Acid, N-Acetyl-L-Tyrosine, Ornithine Hydrochloride, Phosphoric Acid, Potassium, Potassium Acetate, Sodium, Sodium Acetate, Sodium Phosphate Monobasic, Tyrosine.Glycine:
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
- Im-1453
INDICATIONS AND USAGE
1.5% Celemin-10 Plus (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.
CONTRAINDICATIONS
NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.
Do not use in patients with anuria.
WARNINGS
FOR UROLOGIC IRRIGATION ONLY.
Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, Celemin-10 Plus (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Celemin-10 Plus (Glycine) may significantly alter cardiopulmonary and renal dynamics.
Do not heat container over 66°C (150°F).
PRECAUTIONS
Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using Celemin-10 Plus (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.
Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of Celemin-10 Plus (Glycine) may accumulate in the blood.
Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.
Do not administer unless solution is clear, seal is intact and container is undamaged. Discard unused portion.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Celemin-10 Plus (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Nursing Mothers: Caution should be exercised when Celemin-10 Plus (Glycine) Irrigation, USP is administered to a nursing woman.
Pregnancy: Teratogenic Effects.
Pregnancy Category C. Animal reproduction studies have not been conducted with Celemin-10 Plus (Glycine) Irrigation, USP. It is also not known whether Celemin-10 Plus (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Celemin-10 Plus (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.
Pediatric Use: The safety and effectiveness of Celemin-10 Plus (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.
ADVERSE REACTIONS
Adverse reactions may result from intravascular absorption of Celemin-10 Plus (Glycine). Large intravenous doses of Celemin-10 Plus (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from Celemin-10 Plus (Glycine) are unknown or exceedingly rare.
Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.
OVERDOSAGE
In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.
DOSAGE AND ADMINISTRATION
1.5% Celemin-10 Plus (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.
Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.
Drug Interactions
Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution container permits. See PRECAUTIONS.
HOW SUPPLIED
1.5% Celemin-10 Plus (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).
Revised: October 2004
©Hospira 2004 EN-0577 Printed in USA
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
IM-1453
iv bag ndc 0409-7974-082
HDPE
TO OPEN TEAR AT NOTCH
DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING
THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.
IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.
RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE
HEAT. PROTECT FROM FREEZING. SEE INSERT.
98-4321-R14-3/98
L-Alanine:
A non-essential amino acid that occurs in high levels in its free state in plasma. It is produced from pyruvate by transamination. It is involved in sugar and acid metabolism, increases immunity, and provides energy for muscle tissue, brain, and the central nervous system.
Indication: Used for protein synthesis.
Is an important source of energy for muscle tissue, the brain and central nervous system; strengthens the immune system by producing antibodies; helps in the metabolism of sugars and organic acids.
L-Arginine:
An essential amino acid that is physiologically active in the L-form.
Indication: Used for nutritional supplementation, also for treating dietary shortage or imbalance.
Studies have shown that is has improved immune responses to bacteria, viruses and tumor cells; promotes wound healing and regeneration of the liver; causes the release of growth hormones; considered crucial for optimal muscle growth and tissue repair.
L-Aspartic Acid:
One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter.
Indication: There is no support for the claim that aspartates are exercise performance enhancers, i.e. ergogenic aids.
L-aspartate is considered a non-essential amino acid, meaning that, under normal physiological conditions, sufficient amounts of the amino acid are synthesized in the body to meet the body's requirements. L-aspartate is formed by the transamination of the Krebs cycle intermediate oxaloacetate. The amino acid serves as a precursor for synthesis of proteins, oligopeptides, purines, pyrimidines, nucleic acids and L-arginine. L-aspartate is a glycogenic amino acid, and it can also promote energy production via its metabolism in the Krebs cycle. These latter activities were the rationale for the claim that supplemental aspartate has an anti-fatigue effect on skeletal muscle, a claim that was never confirmed.
L-Cysteine Hydrochloride:
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Drug abuse and dependence
- Dosage and administration
- Directions for proper use of pharmacy bulk package
- Recommended storage conditions after opening
- How supplied
INDICATIONS AND USAGE
Celemin-10 Plus (L-Cysteine Hydrochloride) Hydrochloride Injection, USP is intended for use only after dilution as an additive to Crystalline Amino Acid Injections to meet the intravenous amino acid nutritional requirements of infants receiving total parenteral nutrition.
CONTRAINDICATIONS
This preparation should not be used in patients with hepatic coma or metabolic disorders involving impaired nitrogen utilization.
WARNINGS
Peripheral intravenous infusion of amino acids may induce a rise in blood urea nitrogen (BUN) especially in patients with impaired hepatic or renal function. Appropriate laboratory tests should be performed periodically and infusion discontinued if BUN levels exceed normal postprandial limits and continue to rise. It should be noted that a modest rise in BUN normally occurs as a result of increased protein intake.
Administration of amino acid solutions to a patient with hepatic insufficiency may result in serum amino acid imbalances, metabolic alkalosis, prerenal azotemia, hyperammonemia, stupor and coma.
Administration of amino acid solutions in the presence of impaired renal function may augment an increasing BUN, as does any protein dietary component.
Solutions containing sodium ion should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium retention.
Solutions which contain potassium ion should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is present.
Solutions containing acetate ion should be used with great care in patients with metabolic or respiratory alkalosis. Acetate should be administered with great care in those conditions in which there is an increased level or an impaired utilization of this ion such as severe hepatic insufficiency.
Hyperammonemia is of special significance in infants, as it can result in mental retardation. Therefore it is essential that blood ammonia levels be measured frequently in infants.
Instances of asymptomatic hyperammonemia have been reported in patients without overt liver dysfunction. The mechanisms of this reaction are not clearly defined but may involve genetic defects and immature or subclinically impaired liver function.
Frequent Clinical Evaluation and Laboratory Determinations are Necessary for Proper Monitoring During Administration. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolarity and glucose should be determined frequently.
Safe use during pregnancy has not been established, therefore, infusion of amino acids should be undertaken during pregnancy only when this is deemed essential to the patients' welfare, as judged by the physician.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration
PRECAUTIONS
Special care must be taken when administering hypertonic glucose to provide calories in diabetic or prediabetic patients.
Because of its antianabolic activity, concurrent administration of tetracycline may reduce the nitrogen sparing effects of infused amino acids.
Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen containing substances may occur.
Intravenous feeding regimens which include amino acids should be used with caution in patients with a history of renal disease, pulmonary disease, or with cardiac insufficiency so as to avoid excessive fluid accumulation.
The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time.
Nitrogen intake should be carefully monitored in patients with impaired renal function. For long-term total nutrition, or if a patient has inadequate fat stores, it is essential to provide adequate exogenous calories concurrently with the amino acids. Concentrated dextrose solutions are an effective source of such calories. Such strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava.
ADVERSE REACTIONS
Local reactions consisting of a warm sensation, erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids, particularly if the other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Electrolyte additives should be spread throughout the day. Irritating additive medications may need to be injected at another venous site.
Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.
Drug Abuse and Dependence
None known.
DOSAGE AND ADMINISTRATION
Celemin-10 Plus (L-Cysteine Hydrochloride) Hydrochloride Injection USP is intended for use only after dilution in Crystalline Amino Acid Injection. Each 0.5 gram of Celemin-10 Plus (L-Cysteine Hydrochloride) Hydrochloride Monohydrate should be combined aseptically with 12.5 grams of Crystalline Amino Acid Injection, such as that present in 250 mL of 5% Crystalline Amino Acid Injection. The admixture is then diluted with 250 mL of dextrose 50% or such lesser volume as indicated. Equal volumes of 5% Crystalline Amino Acid Injection and dextrose 50% produce a final solution which contains Crystalline Amino Acid Injection 2.5% in dextrose 25%, which is suitable for administration by central venous infusion. Administration of the final admixture should begin within one hour of mixing. Otherwise, the admixture should be refrigerated immediately and used within 24 hours of the time of mixing. For the recommended rate of administration, see the Crystalline Amino Acid Injection package insert.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE
The pharmacy bulk package is for use in a Pharmacy Admixture Service only.
Use of this product is restricted to a suitable work area, such as a laminar flow hood. Prior to entering the vial, remove the flip-off seal and cleanse the rubber closure with a suitable antiseptic agent.
The container closure may be penetrated only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents. The date and time the vial was initially opened should be recorded in the space provided on the label. Transfer individual doses(s) to appropriate intravenous infusion solutions. Use of a syringe with needle is not recommended. Multiple entries increase the potential of microbial and particulate contamination.
The withdrawal of container contents should be accomplished without delay using aseptic technique. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations.
RECOMMENDED STORAGE CONDITIONS AFTER OPENING
Keep under laminar flow hood at room temperature. Any unused portion of the vial must be discarded within 4 hours after initial entry.
HOW SUPPLIED
Celemin-10 Plus (L-Cysteine Hydrochloride) Hydrochloride Injection, USP (50 mg/mL) is supplied as follows:
| NDC Number | Volume |
| 66758-005-01 | 50 mL |
| 66758-005-02 | 5 × 50 mL |
Also available as:
| NDC Number | Volume |
| 66758-004-01 | 10 mL |
| 66758-004-02 | 10 × 10 mL |
Store at controlled room temperature 15°-30°C (59°-86°F) Do not freeze.
