Sanatogen

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Sanatogen uses

Sanatogen consists of Casein, Sodium Glycerophosphate.

Casein:


INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnostic testing and as part of a treatment regime for allergic disease, as established by allergy history and skin test reactivity.

Allergenic extracts are indicated for the treatment of allergen specific allergic disease for use as hyposensitization or immunotherapy when avoidance of specific allergens can not be attained. The use of allergenic extracts for therapeutic purpose has been established by well-controlled clinical studies. Allergenic extracts may be used as adjunctive therapy along with pharmacotherapy which includes antihistamines, corticosteroids, and cromoglycate, and avoidance measures. Allergenic extracts for therapeutic use should be given using only the allergen selection to which the patient is allergic, has a history of exposure and are likely to be exposed to again.

CONTRAINDICATIONS

Allergenic extracts should not be used if the patient has asthma, cardiovascular disease, emphysema, diabetes, bleeding diathesis or pregnancy, unless a specific diagnosis of type 1 allergic disease is made based on skin testing and the benefits of treatment outweigh the risks of an adverse reaction during testing or treatment. Allergenic extracts are not indicated for use in patients who are not clinically allergic or who are not skin reactive to an allergen. Allergenic extracts should be discontinued or the concentration of potency substantially reduced in patients who experience unacceptable adverse reactions.

WARNINGS

DO NOT INJECT INTRAVENOUSLY.

Epinephrine 1:1000 should be available.

Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing. All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.(4) An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

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PRECAUTIONS

GENERAL: Epinephrine 1:1000 should be available as well as personnel trained in administering emergency treatment. Allergenic Extracts are not intended for intravenous injections. For safe and effective use of allergenic extracts, sterile diluents, sterile vials, sterile syringes should be used and aseptic precautions observed when making a dilution and/or administering the allergenic extract injection. A sterile tuberculin syringe graduated in 0.1 ml units to measure each dose for the prescribed dilution should be used. To reduce the risk of an occurrence of adverse reactions, begin with a careful personal history plus a physical exam. Confirm your findings with scratch or intradermal skin testing.

Standardized extracts are those labeled in AU/ml units or BAU/ml units. Standardized extracts are not interchangeable with extracts previously labeled as wt/vol or PNU/ml. Before administering a standardized extract, read the accompanying insert contained with standardized extracts.

Information for Patients: All concentrates of allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients. Patients should be informed of this risk prior to skin testing and immunotherapy. Patients should be instructed to recognize adverse reaction symptoms that may occur and to report all adverse reactions to a physician. Patients should be instructed to remain in the office for 30 minutes during testing using allergenic extracts and at least 30 minutes after therapeutic injections using allergenic extracts.

DRUG INTERACTIONS: Some drugs may affect the reactivity of the skin; patients should be instructed to avoid medications, particularly antihistamines and sympathomimetic drugs, for at least 24 hours prior to skin testing. Antihistamines and Hydroxyzine can significantly inhibit the immediate skin test reactions as they tend to neutralize or antagonize the action of histamine.(3) This effect has been primarily documented when testing was performed within 1 to 2 hours after drug ingestion. Partial inhibition of the skin test reaction had been observed for longer periods. Epinephrine injection inhibits the immediate skin test reactions for several hours. Patients on delayed absorption antihistamine tablets should be free of such medication for 48 hours before testing. Patients using Astemizole (Hismanal) may experience prolonged suppression and should be free from such medication for up to 6 to 8 weeks prior to testing. Refer to package insert from an applicable long acting antihistamine manufacturer for additional information.

Extreme caution should be taken when using allergenic extracts on patients who are taking beta-blockers. Patients on non-selective beta blockers may be more reactive to allergens given for testing or treatment and may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Carcinogenesis, mutagenesis, impairment of fertility:

Long term studies in animals have not been conducted with allergenic extracts to determine their potential carcinogenicity, mutagenicity or impairment of fertility.

Pregnancy: Category C: Animal reproduction studies have not been conducted with Allergenic Extracts. It is not known whether allergenic extracts can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Allergenic extracts should be given to pregnant women only if clearly needed.

Nursing Mothers: It is not known whether this drug appears in human milk. Because many drugs are detected in human milk, caution should be exercised when Allergenic Extracts are administered to a nursing woman. There are no current studies on extract components in human milk, or their effect on the nursing infant.