For Sandoz Inc. Customer Service, call 1-800-525-8747
Rx only
Manufactured for:
SANDOZ
Princeton, NJ 08540
Revised: November 2009
L-028-00
SANDOZ
Rx only NDC 66758-005-01
Celemin-10 Plus (L-Cysteine Hydrochloride)
Hydrochloride Injection, USP
PHARMACY BULK PACKAGE
NOT FOR DIRECT INFUSION
50 mg/mL
For IV Use Only After Dilution
Do Not Dispense As A Unit
50 mL
L-018-00
PHARMACY BULK PACKAGE
SANDOZ
5 × 50 mL Vials NDC 66758-005-02
Celemin-10 Plus (L-Cysteine Hydrochloride) Hydrochloride
Injection, USP
50 mg/mL
Pharmacy Bulk Package
Not For Direct Infusion
For IV Use Only After Dilution
Rx only
vial carton
L-Glutamic Acid:
A peptide that is a homopolymer of glutamic acid.
Indication: Considered to be nature's "Brain food" by improving mental capacities; helps speed the healing of ulcers; gives a "lift" from fatigue; helps control alcoholism, schizophrenia and the craving for sugar.
In addition to being one of the building blocks in protein synthesis, it is the most widespread neurotransmitter in brain function, as an excitatory neurotransmitter and as a precursor for the synthesis of GABA in GABAergic neurons.
L-Histidine:
An essential amino acid that is required for the production of histamine.
Indication: The actions of supplemental Celemin-10 Plus (L-Histidine) are entirely unclear. It may have some immunomodulatory as well as antioxidant activity. Celemin-10 Plus (L-Histidine) may be indicated for use in some with rheumatoid arthritis. It is not indicated for treatment of anemia or uremia or for lowering serum cholesterol.
Is found abundantly in hemoglobin; has been used in the treatment of rheumatoid arthritis, allergic diseases, ulcers and anemia. A deficiency can cause poor hearing.
L-Isoleucine:
An essential branched-chain aliphatic amino acid found in many proteins. It is an isomer of leucine. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels.
Indication: The branched-chain amino acids may have antihepatic encephalopathy activity in some. They may also have anticatabolic and antitardive dyskinesia activity.
They provide ingredients for the manufacturing of other essential biochemical components in the body, some of which are utilized for the production of energy, stimulants to the upper brain and helping you to be more alert.
L-Leucine:
An essential branched-chain amino acid important for hemoglobin formation.
Indication: Indicated to assist in the prevention of the breakdown of muscle proteins that sometimes occur after trauma or severe stress.
An essential amino acid. (Claim) Leucine helps with the regulation of blood-sugar levels, the growth and repair of muscle tissue (such as bones, skin and muscles), growth hormone production, wound healing as well as energy regulation. It can assist to prevent the breakdown of muscle proteins that sometimes occur after trauma or severe stress. It may also be beneficial for individuals with phenylketonuria - a condition in which the body cannot metabolize the amino acid phenylalanine
L-Methionine:
A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals.
Indication: Used for protein synthesis including the formation of SAMe, L-homocysteine, L-cysteine, taurine, and sulfate.
Celemin-10 Plus (L-Methionine) is a principle supplier of sulfur which prevents disorders of the hair, skin and nails; helps lower cholesterol levels by increasing the liver's production of lecithin; reduces liver fat and protects the kidneys; a natural chelating agent for heavy metals; regulates the formation of ammonia and creates ammonia-free urine which reduces bladder irritation; influences hair follicles and promotes hair growth. Celemin-10 Plus (L-Methionine) may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.
L-Phenylalanine:
An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine.
Indication: Celemin-10 Plus (L-Phenylalanine) may be helpful in some with depression. It may also be useful in the treatment of vitiligo. There is some evidence that Celemin-10 Plus (L-Phenylalanine) may exacerbate tardive dyskinesia in some schizophrenic patients and in some who have used neuroleptic drugs.
Used by the brain to produce Norepinephrine, a chemical that transmits signals between nerve cells and the brain; keeps you awake and alert; reduces hunger pains; functions as an antidepressant and helps improve memory.
L-Proline:
A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons.
Indication: Celemin-10 Plus (L-Proline) is extremely important for the proper functioning of joints and tendons and also helps maintain and strengthen heart muscles.
Celemin-10 Plus (L-Proline) is a major amino acid found in cartilage and is important for maintaining youthful skin as well as repair of muscle, connective tissue and skin damage. It is also essential for the immune system, and for necessary balance of this formula. It is an essential component of collagen and is important for proper functioning of joints and tendons. Celemin-10 Plus (L-Proline) is extremely important for the proper functioning of joints and tendons. Helps maintain and strengthen heart muscles.
L-Serine:
A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids.
Indication: Used as a natural moisturizing agent in some cosmetics and skin care products.
Serine is classified as a nutritionally non-essential amino acid. Serine is critical for the production of the body's proteins, enzymes and muscle tissue. Serine is needed for the proper metabolism of fats and fatty acids. It also helps in the production of antibodies. Serine is used as a natural moisturizing agent in some cosmetics and skin care products. The main source of essential amino acids is from the diet, non-essential amino acids are normally synthesize by humans and other mammals from common intermediates.
L-Threonine:
An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.
Indication: Celemin-10 Plus (L-Threonine) makes up collagen, elastin, and enamel protein. It aids proper fat metabolism in the liver, helps the digestive and intestinal tracts function more smoothly, and assists in metabolism and assimilation.
Celemin-10 Plus (L-Threonine) is an essential amino acid that helps to maintain the proper protein balance in the body. It is important for the formation of collagen, elastin, and tooth enamel, and aids liver and lipotropic function when combined with aspartic acid and methionine.
L-Tryptophan:
An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor of indole alkaloids in plants. It is a precursor of serotonin (hence its use as an antidepressant and sleep aid). It can be a precursor to niacin, albeit inefficiently, in mammals.
Indication: Tryptophan may be useful in increasing serotonin production, promoting healthy sleep, managing depression by enhancing mental and emotional well-being, managing pain tolerance, and managing weight.
Tryptophan is critical for the production of the body's proteins, enzymes and muscle tissue. It is also essential for the production of niacin, the synthesis of the neurotransmitter serotonin and melatonin. Tryptophan supplements can be used as natural relaxants to help relieve insomnia. Tryptophan can also reduce anxiety and depression and has been shown to reduce the intensity of migraine headaches. Other promising indications include the relief of chronic pain, reduction of impulsivity or mania and the treatment of obsessive or compulsive disorders. Tryptophan also appears to help the immune system and can reduce the risk of cardiac spasms. Tryptophan deficiencies may lead to coronary artery spasms. Tryptophan is used as an essential nutrient in infant formulas and intravenous feeding. Tryptophan is marketed as a prescription drug (Tryptan) for those who do not seem to respond well to conventional antidepressants. It may also be used to treat those afflicted with seasonal affective disorder (a winter-onset depression). Tryptopan serves as the precursor for the synthesis of serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine).
L-Valine:
A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway.
Indication: Promotes mental vigor, muscle coordination, and calm emotions. May also be of use in a minority of patients with hepatic encephalopathy and in some with phenylketonuria.
Celemin-10 Plus (L-Valine) is a branched-chain essential amino acid (BCAA) that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. Valine is one of three branched-chain amino acids (the others are leucine and isoleucine) that enhance energy, increase endurance, and aid in muscle tissue recovery and repair. This group also lowers elevated blood sugar levels and increases growth hormone production. Supplemental valine should always be combined with isoleucine and leucine at a respective milligram ratio of 2:1:2. It is an essential amino acid found in proteins; important for optimal growth in infants and for growth in children and nitrogen balance in adults. The lack of Celemin-10 Plus (L-Valine) may influence the growth of body, cause neuropathic obstacle, anaemia. It has wide applications in the field of pharmaceutical and food industry.
Magnesium:
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
- References
Celemin-10 Plus (Magnesium) Sulfate
Injection, USP
Ansyr Plastic Syringe
Rx only
DESCRIPTION
Celemin-10 Plus (Magnesium) Sulfate Injection, USP is a sterile solution of Celemin-10 Plus (Magnesium) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).
The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.
Celemin-10 Plus (Magnesium) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.
The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.
CLINICAL PHARMACOLOGY
Celemin-10 Plus (Magnesium) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.
As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Celemin-10 Plus (Magnesium) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.
Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Celemin-10 Plus (Magnesium). While there are large stores of Celemin-10 Plus (Magnesium) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Celemin-10 Plus (Magnesium) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.
Celemin-10 Plus (Magnesium) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Celemin-10 Plus (Magnesium) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Celemin-10 Plus (Magnesium) levels range from 1.5 to 2.5 mEq/liter.
As plasma Celemin-10 Plus (Magnesium) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Celemin-10 Plus (Magnesium). Serum Celemin-10 Plus (Magnesium) concentrations in excess of 12 mEq/L may be fatal.
Celemin-10 Plus (Magnesium) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Celemin-10 Plus (Magnesium) poisoning are antagonized to some extent by intravenous administration of calcium.
Pharmacokinetics
With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Celemin-10 Plus (Magnesium) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.
INDICATIONS AND USAGE
Celemin-10 Plus (Magnesium) Sulfate Injection, USP is suitable for replacement therapy in Celemin-10 Plus (Magnesium) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Celemin-10 Plus (Magnesium) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.
In total parenteral nutrition (TPN), Celemin-10 Plus (Magnesium) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.
Celemin-10 Plus (Magnesium) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.
CONTRAINDICATIONS
Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.
WARNINGS
FETAL HARM: Continuous administration of Celemin-10 Plus (Magnesium) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Celemin-10 Plus (Magnesium) sulfate should be used during pregnancy only if clearly needed. If Celemin-10 Plus (Magnesium) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Celemin-10 Plus (Magnesium) sulfate beyond 5 to 7 days may cause fetal abnormalities.
ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Parenteral use in the presence of renal insufficiency may lead to Celemin-10 Plus (Magnesium) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.
PRECAUTIONS
General
Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Celemin-10 Plus (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Celemin-10 Plus (Magnesium).
Because Celemin-10 Plus (Magnesium) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Celemin-10 Plus (Magnesium) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Celemin-10 Plus (Magnesium) should be given until they return. Serum Celemin-10 Plus (Magnesium) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Celemin-10 Plus (Magnesium) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Celemin-10 Plus (Magnesium) intoxication in eclampsia.
50% Celemin-10 Plus (Magnesium) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.
Laboratory Tests
Celemin-10 Plus (Magnesium) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Celemin-10 Plus (Magnesium) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.
Drug Interactions
CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Celemin-10 Plus (Magnesium), their dosage should be adjusted with caution because of additive CNS depressant effects of Celemin-10 Plus (Magnesium). CNS depression and peripheral transmission defects produced by Celemin-10 Plus (Magnesium) may be antagonized by calcium.
Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Celemin-10 Plus (Magnesium) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.
Cardiac Glycosides - Celemin-10 Plus (Magnesium) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Celemin-10 Plus (Magnesium) toxicity.
Pregnancy
Teratogenic Effects
Pregnancy Category D (See WARNINGS and PRECAUTIONS )
See WARNINGS and PRECAUTIONS .
Celemin-10 Plus (Magnesium) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Celemin-10 Plus (Magnesium) sulfate for more than 5 to 7 days.1-10 Celemin-10 Plus (Magnesium) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.
Nonteratogenic Effects
When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Celemin-10 Plus (Magnesium) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).
Labor and Delivery
Continuous administration of Celemin-10 Plus (Magnesium) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Celemin-10 Plus (Magnesium) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
Nursing Mothers
Since Celemin-10 Plus (Magnesium) is distributed into milk during parenteral Celemin-10 Plus (Magnesium) sulfate administration, the drug should be used with caution in nursing women.
Geriatrics
Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Celemin-10 Plus (Magnesium) should be monitored in such patients.
ADVERSE REACTIONS
The adverse effects of parenterally administered Celemin-10 Plus (Magnesium) usually are the result of Celemin-10 Plus (Magnesium) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Celemin-10 Plus (Magnesium) sulfate therapy for eclampsia has been reported.
OVERDOSAGE
Celemin-10 Plus (Magnesium) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Celemin-10 Plus (Magnesium) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Celemin-10 Plus (Magnesium).
For Treatment of Overdose
Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.
Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.
DOSAGE AND ADMINISTRATION
Dosage of Celemin-10 Plus (Magnesium) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.
Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Celemin-10 Plus (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.
In Celemin-10 Plus (Magnesium) Deficiency
In the treatment of mild Celemin-10 Plus (Magnesium) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Celemin-10 Plus (Magnesium) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Celemin-10 Plus (Magnesium) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.
In Hyperalimentation
In total parenteral nutrition, maintenance requirements for Celemin-10 Plus (Magnesium) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.
In Pre-eclampsia or Eclampsia
In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Celemin-10 Plus (Magnesium) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Celemin-10 Plus (Magnesium) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Celemin-10 Plus (Magnesium) sulfate is 20 grams/48 hours and frequent serum Celemin-10 Plus (Magnesium) concentrations must be obtained. Continuous use of Celemin-10 Plus (Magnesium) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Other Uses
In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Celemin-10 Plus (Magnesium) sulfate is 1 gram to 2 grams given intravenously.
For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.
In paroxysmal atrial tachycardia, Celemin-10 Plus (Magnesium) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.
For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.
Incompatibilities
Celemin-10 Plus (Magnesium) sulfate in solution may result in a precipitate formation when mixed with solutions containing:
Alcohol (in high Heavy Metals
concentrations) Hydrocortisone sodium
Alkali carbonates and succinate
bicarbonates Phosphates
Alkali hydroxides Polymixin B sulfate
Arsenates Procaine hydrochloride
Barium Salicylates
Calcium Strontium
Clindamycin phosphate Tartrates
The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.
It has been reported that Celemin-10 Plus (Magnesium) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Celemin-10 Plus (Magnesium) Sulfate Injection, USP is supplied in single-dose containers as follows:
| NDC No. | Container | Total Amount | Concentration | mEq Mg++/mL |
| 0409-1754-10 | Ansyr Plastic Syringe | 5 g/10 mL | 50% | 4 mEq/mL |
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Store at 20 to 25°C (68 to 77°F).
REFERENCES
- Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Celemin-10 Plus (Magnesium) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
- Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Celemin-10 Plus (Magnesium) toxicity. J. Perinatol. 2006; 26(6):371-4.
- Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Celemin-10 Plus (Magnesium) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
- Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Celemin-10 Plus (Magnesium) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
- Matsuda Y, Maeda Y, Ito M, et al. Effect of Celemin-10 Plus (Magnesium) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
- Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Celemin-10 Plus (Magnesium) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
- Santi MD, Henry GW, Douglas GL. Celemin-10 Plus (Magnesium) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
- Holcomb WL, Shackelford GD, Petrie RH. Celemin-10 Plus (Magnesium) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
- Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
- Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Celemin-10 Plus (Magnesium) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
- McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Celemin-10 Plus (Magnesium) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
- Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Celemin-10 Plus (Magnesium) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.
Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1024-1.0
April 2017
Hospira Logo
50% Celemin-10 Plus (Magnesium) Sulfate 5 g/10 mL (500 mg/mL)
Rx only
NDC 0409-1754-10
10 mL Single-dose syringe
50% Celemin-10 Plus (Magnesium) Sulfate Injection, USP
5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)
MUST BE DILUTED FOR INTRAVENOUS USE.
For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).
Contains no more than 75 mcg/L of aluminum.
Hospira, Inc., Lake Forest, IL 60045 USA
Hospira
RL-6891
Magnesium Acetate:
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
- References
Celemin-10 Plus (Magnesium Acetate) Sulfate
Injection, USP
Ansyr Plastic Syringe
Rx only
DESCRIPTION
Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP is a sterile solution of Celemin-10 Plus (Magnesium Acetate) sulfate heptahydrate in Water for Injection, USP administered by the intravenous or intramuscular routes as an electrolyte replenisher or anticonvulsant. Must be diluted before intravenous use. May contain sulfuric acid and/or sodium hydroxide for pH adjustment. The pH is 5.5 to 7.0. The 50% concentration has an osmolarity of 4.06 mOsmol/mL (calc.).
The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended only for use as a single-dose injection. When smaller doses are required the unused portion should be discarded with the entire unit.
Celemin-10 Plus (Magnesium Acetate) Sulfate, USP heptahydrate is chemically designated MgSO4 - 7H2O with molecular weight of 246.48 and occurs as colorless crystals or white powder freely soluble in water.
The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.
CLINICAL PHARMACOLOGY
Celemin-10 Plus (Magnesium Acetate) (Mg++) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability.
As a nutritional adjunct in hyperalimentation, the precise mechanism of action for Celemin-10 Plus (Magnesium Acetate) is uncertain. Early symptoms of hypomagnesemia (less than 1.5 mEq/liter) may develop as early as three to four days or within weeks.
Predominant deficiency effects are neurological, e.g., muscle irritability, clonic twitching and tremors. Hypocalcemia and hypokalemia often follow low serum levels of Celemin-10 Plus (Magnesium Acetate). While there are large stores of Celemin-10 Plus (Magnesium Acetate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Celemin-10 Plus (Magnesium Acetate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.
Celemin-10 Plus (Magnesium Acetate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Celemin-10 Plus (Magnesium Acetate) is said to have a depressant effect on the central nervous system (CNS), but it does not adversely affect the woman, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal plasma Celemin-10 Plus (Magnesium Acetate) levels range from 1.5 to 2.5 mEq/liter.
As plasma Celemin-10 Plus (Magnesium Acetate) rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the plasma level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower plasma levels of Celemin-10 Plus (Magnesium Acetate). Serum Celemin-10 Plus (Magnesium Acetate) concentrations in excess of 12 mEq/L may be fatal.
Celemin-10 Plus (Magnesium Acetate) acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of Celemin-10 Plus (Magnesium Acetate) poisoning are antagonized to some extent by intravenous administration of calcium.
Pharmacokinetics
With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Celemin-10 Plus (Magnesium Acetate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.
INDICATIONS AND USAGE
Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP is suitable for replacement therapy in Celemin-10 Plus (Magnesium Acetate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Celemin-10 Plus (Magnesium Acetate) (Mg++) level is usually below the lower limit of normal (1.5 to 2.5 mEq/liter) and the serum calcium (Ca++) level is normal (4.3 to 5.3 mEq/liter) or elevated.
In total parenteral nutrition (TPN), Celemin-10 Plus (Magnesium Acetate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.
Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP is also indicated for the prevention and control of seizures (convulsions) in pre-eclampsia and eclampsia, respectively.
CONTRAINDICATIONS
Parenteral administration of the drug is contraindicated in patients with heart block or myocardial damage.
WARNINGS
FETAL HARM: Continuous administration of Celemin-10 Plus (Magnesium Acetate) sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Celemin-10 Plus (Magnesium Acetate) sulfate should be used during pregnancy only if clearly needed. If Celemin-10 Plus (Magnesium Acetate) sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of Celemin-10 Plus (Magnesium Acetate) sulfate beyond 5 to 7 days may cause fetal abnormalities.
ALUMINUM TOXICITY: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Parenteral use in the presence of renal insufficiency may lead to Celemin-10 Plus (Magnesium Acetate) intoxication. Intravenous use in the eclampsia should be reserved for immediate control of life-threatening convulsions.