Pediatric Use: Allergenic extracts have been used in children over two years of age.(5)

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ADVERSE REACTIONS

Adverse systemic reactions usually occur within minutes and consist primarily of allergic symptoms such as: generalized skin erythema, urticaria, pruritus, angioedema, rhinitis, wheezing, laryngeal edema, itching of nose and throat, breathlessness, dyspnea, coughing, hypotension and marked perspiration. Less commonly, nausea, emesis, abdominal cramps, diarrhea and uterine contractions may occur. Severe reactions may cause anaphylaxis or shock and loss of consciousness and rarely death.

The treatment of systemic allergic reactions is dependent upon the system complex. Antihistamines may offer relief of recurrent urticaria, associated skin reactions and gastrointestinal symptoms. Corticosteroids may provide benefit if symptoms are prolonged or recurrent.

Local Reactions consisting of erythema, itching, swelling tenderness and sometimes pain may occur at the injection site. These reactions may appear within a few minutes to hours and persist for several days. Local cold applications and oral antihistamines may be effective treatment. For marked and prolonged local reactions the use of antihistamines or anti-inflammatory medications may be dictated. Serious adverse reactions should be reported to Nelco Laboratories immediately and a report can be filed to: MedWatch, The FDA Medical Product Problem Reporting Program, at 5600 Fishers Lane, Rockville, MD 20852-9787, call 1-800-FDA-1088.

OVERDOSAGE

Overdose can cause both local and systemic reactions. An overdose may be prevented by careful observation and questioning of the patient about the previous injection.

If systemic or anaphylactic reaction, does occur, apply a tourniquet above the site of injection and inject intramuscularly or subcutaneously 0.3 to 0.5ml of 1:1000 Epinephrine Hydrochloride into the opposite arm. The dose may be repeated in 5-10 minutes if necessary. Loosen the tourniquet at least every 10 minutes. The Epinephrine Hydrochloride 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml, for children 2 to 6 years it is 0.15 ml, for children 6-12 years it is 0.2 ml.

Patients unresponsive to Epinephrine may be treated with Theophylline. Studies on asthmatic subjects reveal that plasma concentrations of Theophylline of 5 to 20 µg/ml are associated with therapeutic effects. Toxicity is particularly apparent at concentrations greater than 20 µg/ml. A loading dose of Aminophylline of 5.8 mg/kg intravenously followed by 0.9 mg/kg per hour results in plasma concentrations of approximately 10 µg/ml for patients not previously receiving theophylline. (Mitenko and Ogilive, Nicholoson and Chick,1973)

Other beta-adrenergic drugs such as Isoproterenol, Isoetharine, or Albuterol may be used by inhalation. The usual dose to relieve broncho-constriction in asthma is 0.5 ml of the 0.5% solution for Isoproterenol HCl. The Albuterol inhaler delivers approximately 90 mcg of Albuterol from the mouthpiece. The usual dosage for adults and children would be two inhalations repeated every 4-6 hours. Isoetharine supplied in the Bronkometer unit delivers approximately 340 mcg Isoetharine. The average dose is one to two inhalations. Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require oxygen, intubation and the use of life support systems.

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DOSAGE AND ADMINISTRATION

General Precautions

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits.

The dosage of allergenic extracts is dependent upon the purpose of the administration. Allergenic extracts can be administered for diagnostic use or for therapeutic use.

When allergenic extracts are administered for diagnostic use, the dosage is dependent upon the method used. Two methods commonly used are scratch testing and intradermal testing. Both types of tests result in a wheal and flare response at the site of the test which usually develops rapidly and may be read in 20-30 minutes.

Diagnostic Use : Scratch Testing Method

Scratch testing is considered a simple and safe method although less sensitive than the intradermal test. Scratch testing can be used to determine the degree of sensitivity to a suspected allergen before using the intradermal test. This combination lessens the severity of response to an allergen which can occur in a very sensitive patient.

The most satisfactory testing site is the patient's back or volar surface of the arms from the axilla to 2.5 or 5cm above the wrist, skipping the anti-cubital space. If using the back as a testing site, the most satisfactory area are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins.

Allergenic extracts for diagnostic use are to be administered in the following manner: To scratch surface of skin, use a circular scarifier. Do not draw blood. Tests sites should be 4 cm apart to allow for wheal and flare reaction. 1-30 scratch tests may be done at a time. A separate sterile scratch instrument is to be used on each patient to prevent transmission of homologous serum hepatitis or other infectious agents from one patient to another.