PRECAUTIONS
General
Administer with caution if flushing and sweating occurs. When barbiturates, narcotics or other hypnotics (or systemic anesthetics) are to be given in conjunction with Celemin-10 Plus (Magnesium Acetate), their dosage should be adjusted with caution because of additive CNS depressant effects of Celemin-10 Plus (Magnesium Acetate).
Because Celemin-10 Plus (Magnesium Acetate) is removed from the body solely by the kidneys, the drug should be used with caution in patients with renal impairment. Urine output should be maintained at a level of 100 mL or more during the four hours preceding each dose. Monitoring serum Celemin-10 Plus (Magnesium Acetate) levels and the patient's clinical status is essential to avoid the consequences of overdosage in toxemia. Clinical indications of a safe dosage regimen include the presence of the patellar reflex (knee jerk) and absence of respiratory depression (approximately 16 breaths or more/minute). When repeated doses of the drug are given parenterally, knee jerk reflexes should be tested before each dose and if they are absent, no additional Celemin-10 Plus (Magnesium Acetate) should be given until they return. Serum Celemin-10 Plus (Magnesium Acetate) levels usually sufficient to control convulsions range from 3 to 6 mg/100 mL (2.5 to 5 mEq/liter). The strength of the deep tendon reflexes begins to diminish when Celemin-10 Plus (Magnesium Acetate) levels exceed 4 mEq/liter. Reflexes may be absent at 10 mEq magnesium/liter, where respiratory paralysis is a potential hazard. An injectable calcium salt should be immediately available to counteract the potential hazards of Celemin-10 Plus (Magnesium Acetate) intoxication in eclampsia.
50% Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP must be diluted to a concentration of 20% or less prior to intravenous infusion. Rate of administration should be slow and cautious, to avoid producing hypermagnesemia. The 50% solution also should be diluted to 20% or less for intramuscular injection in infants and children.
Laboratory Tests
Celemin-10 Plus (Magnesium Acetate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Celemin-10 Plus (Magnesium Acetate) is monitored. The normal serum level is 1.5 to 2.5 mEq/L.
Drug Interactions
CNS Depressants - When barbiturates, narcotics or other hypnotics (or systemic anesthetics), or other CNS depressants are to be given in conjunction with Celemin-10 Plus (Magnesium Acetate), their dosage should be adjusted with caution because of additive CNS depressant effects of Celemin-10 Plus (Magnesium Acetate). CNS depression and peripheral transmission defects produced by Celemin-10 Plus (Magnesium Acetate) may be antagonized by calcium.
Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Celemin-10 Plus (Magnesium Acetate) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.
Cardiac Glycosides - Celemin-10 Plus (Magnesium Acetate) sulfate should be administered with extreme caution in digitalized patients, because serious changes in cardiac conduction which can result in heart block may occur if administration of calcium is required to treat Celemin-10 Plus (Magnesium Acetate) toxicity.
Pregnancy
Teratogenic Effects
Pregnancy Category D (See WARNINGS and PRECAUTIONS )
See WARNINGS and PRECAUTIONS .
Celemin-10 Plus (Magnesium Acetate) sulfate can cause fetal abnormalities when administered beyond 5 to 7 days to pregnant women. There are retrospective epidemiological studies and case reports documenting fetal abnormalities such as hypocalcemia, skeletal demineralization, osteopenia and other skeletal abnormalities with continuous maternal administration of Celemin-10 Plus (Magnesium Acetate) sulfate for more than 5 to 7 days.1-10 Celemin-10 Plus (Magnesium Acetate) sulfate injection should be used during pregnancy only if clearly needed. If this drug is used during pregnancy, the woman should be apprised of the potential harm to the fetus.
Nonteratogenic Effects
When administered by continuous intravenous infusion (especially for more than 24 hours preceding delivery) to control convulsions in a toxemic woman, the newborn may show signs of Celemin-10 Plus (Magnesium Acetate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).
Labor and Delivery
Continuous administration of Celemin-10 Plus (Magnesium Acetate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Celemin-10 Plus (Magnesium Acetate) sulfate outside of its approved indication in pregnant women should be by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
Nursing Mothers
Since Celemin-10 Plus (Magnesium Acetate) is distributed into milk during parenteral Celemin-10 Plus (Magnesium Acetate) sulfate administration, the drug should be used with caution in nursing women.
Geriatrics
Geriatric patients often require reduced dosage because of impaired renal function. In patients with severe impairment, dosage should not exceed 20 grams in 48 hours. Serum Celemin-10 Plus (Magnesium Acetate) should be monitored in such patients.
ADVERSE REACTIONS
The adverse effects of parenterally administered Celemin-10 Plus (Magnesium Acetate) usually are the result of Celemin-10 Plus (Magnesium Acetate) intoxication. These include flushing, sweating, hypotension, depressed reflexes, flaccid paralysis, hypothermia, circulatory collapse, cardiac and central nervous system depression proceeding to respiratory paralysis. Hypocalcemia with signs of tetany secondary to Celemin-10 Plus (Magnesium Acetate) sulfate therapy for eclampsia has been reported.
OVERDOSAGE
Celemin-10 Plus (Magnesium Acetate) intoxication is manifested by a sharp drop in blood pressure and respiratory paralysis. Disappearance of the patellar reflex is a useful clinical sign to detect the onset of Celemin-10 Plus (Magnesium Acetate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Celemin-10 Plus (Magnesium Acetate).
For Treatment of Overdose
Artificial respiration is often required. Intravenous calcium, 10 to 20 mL of a 5% solution (diluted if desirable with isotonic sodium chloride for injection) is used to counteract effects of hypermagnesemia. Subcutaneous physostigmine, 0.5 to 1 mg may be helpful.
Hypermagnesemia in the newborn may require resuscitation and assisted ventilation via endotracheal intubation or intermittent positive pressure ventilation as well as intravenous calcium.
DOSAGE AND ADMINISTRATION
Dosage of Celemin-10 Plus (Magnesium Acetate) sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.
Both intravenous and intramuscular administration are appropriate. Intramuscular administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas intravenous doses will provide a therapeutic level almost immediately. The rate of intravenous injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures. Continuous maternal administration of Celemin-10 Plus (Magnesium Acetate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Solutions for intravenous infusion must be diluted to a concentration of 20% or less prior to administration. The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP. Deep intramuscular injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.
In Celemin-10 Plus (Magnesium Acetate) Deficiency
In the treatment of mild Celemin-10 Plus (Magnesium Acetate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Celemin-10 Plus (Magnesium Acetate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Celemin-10 Plus (Magnesium Acetate) per 24 hours). For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given intramuscularly within a period of four hours if necessary. Alternatively, 5 grams, (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow intravenous infusion over a three-hour period. In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.
In Hyperalimentation
In total parenteral nutrition, maintenance requirements for Celemin-10 Plus (Magnesium Acetate) are not precisely known. The maintenance dose used in adults ranges from 8 to 24 mEq (1 gram to 3 grams) daily; for infants, the range is 2 to 10 mEq (0.25 gram to 1.25 grams) daily.
In Pre-eclampsia or Eclampsia
In severe pre-eclampsia or eclampsia, the total initial dose is 10 grams to 14 grams of Celemin-10 Plus (Magnesium Acetate) sulfate. Intravenously, a dose of 4 grams to 5 grams in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused. Simultaneously, intramuscular doses of up to 10 grams (5 grams or 10 mL of the undiluted 50% solution in each buttock) are given. Alternatively, the initial intravenous dose of 4 grams may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected intravenously over a period of three to four minutes. Subsequently, 4 grams to 5 grams (8 to 10 mL of the 50% solution) are injected intramuscularly into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function. Alternatively, after the initial intravenous dose, some clinicians administer 1 gram to 2 grams/hour by constant intravenous infusion. Therapy should continue until paroxysms cease. A serum Celemin-10 Plus (Magnesium Acetate) level of 6 mg/100 mL is considered optimal for control of seizures. A total daily (24 hr) dose of 30 grams to 40 grams should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of Celemin-10 Plus (Magnesium Acetate) sulfate is 20 grams/48 hours and frequent serum Celemin-10 Plus (Magnesium Acetate) concentrations must be obtained. Continuous use of Celemin-10 Plus (Magnesium Acetate) sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.
Other Uses
In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of Celemin-10 Plus (Magnesium Acetate) sulfate is 1 gram to 2 grams given intravenously.
For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 gram administered intramuscularly or intravenously.
In paroxysmal atrial tachycardia, Celemin-10 Plus (Magnesium Acetate) should be used only if simpler measures have failed and there is no evidence of myocardial damage. The usual dose is 3 grams to 4 grams (30 to 40 mL of a 10% solution) administered intravenously over 30 seconds with extreme caution.
For reduction of cerebral edema, 2.5 grams (25 mL of a 10% solution) is given intravenously.
Incompatibilities
Celemin-10 Plus (Magnesium Acetate) sulfate in solution may result in a precipitate formation when mixed with solutions containing:
Alcohol (in high Heavy Metals
concentrations) Hydrocortisone sodium
Alkali carbonates and succinate
bicarbonates Phosphates
Alkali hydroxides Polymixin B sulfate
Arsenates Procaine hydrochloride
Barium Salicylates
Calcium Strontium
Clindamycin phosphate Tartrates
The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.
It has been reported that Celemin-10 Plus (Magnesium Acetate) may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP is supplied in single-dose containers as follows:
| NDC No. | Container | Total Amount | Concentration | mEq Mg++/mL |
| 0409-1754-10 | Ansyr Plastic Syringe | 5 g/10 mL | 50% | 4 mEq/mL |
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Store at 20 to 25°C (68 to 77°F).
REFERENCES
- Yokoyama K, Takahashi N, Yada Y. Prolonged maternal Celemin-10 Plus (Magnesium Acetate) administration and bone metabolism in neonates. Early Hum Dev. 2010;86(3):187-91. Epub 2010 Mar 12.
- Wedig KE, Kogan J, Schorry EK et al. Skeletal demineralization and fractures caused by fetal Celemin-10 Plus (Magnesium Acetate) toxicity. J. Perinatol. 2006; 26(6):371-4.
- Nassar AH, Sakhel K, Maarouf H, et al. Adverse maternal and neonatal outcome of prolonged course of Celemin-10 Plus (Magnesium Acetate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
- Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Celemin-10 Plus (Magnesium Acetate) sulphate for tocolysis of premature labor. Pediatr Radiol. 2004;34(5):384-6. Epub 2004 Feb 18.
- Matsuda Y, Maeda Y, Ito M, et al. Effect of Celemin-10 Plus (Magnesium Acetate) sulfate treatment on neonatal bone abnormalities. Gynecol Obstet Invest. 1997;44(2):82-8.
- Schanler RJ, Smith LG, Burns PA. Effects of long-term maternal intravenous Celemin-10 Plus (Magnesium Acetate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
- Santi MD, Henry GW, Douglas GL. Celemin-10 Plus (Magnesium Acetate) sulfate treatment of preterm labor as a cause of abnormal neonatal bone mineralization. J Pediatr Orthrop. 1994;14(2):249-53.
- Holcomb WL, Shackelford GD, Petrie RH. Celemin-10 Plus (Magnesium Acetate) tocolysis and neonatal bone abnormalities; a controlled study. Obstet Gynecol. 1991; 78(4):611-4.
- Cumming WA, Thomas VJ. Hypermagnesemia: a cause of abnormal metaphyses in the neonate. Am J Roentgenol. 1989; 152(5):1071-2.
- Lamm CL, Norton KL, Murphy RJ. Congenital rickets associated with Celemin-10 Plus (Magnesium Acetate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
- McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Celemin-10 Plus (Magnesium Acetate) sulfate treatment on perinatal calcium metabolism. II. Neonatal responses. Obstet Gynecol. 1980; 56(5): 595-600.
- Riaz M, Porat R, Brodsky NL, et al. The effects of maternal Celemin-10 Plus (Magnesium Acetate) sulfate treatment on newborns: a prospective controlled study. J. Perinatol. 1998;18(6 pt 1):449-54.
Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1024-1.0
April 2017
Hospira Logo
50% Celemin-10 Plus (Magnesium Acetate) Sulfate 5 g/10 mL (500 mg/mL)
Rx only
NDC 0409-1754-10
10 mL Single-dose syringe
50% Celemin-10 Plus (Magnesium Acetate) Sulfate Injection, USP
5 g/10 mL (500 mg/mL) (4 mEq Mg++/mL)
MUST BE DILUTED FOR INTRAVENOUS USE.
For Intravenous or Intramuscular Use. Sterile. 4.06 mOsmol/mL (calc.).
Contains no more than 75 mcg/L of aluminum.
Hospira, Inc., Lake Forest, IL 60045 USA
Hospira
RL-6891
Potassium:
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
Celemin-10 Plus (Potassium) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K
Rx Only
DESCRIPTION
The Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Celemin-10 Plus (Potassium) chloride containing 1500 mg of microencapsulated Celemin-10 Plus (Potassium) chloride, USP equivalent to 20 mEq of Celemin-10 Plus (Potassium) in a tablet.
These formulations are intended to slow the release of Celemin-10 Plus (Potassium) so that the likelihood of a high localized concentration of Celemin-10 Plus (Potassium) chloride within the gastrointestinal tract is reduced.
Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Celemin-10 Plus (Potassium) chloride, and the structural formula is KCl. Celemin-10 Plus (Potassium) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.
Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Celemin-10 Plus (Potassium) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Celemin-10 Plus (Potassium) chloride.
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.
CLINICAL PHARMACOLOGY
The Celemin-10 Plus (Potassium) ion is the principal intracellular cation of most body tissues. Celemin-10 Plus (Potassium) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.
The intracellular concentration of Celemin-10 Plus (Potassium) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.
Celemin-10 Plus (Potassium) is a normal dietary constituent and under steady-state conditions the amount of Celemin-10 Plus (Potassium) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Celemin-10 Plus (Potassium) is 50 to 100 mEq per day.
Celemin-10 Plus (Potassium) depletion will occur whenever the rate of Celemin-10 Plus (Potassium) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Celemin-10 Plus (Potassium) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Celemin-10 Plus (Potassium) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Celemin-10 Plus (Potassium) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Celemin-10 Plus (Potassium) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.
If Celemin-10 Plus (Potassium) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Celemin-10 Plus (Potassium) in the form of high Celemin-10 Plus (Potassium) food or Celemin-10 Plus (Potassium) chloride may be able to restore normal Celemin-10 Plus (Potassium) levels.
In rare circumstances (eg, patients with renal tubular acidosis) Celemin-10 Plus (Potassium) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Celemin-10 Plus (Potassium) replacement should be accomplished with Celemin-10 Plus (Potassium) salts other than the chloride, such as Celemin-10 Plus (Potassium) bicarbonate, Celemin-10 Plus (Potassium) citrate, Celemin-10 Plus (Potassium) acetate, or Celemin-10 Plus (Potassium) gluconate.
INDICATIONS AND USAGE
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Celemin-10 Plus (Potassium) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Celemin-10 Plus (Potassium) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.
The use of Celemin-10 Plus (Potassium) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Celemin-10 Plus (Potassium) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Celemin-10 Plus (Potassium) salts may be indicated.
CONTRAINDICATIONS
Celemin-10 Plus (Potassium) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Celemin-10 Plus (Potassium) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).
Controlled-release formulations of Celemin-10 Plus (Potassium) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Celemin-10 Plus (Potassium) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Celemin-10 Plus (Potassium) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).
All solid oral dosage forms of Celemin-10 Plus (Potassium) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.
WARNINGS
Hyperkalemia (see OVERDOSAGE )
In patients with impaired mechanisms for excreting Celemin-10 Plus (Potassium), the administration of Celemin-10 Plus (Potassium) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Celemin-10 Plus (Potassium) by the intravenous route but may also occur in patients given Celemin-10 Plus (Potassium) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Celemin-10 Plus (Potassium) salts in patients with chronic renal disease, or any other condition which impairs Celemin-10 Plus (Potassium) excretion, requires particularly careful monitoring of the serum Celemin-10 Plus (Potassium) concentration and appropriate dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of Celemin-10 Plus (Potassium) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Celemin-10 Plus (Potassium) retention by inhibiting aldosterone production. Celemin-10 Plus (Potassium) supplements should be given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of Celemin-10 Plus (Potassium) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Celemin-10 Plus (Potassium) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Celemin-10 Plus (Potassium) chloride and thus to minimize the possibility of a high local concentration of Celemin-10 Plus (Potassium) near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Celemin-10 Plus (Potassium) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Celemin-10 Plus (Potassium) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Celemin-10 Plus (Potassium) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Celemin-10 Plus (Potassium) salt such as Celemin-10 Plus (Potassium) bicarbonate, Celemin-10 Plus (Potassium) citrate, Celemin-10 Plus (Potassium) acetate, or Celemin-10 Plus (Potassium) gluconate.
PRECAUTIONS
General
The diagnosis of Celemin-10 Plus depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Celemin-10 Plus (Potassium) depletion. In interpreting the serum Celemin-10 Plus (Potassium) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Celemin-10 Plus (Potassium) while acute acidosis per se can increase the serum Celemin-10 Plus (Potassium) concentration into the normal range even in the presence of a reduced total body Celemin-10 Plus (Potassium). The treatment of Celemin-10 Plus (Potassium) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.
Information for Patients
Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
3. Stir for about half a minute after the tablet(s) has disintegrated.
4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
5. Add another 1 fluid ounce of water, swirl, and consume immediately.
6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Celemin-10 Plus (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.
Laboratory Tests
When blood is drawn for analysis of plasma Celemin-10 Plus it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.
Drug Interactions
Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Celemin-10 Plus is a normal dietary constituent.
Pregnancy Category C
Animal reproduction studies have not been conducted with Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Celemin-10 Plus (Potassium) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.
Nursing Mothers
The normal Celemin-10 Plus ion content of human milk is about 13 mEq per liter. Since oral Celemin-10 Plus (Potassium) becomes part of the body Celemin-10 Plus (Potassium) pool, so long as body Celemin-10 Plus (Potassium) is not excessive, the contribution of Celemin-10 Plus (Potassium) chloride supplementation should have little or no effect on the level in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Celemin-10 Plus (Potassium) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.
ADVERSE REACTIONS
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Celemin-10 Plus (Potassium) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.
OVERDOSAGE
The administration of oral Celemin-10 Plus (Potassium) salts to persons with normal excretory mechanisms for Celemin-10 Plus (Potassium) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Celemin-10 Plus (Potassium) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Celemin-10 Plus (Potassium) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).
Treatment measures for hyperkalemia include the following:
- Patients should be closely monitored for arrhythmias and electrolyte changes.
- Elimination of foods and medications containing Celemin-10 Plus (Potassium) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
- Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
- Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
- Correction of acidosis, if present, with intravenous sodium bicarbonate.
- Use of exchange resins, hemodialysis, or peritoneal dialysis.
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Celemin-10 Plus (Potassium) concentration can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
DOSAGE AND ADMINISTRATION
The usual dietary intake of Celemin-10 Plus (Potassium) by the average adult is 50 to 100 mEq per day. Celemin-10 Plus (Potassium) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Celemin-10 Plus (Potassium) from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Celemin-10 Plus (Potassium) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.