The recommended usual dosage for Scratch testing is one drop of allergen applied to each scratch site. Do not let dropper touch skin. Always apply a control scratch with each test set. Sterile Diluent (for a negative control) is used in exactly the same way as an active test extract. Histamine may be used as a positive control. Scratch or prick test sites should be examined at 15 and 30 minutes. To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears. Record the size of the reaction.

Interpretation of Scratch Test

Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes. Wheal and erythema size may be recorded by actual measurement as compared with positive and negative controls. A positive reaction consists of an area of erythema surrounding the scarification that is larger than the control site. For uniformity in reporting reactions, the following system is recommended. (6)

REACTION SYMBOL CRITERIA
Negative - No wheal. Erythema absent or very slight (not more than 1 mm diameter).
One Plus + Wheal absent or very slight erythema present (not more than 3 mm diameter).
Two Plus ++ Wheal not more than 3mm or erythema not more than 5mm diameter.
Three Plus +++ Wheal between 3mm and 5mm diameter, with erythema. Possible pseudopodia and itching.
Four Plus ++++ A larger reaction with itching and pain.
Diagnostic Use: Intradermal Skin Testing Method

Do not perform intradermal test with allergens which have evoked a 2+ or greater response to a Scratch test. Clean test area with alcohol, place sites 5 cm apart using separate sterile tuberculin syringe and a 25 gauge needle for each allergen. Insert needle tip, bevel up, into intracutaneous space. Avoid injecting into blood vessel, pull back gently on syringe plunger, if blood enters syringe change position of needle. The recommended dosage and range for intradermal testing is 0.05 ml of not more than 100 pnu/ml or 1:1000 w/v (only if puncture test is negative) of allergenic extract. Inject slowly until a small bleb is raised. It is important to make each bleb the same size.

Interpretation of Intradermal Test:

The patient's reaction is graded on the basis of size of wheal and flare as compared to control. Use 0.05 ml sterile diluent as a negative control to give accurate interpretation. The tests may be accurately interpreted only when the saline control site has shown a negative response. Observe patient for at least 30 minutes. Tests can be read in 15-20 minutes. Edema, erythema and presence of pseudopods, pain and itching may be observed in 4 plus reactions. For uniformity in reporting reactions the following system is recommended. (6)

REACTION SYMBOL CRITERIA
Negative - No increase in size of bleb since injection. No erythema.
One Plus + An increase in size of bleb to a wheal not more than 5mm diameter, with associated erythema.
Two Plus ++ Wheal between 5mm and 8mm diameter with erythema.
Three Plus +++ Wheal between 8mm and 12mm diameter with erythema and possible pseudopodia and itching or pain.
Four Plus ++++ Any larger reaction with itch and pain, and possible diffuse blush of the skin surrounding the reaction area.
Therapeutic Use: Recommended dosage & range

Check the listed ingredients to verify that it matches the prescription ordered. When using a prescription set, verify the patient's name and the ingredients listed with the prescription order. Assess the patient's physical and emotional status prior to giving as injection. Do not give injections to patients who are in acute distress. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response and tolerance to the extract administered during the early phases of an injection regimen. The dosage must be reduced when transferring a patient from non-standardized or modified extract to standardized extract. Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy as well as during maintenance therapy. After therapeutic injections patients should be observed for at least 20 minutes for reaction symptoms.

SUGGESTED DOSAGE SCHEDULE

The following schedule may act as a guide. This schedule has not been proven to be safe or effective. Sensitive patients may begin with smaller doses of weaker solutions and the dosage increments can be less.

STRENGTH DOSE VOLUME
Vial #1 1 0.05
1:100,000 w/v 2 0.10
10 pnu/ml 3 0.15
1 AU/ml 4 0.20
1 BAU/ml 5 0.30
6 0.40
7 0.50
Vial #2 8 0.05
1:10,000 w/v 9 0.10
100 pnu/ml 10 0.15
10 AU/ml 11 0.20
10 BAU/ml 12 0.30
13 0.40
14 0.50
Vial #3 15 0.05
1:1,000 w/v 16 0.10
1,000 pnu/ml 17 0.15
100 AU/ml 18 0.20
100 BAU/ml 19 0.30
20 0.40
21 0.50
Vial #4 22 0.05
1:100 w/v 23 0.07
10,000 pnu/ml 24 0.10
1,000 AU/ml 25 0.15
1,000 BAU/ml 26 0.20
27 0.25
Maintenance Refill 28 0.25
1:100 w/v 29 0.25
10,000 pnu/ml 30 0.25
1,000 AU/ml 31 0.25
1,000 BAU/ml 32 0.25
subsequent doses 33 0.25
Preparation Instructions:

All dilutions may be made using sterile buffered diluent. The calculation may be based on the following ratio:

Volume desired x Concentration desired = Volume needed x Concentration available.