Each Celemin-10 Plus (Potassium) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Celemin-10 Plus (Potassium) chloride.
Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).
Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
- Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
- Allow approximately 2 minutes for the tablet(s) to disintegrate.
- Stir for about half a minute after the tablet(s) has disintegrated.
- Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
- Add another 1 fluid ounce of water, swirl, and consume immediately.
- Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Celemin-10 Plus (Potassium) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
HOW SUPPLIED
Celemin-10 Plus (Potassium) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.
Storage Conditions
Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).
Manufactured by:
Eurand, Inc.
Vandalia, OH 45377 USA
Distributed by:
Watson Pharma, Inc.
Rev. Date (01/09) 173714
Celemin-10 Plus (Potassium) chloride 20 Meq
Potassium Acetate:
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
Celemin-10 Plus (Potassium Acetate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K
Rx Only
DESCRIPTION
The Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Celemin-10 Plus (Potassium Acetate) chloride containing 1500 mg of microencapsulated Celemin-10 Plus (Potassium Acetate) chloride, USP equivalent to 20 mEq of Celemin-10 Plus (Potassium Acetate) in a tablet.
These formulations are intended to slow the release of Celemin-10 Plus (Potassium Acetate) so that the likelihood of a high localized concentration of Celemin-10 Plus (Potassium Acetate) chloride within the gastrointestinal tract is reduced.
Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Celemin-10 Plus (Potassium Acetate) chloride, and the structural formula is KCl. Celemin-10 Plus (Potassium Acetate) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.
Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Celemin-10 Plus (Potassium Acetate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Celemin-10 Plus (Potassium Acetate) chloride.
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.
CLINICAL PHARMACOLOGY
The Celemin-10 Plus (Potassium Acetate) ion is the principal intracellular cation of most body tissues. Celemin-10 Plus (Potassium Acetate) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.
The intracellular concentration of Celemin-10 Plus (Potassium Acetate) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.
Celemin-10 Plus (Potassium Acetate) is a normal dietary constituent and under steady-state conditions the amount of Celemin-10 Plus (Potassium Acetate) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Celemin-10 Plus (Potassium Acetate) is 50 to 100 mEq per day.
Celemin-10 Plus (Potassium Acetate) depletion will occur whenever the rate of Celemin-10 Plus (Potassium Acetate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Celemin-10 Plus (Potassium Acetate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Celemin-10 Plus (Potassium Acetate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Celemin-10 Plus (Potassium Acetate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Celemin-10 Plus (Potassium Acetate) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.
If Celemin-10 Plus (Potassium Acetate) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Celemin-10 Plus (Potassium Acetate) in the form of high Celemin-10 Plus (Potassium Acetate) food or Celemin-10 Plus (Potassium Acetate) chloride may be able to restore normal Celemin-10 Plus (Potassium Acetate) levels.
In rare circumstances (eg, patients with renal tubular acidosis) Celemin-10 Plus (Potassium Acetate) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Celemin-10 Plus (Potassium Acetate) replacement should be accomplished with Celemin-10 Plus (Potassium Acetate) salts other than the chloride, such as Celemin-10 Plus (Potassium Acetate) bicarbonate, Celemin-10 Plus (Potassium Acetate) citrate, Celemin-10 Plus (Potassium Acetate) acetate, or Celemin-10 Plus (Potassium Acetate) gluconate.
INDICATIONS AND USAGE
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Celemin-10 Plus (Potassium Acetate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Celemin-10 Plus (Potassium Acetate) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.
The use of Celemin-10 Plus (Potassium Acetate) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Celemin-10 Plus (Potassium Acetate) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Celemin-10 Plus (Potassium Acetate) salts may be indicated.
CONTRAINDICATIONS
Celemin-10 Plus (Potassium Acetate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Celemin-10 Plus (Potassium Acetate) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).
Controlled-release formulations of Celemin-10 Plus (Potassium Acetate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Celemin-10 Plus (Potassium Acetate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Celemin-10 Plus (Potassium Acetate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).
All solid oral dosage forms of Celemin-10 Plus (Potassium Acetate) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.
WARNINGS
Hyperkalemia (see OVERDOSAGE )
In patients with impaired mechanisms for excreting Celemin-10 Plus (Potassium Acetate), the administration of Celemin-10 Plus (Potassium Acetate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Celemin-10 Plus (Potassium Acetate) by the intravenous route but may also occur in patients given Celemin-10 Plus (Potassium Acetate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Celemin-10 Plus (Potassium Acetate) salts in patients with chronic renal disease, or any other condition which impairs Celemin-10 Plus (Potassium Acetate) excretion, requires particularly careful monitoring of the serum Celemin-10 Plus (Potassium Acetate) concentration and appropriate dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of Celemin-10 Plus (Potassium Acetate) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Celemin-10 Plus (Potassium Acetate) retention by inhibiting aldosterone production. Celemin-10 Plus (Potassium Acetate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of Celemin-10 Plus (Potassium Acetate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Celemin-10 Plus (Potassium Acetate) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Celemin-10 Plus (Potassium Acetate) chloride and thus to minimize the possibility of a high local concentration of Celemin-10 Plus (Potassium Acetate) near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Celemin-10 Plus (Potassium Acetate) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Celemin-10 Plus (Potassium Acetate) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Celemin-10 Plus (Potassium Acetate) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Celemin-10 Plus (Potassium Acetate) salt such as Celemin-10 Plus (Potassium Acetate) bicarbonate, Celemin-10 Plus (Potassium Acetate) citrate, Celemin-10 Plus (Potassium Acetate) acetate, or Celemin-10 Plus (Potassium Acetate) gluconate.
PRECAUTIONS
General
The diagnosis of Celemin-10 Plus depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Celemin-10 Plus (Potassium Acetate) depletion. In interpreting the serum Celemin-10 Plus (Potassium Acetate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Celemin-10 Plus (Potassium Acetate) while acute acidosis per se can increase the serum Celemin-10 Plus (Potassium Acetate) concentration into the normal range even in the presence of a reduced total body Celemin-10 Plus (Potassium Acetate). The treatment of Celemin-10 Plus (Potassium Acetate) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.
Information for Patients
Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
3. Stir for about half a minute after the tablet(s) has disintegrated.
4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
5. Add another 1 fluid ounce of water, swirl, and consume immediately.
6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Celemin-10 Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.
Laboratory Tests
When blood is drawn for analysis of plasma Celemin-10 Plus it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.
Drug Interactions
Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Celemin-10 Plus is a normal dietary constituent.
Pregnancy Category C
Animal reproduction studies have not been conducted with Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Celemin-10 Plus (Potassium Acetate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.
Nursing Mothers
The normal Celemin-10 Plus ion content of human milk is about 13 mEq per liter. Since oral Celemin-10 Plus (Potassium Acetate) becomes part of the body Celemin-10 Plus (Potassium Acetate) pool, so long as body Celemin-10 Plus (Potassium Acetate) is not excessive, the contribution of Celemin-10 Plus (Potassium Acetate) chloride supplementation should have little or no effect on the level in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Celemin-10 Plus (Potassium Acetate) Chloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; and it may be useful to monitor renal function.
ADVERSE REACTIONS
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Celemin-10 Plus (Potassium Acetate) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.
OVERDOSAGE
The administration of oral Celemin-10 Plus (Potassium Acetate) salts to persons with normal excretory mechanisms for Celemin-10 Plus (Potassium Acetate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Celemin-10 Plus (Potassium Acetate) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Celemin-10 Plus (Potassium Acetate) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).
Treatment measures for hyperkalemia include the following:
- Patients should be closely monitored for arrhythmias and electrolyte changes.
- Elimination of foods and medications containing Celemin-10 Plus (Potassium Acetate) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
- Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
- Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
- Correction of acidosis, if present, with intravenous sodium bicarbonate.
- Use of exchange resins, hemodialysis, or peritoneal dialysis.
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Celemin-10 Plus (Potassium Acetate) concentration can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
DOSAGE AND ADMINISTRATION
The usual dietary intake of Celemin-10 Plus (Potassium Acetate) by the average adult is 50 to 100 mEq per day. Celemin-10 Plus (Potassium Acetate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Celemin-10 Plus (Potassium Acetate) from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Celemin-10 Plus (Potassium Acetate) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.
Each Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Celemin-10 Plus (Potassium Acetate) chloride.
Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).
Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:
- Break the tablet in half, and take each half separately with a glass of water.
- Prepare an aqueous (water) suspension as follows:
- Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
- Allow approximately 2 minutes for the tablet(s) to disintegrate.
- Stir for about half a minute after the tablet(s) has disintegrated.
- Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
- Add another 1 fluid ounce of water, swirl, and consume immediately.
- Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.
Aqueous suspension of Celemin-10 Plus (Potassium Acetate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.
HOW SUPPLIED
Celemin-10 Plus (Potassium Acetate) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.
Storage Conditions
Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).
Manufactured by:
Eurand, Inc.
Vandalia, OH 45377 USA
Distributed by:
Watson Pharma, Inc.
Rev. Date (01/09) 173714
Celemin-10 Plus (Potassium Acetate) chloride 20 Meq
Sodium:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Celemin-10 Plus nitrite is indicated for sequential use with Celemin-10 Plus (Sodium) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Celemin-10 Plus (Sodium) Nitrite Injection is indicated for sequential use with Celemin-10 Plus (Sodium) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Celemin-10 Plus (Sodium) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 Identifying Patients with Cyanide Poisoning
Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Celemin-10 Plus nitroprusside.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Celemin-10 Plus (Sodium) Nitrite Injection and Celemin-10 Plus (Sodium) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
Smoke Inhalation
Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Celemin-10 Plus (Sodium) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
- Exposure to fire or smoke in an enclosed area
- Presence of soot around the mouth, nose, or oropharynx
- Altered mental status
Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Celemin-10 Plus (Sodium) thiosulfate, simultaneously with Celemin-10 Plus (Sodium) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Celemin-10 Plus (Sodium) thiosulfate, with Celemin-10 Plus (Sodium) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Celemin-10 Plus Nitrite and Celemin-10 Plus (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Celemin-10 Plus (Sodium) nitrite, followed by Celemin-10 Plus (Sodium) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate.
Celemin-10 Plus (Sodium) nitrite injection and Celemin-10 Plus (Sodium) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Celemin-10 Plus (Sodium) nitrite should be administered first, followed immediately by Celemin-10 Plus (Sodium) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
| Age | Intravenous Dose of Celemin-10 Plus (Sodium) Nitrite and Celemin-10 Plus (Sodium) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Celemin-10 Plus (Sodium) nitrite should be reduced proportionately to the hemoglobin concentration.
All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Celemin-10 Plus Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
Methemoglobin level: Administrations of Celemin-10 Plus (Sodium) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Celemin-10 Plus (Sodium) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Celemin-10 Plus (Sodium) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Celemin-10 Plus (Sodium) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Celemin-10 Plus (Sodium) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Celemin-10 Plus (Sodium) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Celemin-10 Plus (Sodium) thiosulfate and Celemin-10 Plus (Sodium) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Celemin-10 Plus (Sodium) Nitrite Injection consists of:
- One vial of Celemin-10 Plus (Sodium) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Celemin-10 Plus nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Celemin-10 Plus (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
- Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Celemin-10 Plus (Sodium) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Celemin-10 Plus (Sodium) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
5.2 Methemoglobinemia
Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Celemin-10 Plus nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Celemin-10 Plus (Sodium) nitrite whenever possible. When Celemin-10 Plus (Sodium) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Celemin-10 Plus (Sodium) nitrite administered to an adult. Celemin-10 Plus (Sodium) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Celemin-10 Plus (Sodium) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Celemin-10 Plus (Sodium) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Celemin-10 Plus (Sodium) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Celemin-10 Plus (Sodium) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Celemin-10 Plus nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.
5.5 Neonates and Infants
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Celemin-10 Plus (Sodium) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Celemin-10 Plus nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Celemin-10 Plus (Sodium) nitrite.
5.7 Use with Other Drugs
Celemin-10 Plus (Sodium) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Celemin-10 Plus (Sodium) nitrite.
The medical literature has reported the following adverse events in association with Celemin-10 Plus (Sodium) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia
Hematological: methemoglobinemia
Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma
Gastrointestinal system: nausea, vomiting, abdominal pain
Respiratory system: tachypnea, dyspnea
Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling
Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Celemin-10 Plus (Sodium) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
- Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Celemin-10 Plus (Sodium) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Celemin-10 Plus nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Celemin-10 Plus (Sodium) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Celemin-10 Plus (Sodium) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Celemin-10 Plus (Sodium) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Celemin-10 Plus (Sodium) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Celemin-10 Plus (Sodium) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Celemin-10 Plus (Sodium) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Celemin-10 Plus (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Celemin-10 Plus (Sodium) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Celemin-10 Plus (Sodium) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Celemin-10 Plus (Sodium) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Celemin-10 Plus (Sodium) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Celemin-10 Plus (Sodium) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.
8.2 Labor and Delivery
Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Celemin-10 Plus nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Celemin-10 Plus (Sodium) nitrite is excreted in human milk. Because Celemin-10 Plus (Sodium) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Celemin-10 Plus (Sodium) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Celemin-10 Plus (Sodium) nitrite. In studies conducted with Long-Evans rats, Celemin-10 Plus (Sodium) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Celemin-10 Plus nitrite in conjunction with Celemin-10 Plus (Sodium) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Celemin-10 Plus (Sodium) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
Celemin-10 Plus (Sodium) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.
Mortality attributed to Celemin-10 Plus (Sodium) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
8.5 Geriatric Use
Celemin-10 Plus (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
8.6 Renal Disease
Celemin-10 Plus (Sodium) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
10 OVERDOSAGE
Large doses of Celemin-10 Plus (Sodium) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Celemin-10 Plus (Sodium) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Celemin-10 Plus (Sodium) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Celemin-10 Plus (Sodium) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.
Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.
11 DESCRIPTION
Celemin-10 Plus (Sodium) nitrite has the chemical name nitrous acid Celemin-10 Plus (Sodium) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Celemin-10 Plus (Sodium) Nitrite
Celemin-10 Plus (Sodium) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Celemin-10 Plus (Sodium) nitrite injection.
Celemin-10 Plus (Sodium) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Celemin-10 Plus (Sodium) nitrite in 10 mL solution (30 mg/mL). Celemin-10 Plus (Sodium) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of Celemin-10 Plus nitrite and Celemin-10 Plus (Sodium) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Celemin-10 Plus (Sodium) Nitrite
Celemin-10 Plus (Sodium) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin
Vasodilation has also been cited to account for at least part of the therapeutic effect of Celemin-10 Plus (Sodium) nitrite. It has been suggested that Celemin-10 Plus (Sodium) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Celemin-10 Plus (Sodium) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Celemin-10 Plus (Sodium) Thiosulfate
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Celemin-10 Plus (Sodium) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Chemical Structure
12. 2 Pharmacodynamics
Celemin-10 Plus (Sodium) Nitrite
When 4 mg/kg Celemin-10 Plus (Sodium) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Celemin-10 Plus (Sodium) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.
Oral doses of 120 to 180 mg of Celemin-10 Plus (Sodium) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.
The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Celemin-10 Plus (Sodium) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Celemin-10 Plus (Sodium) Nitrite
Celemin-10 Plus (Sodium) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Celemin-10 Plus (Sodium) nitrite in humans have not been well studied. It has been reported that approximately 40% of Celemin-10 Plus (Sodium) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
Thiocyanate
After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The potential benefit of an acute exposure to Celemin-10 Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Celemin-10 Plus (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Celemin-10 Plus (Sodium) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Celemin-10 Plus (Sodium) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Celemin-10 Plus (Sodium) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Celemin-10 Plus (Sodium) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Celemin-10 Plus (Sodium) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Celemin-10 Plus (Sodium) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Celemin-10 Plus (Sodium) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Celemin-10 Plus (Sodium) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Celemin-10 Plus (Sodium) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Celemin-10 Plus (Sodium) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Celemin-10 Plus (Sodium) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Celemin-10 Plus (Sodium) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Celemin-10 Plus (Sodium) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Celemin-10 Plus (Sodium) nitrite or 1 g/kg Celemin-10 Plus (Sodium) thiosulfate alone or in sequence immediately after subcutaneous injection of Celemin-10 Plus (Sodium) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Celemin-10 Plus (Sodium) nitrite and/or 0.5 g/kg Celemin-10 Plus (Sodium) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Celemin-10 Plus (Sodium) cyanide required to cause death, and when administered together, Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate resulted in a synergistic effect in raising the lethal dose of Celemin-10 Plus (Sodium) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Celemin-10 Plus (Sodium) nitrite and Celemin-10 Plus (Sodium) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Celemin-10 Plus (Sodium) nitrite, with or without Celemin-10 Plus (Sodium) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Celemin-10 Plus (Sodium) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Celemin-10 Plus (Sodium) thiosulfate report its use in conjunction with Celemin-10 Plus (Sodium) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Celemin-10 Plus (Sodium) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Celemin-10 Plus (Sodium) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Celemin-10 Plus (Sodium) nitrite injection 30 mg/mL (containing 300 mg of Celemin-10 Plus (Sodium) nitrite);
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Celemin-10 Plus (Sodium) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Celemin-10 Plus Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Celemin-10 Plus (Sodium) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Celemin-10 Plus (Sodium) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Sodium Acetate:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Celemin-10 Plus nitrite is indicated for sequential use with Celemin-10 Plus (Sodium Acetate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Celemin-10 Plus (Sodium Acetate) Nitrite Injection is indicated for sequential use with Celemin-10 Plus (Sodium Acetate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Celemin-10 Plus (Sodium Acetate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 Identifying Patients with Cyanide Poisoning
Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Celemin-10 Plus nitroprusside.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Celemin-10 Plus (Sodium Acetate) Nitrite Injection and Celemin-10 Plus (Sodium Acetate) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
Smoke Inhalation
Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Celemin-10 Plus (Sodium Acetate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
- Exposure to fire or smoke in an enclosed area
- Presence of soot around the mouth, nose, or oropharynx
- Altered mental status
Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Celemin-10 Plus (Sodium Acetate) thiosulfate, simultaneously with Celemin-10 Plus (Sodium Acetate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Celemin-10 Plus (Sodium Acetate) thiosulfate, with Celemin-10 Plus (Sodium Acetate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Celemin-10 Plus Nitrite and Celemin-10 Plus (Sodium Acetate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Celemin-10 Plus (Sodium Acetate) nitrite, followed by Celemin-10 Plus (Sodium Acetate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate.
Celemin-10 Plus (Sodium Acetate) nitrite injection and Celemin-10 Plus (Sodium Acetate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Celemin-10 Plus (Sodium Acetate) nitrite should be administered first, followed immediately by Celemin-10 Plus (Sodium Acetate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
| Age | Intravenous Dose of Celemin-10 Plus (Sodium Acetate) Nitrite and Celemin-10 Plus (Sodium Acetate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Celemin-10 Plus (Sodium Acetate) nitrite should be reduced proportionately to the hemoglobin concentration.
All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Celemin-10 Plus Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
Methemoglobin level: Administrations of Celemin-10 Plus (Sodium Acetate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Celemin-10 Plus (Sodium Acetate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Celemin-10 Plus (Sodium Acetate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Celemin-10 Plus (Sodium Acetate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Celemin-10 Plus (Sodium Acetate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Celemin-10 Plus (Sodium Acetate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Celemin-10 Plus (Sodium Acetate) thiosulfate and Celemin-10 Plus (Sodium Acetate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Celemin-10 Plus (Sodium Acetate) Nitrite Injection consists of:
- One vial of Celemin-10 Plus (Sodium Acetate) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Celemin-10 Plus nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Celemin-10 Plus (Sodium Acetate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
- Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Celemin-10 Plus (Sodium Acetate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Celemin-10 Plus (Sodium Acetate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
5.2 Methemoglobinemia
Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Celemin-10 Plus nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Celemin-10 Plus (Sodium Acetate) nitrite whenever possible. When Celemin-10 Plus (Sodium Acetate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Celemin-10 Plus (Sodium Acetate) nitrite administered to an adult. Celemin-10 Plus (Sodium Acetate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Celemin-10 Plus (Sodium Acetate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Celemin-10 Plus (Sodium Acetate) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Celemin-10 Plus (Sodium Acetate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Celemin-10 Plus (Sodium Acetate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Celemin-10 Plus nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.
5.5 Neonates and Infants
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Celemin-10 Plus (Sodium Acetate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Celemin-10 Plus nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Celemin-10 Plus (Sodium Acetate) nitrite.
5.7 Use with Other Drugs
Celemin-10 Plus (Sodium Acetate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Celemin-10 Plus (Sodium Acetate) nitrite.
The medical literature has reported the following adverse events in association with Celemin-10 Plus (Sodium Acetate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia
Hematological: methemoglobinemia
Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma
Gastrointestinal system: nausea, vomiting, abdominal pain
Respiratory system: tachypnea, dyspnea
Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling
Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Celemin-10 Plus (Sodium Acetate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
- Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Celemin-10 Plus (Sodium Acetate) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Celemin-10 Plus nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Celemin-10 Plus (Sodium Acetate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Celemin-10 Plus (Sodium Acetate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Celemin-10 Plus (Sodium Acetate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Celemin-10 Plus (Sodium Acetate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Celemin-10 Plus (Sodium Acetate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Celemin-10 Plus (Sodium Acetate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Celemin-10 Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Celemin-10 Plus (Sodium Acetate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Celemin-10 Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Celemin-10 Plus (Sodium Acetate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Celemin-10 Plus (Sodium Acetate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Celemin-10 Plus (Sodium Acetate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.
8.2 Labor and Delivery
Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Celemin-10 Plus nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Celemin-10 Plus (Sodium Acetate) nitrite is excreted in human milk. Because Celemin-10 Plus (Sodium Acetate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Celemin-10 Plus (Sodium Acetate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Celemin-10 Plus (Sodium Acetate) nitrite. In studies conducted with Long-Evans rats, Celemin-10 Plus (Sodium Acetate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Celemin-10 Plus nitrite in conjunction with Celemin-10 Plus (Sodium Acetate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Celemin-10 Plus (Sodium Acetate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
Celemin-10 Plus (Sodium Acetate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.
Mortality attributed to Celemin-10 Plus (Sodium Acetate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
8.5 Geriatric Use
Celemin-10 Plus (Sodium Acetate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
8.6 Renal Disease
Celemin-10 Plus (Sodium Acetate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
10 OVERDOSAGE
Large doses of Celemin-10 Plus (Sodium Acetate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Celemin-10 Plus (Sodium Acetate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Celemin-10 Plus (Sodium Acetate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.
Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Celemin-10 Plus (Sodium Acetate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.
Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.
11 DESCRIPTION
Celemin-10 Plus (Sodium Acetate) nitrite has the chemical name nitrous acid Celemin-10 Plus (Sodium Acetate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Celemin-10 Plus (Sodium Acetate) Nitrite
Celemin-10 Plus (Sodium Acetate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Celemin-10 Plus (Sodium Acetate) nitrite injection.
Celemin-10 Plus (Sodium Acetate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Celemin-10 Plus (Sodium Acetate) nitrite in 10 mL solution (30 mg/mL). Celemin-10 Plus (Sodium Acetate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
The synergy resulting from treatment of cyanide poisoning with the combination of Celemin-10 Plus nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Celemin-10 Plus (Sodium Acetate) Nitrite
Celemin-10 Plus (Sodium Acetate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin
Vasodilation has also been cited to account for at least part of the therapeutic effect of Celemin-10 Plus (Sodium Acetate) nitrite. It has been suggested that Celemin-10 Plus (Sodium Acetate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Celemin-10 Plus (Sodium Acetate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Celemin-10 Plus (Sodium Acetate) Thiosulfate
The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Celemin-10 Plus (Sodium Acetate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
Chemical Structure
12. 2 Pharmacodynamics
Celemin-10 Plus (Sodium Acetate) Nitrite
When 4 mg/kg Celemin-10 Plus (Sodium Acetate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Celemin-10 Plus (Sodium Acetate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.
Oral doses of 120 to 180 mg of Celemin-10 Plus (Sodium Acetate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.
The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Celemin-10 Plus (Sodium Acetate) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Celemin-10 Plus (Sodium Acetate) Nitrite
Celemin-10 Plus (Sodium Acetate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Celemin-10 Plus (Sodium Acetate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Celemin-10 Plus (Sodium Acetate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
Thiocyanate
After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The potential benefit of an acute exposure to Celemin-10 Plus nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Celemin-10 Plus (Sodium Acetate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Celemin-10 Plus (Sodium Acetate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Celemin-10 Plus (Sodium Acetate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Celemin-10 Plus (Sodium Acetate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Celemin-10 Plus (Sodium Acetate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Celemin-10 Plus (Sodium Acetate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Celemin-10 Plus (Sodium Acetate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Celemin-10 Plus (Sodium Acetate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Celemin-10 Plus (Sodium Acetate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Celemin-10 Plus (Sodium Acetate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Celemin-10 Plus (Sodium Acetate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Celemin-10 Plus (Sodium Acetate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Celemin-10 Plus (Sodium Acetate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Celemin-10 Plus (Sodium Acetate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Celemin-10 Plus (Sodium Acetate) nitrite or 1 g/kg Celemin-10 Plus (Sodium Acetate) thiosulfate alone or in sequence immediately after subcutaneous injection of Celemin-10 Plus (Sodium Acetate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Celemin-10 Plus (Sodium Acetate) nitrite and/or 0.5 g/kg Celemin-10 Plus (Sodium Acetate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Celemin-10 Plus (Sodium Acetate) cyanide required to cause death, and when administered together, Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Celemin-10 Plus (Sodium Acetate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Celemin-10 Plus (Sodium Acetate) nitrite and Celemin-10 Plus (Sodium Acetate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Celemin-10 Plus (Sodium Acetate) nitrite, with or without Celemin-10 Plus (Sodium Acetate) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Celemin-10 Plus (Sodium Acetate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Celemin-10 Plus (Sodium Acetate) thiosulfate report its use in conjunction with Celemin-10 Plus (Sodium Acetate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Celemin-10 Plus (Sodium Acetate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Celemin-10 Plus (Sodium Acetate) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Celemin-10 Plus (Sodium Acetate) nitrite injection 30 mg/mL (containing 300 mg of Celemin-10 Plus (Sodium Acetate) nitrite);
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Celemin-10 Plus (Sodium Acetate) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Celemin-10 Plus Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Celemin-10 Plus (Sodium Acetate) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Celemin-10 Plus (Sodium Acetate) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Celemin-10 Plus pharmaceutical active ingredients containing related brand and generic drugs:
Celemin-10 Plus available forms, composition, doses:
Celemin-10 Plus destination | category:
Celemin-10 Plus Anatomical Therapeutic Chemical codes:
Celemin-10 Plus pharmaceutical companies:
References
- Dailymed."L-CYSTEINE HYDROCHLORIDE INJECTION, SOLUTION [SANDOZ INC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."POTASSIUM ACETATE INJECTION, SOLUTION, CONCENTRATE [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."SODIUM ACETATE INJECTION, SOLUTION, CONCENTRATE [APP PHARMACEUTICALS, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Celemin-10 Plus?Depending on the reaction of the Celemin-10 Plus after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Celemin-10 Plus not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Celemin-10 Plus addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Review
sdrugs.com conducted a study on Celemin-10 Plus, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Celemin-10 Plus consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.Visitor reports
One visitor reported useful
How is the drug Celemin-10 Plus useful in reducing or relieving the symptoms? How useful is it?According to the survey conducted by the website sdrugs.com, there are variable results and below are the percentages of the users that say the medicine is useful to them and that say it is not helping them much. It is not ideal to continue taking the medication if you feel it is not helping you much. Contact your healthcare provider to check if there is a need to change the medicine or if there is a need to re-evaluate your condition. The usefulness of the medicine may vary from patient to patient, depending on the other diseases he is suffering from and slightly depends on the brand name.
| Visitors | % | ||
|---|---|---|---|
| Useful | 1 | 100.0% | |
Visitor reported side effects
No survey data has been collected yetVisitor reported price estimates
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No survey data has been collected yetThree visitors reported age
| Visitors | % | ||
|---|---|---|---|
| > 60 | 2 | 66.7% | |
| < 1 | 1 | 33.3% | |
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The information was verified by Dr. Rachana Salvi, MD Pharmacology