Example 1: If a 1:10 w/v extract is available and it is desired to use a 1:1,000 w/v extract substitute as follows:

Vd x Cd = Vn x Ca

10ml x 0.001 = Vn x 0.1

0.1 ml = Vn

Using a sterile technique, remove 0.10 ml of extract from the 1:10 vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting ratio will be a 10 ml vial of 1:1,000 w/v.

Example 2: If a 10,000 pnu/ml extract is available and it is desired to use a 100 pnu/ml extract substitute as follows:

10ml x 100 = Vn x 10,000

0.1 ml = Vn

Using a sterile technique, remove 0.10 ml of extract from the 10,000 pnu/ml vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting concentration will be a 10 ml vial of 100 pnu/ml.

Example 3: If a 10,000 AU/ml or BAU/ml extract is available and it is desired to use a 100 AU/ml or BAU/ml extract substitute as follows: Vd x Cd = Vn x Ca

10ml x 100 = Vn x 10,000

0.1 ml = Vn

Using a sterile technique, remove 0.10 ml of extract from the 10,000 AU/ml or BAU/ml vial and place it into a vial containing 9.90 ml of sterile diluent. The resulting concentration will be 10ml vial of 100 AU/ml or BAU/ml.

Intervals between doses: The optimal interval between doses of allergenic extract has not been definitely established. The amount of allergenic extract is increased at each injection by not more than 50%-100% of the previous amount and the next increment is governed by the response to the last injection. There are three generally accepted methods of pollen hyposensitizing therapy.

1. PRESEASONAL

Treatment starts each year 6 to 8 weeks before onset of seasonal symptoms. Maximal dose reached just before symptoms are expected. Injections discontinued during and following season until next year.

2. CO-SEASONAL

Patient is first treated during season with symptoms. Low initial doses are employed to prevent worsening of condition. This is followed by an intensive schedule of therapy (i.e. injections given 2 to 3 times per week). Fewer Allergists are resorting to this Co-seasonal therapy because of the availability of more effective, symptomatic medications that allow the patient to go through a season relatively symptom free.

3. PERENNIAL

Initially this is the same as pre seasonal. The allergen is administered twice weekly or weekly for about 20 injections to achieve the maximum tolerated dose. Then, maintenance therapy may be administered once a week or less frequently.

Duration of Treatment: The usual duration of treatment has not been established. A period of two or three years of injection therapy constitutes an average minimum course of treatment.

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HOW SUPPLIED

Allergenic extracts are supplied with units listed as: Weight/volume (W/V), Protein Nitrogen Units (PNU/ml), Allergy Units (AU/ml) or Bioequivalent Allergy Units (BAU/ml).

Sizes:

Diagnostic Scratch: 5 ml dropper application vials

Diagnostic Intradermal: 5 ml or 10 ml vials.

Therapeutic Allergens: 5 ml, 10 ml, 50 ml multiple dose vials.

STORAGE

The expiration date of allergen extracts is listed on the container label. Store extracts upon arrival at 2° to 8°C and keep them in this range during office use.

WARRANTY: We warrant that this product was prepared and tested according to the standards of the FDA and is true to label. Because of biological differences in individuals and because allergenic extracts are manufactured to be potent and because we have no control over the conditions of use, we cannot and do not warrant either a good effect or against an ill effect following use.

REFERENCES

1 Jacobs, Robert L., Geoffrey W.Rake,Jr., et.al. Potentiated Anaphylaxis in Patients with Drug-induced Beta-adrenergic Blockade. J.Allergy & Clin. Immunol., 68(2): 125-127. August 1981.

2 Ishizaka,K.: Cellular Events in the IgE Antibody Response. Adv. in Immuno. 23:50-75, 1976.

3. Lockey, R.F., Bukantz, S.C., Allergen Immunotherapy. New York,NY: Marcel Dekker Inc., 1991.

4. Reid,M.J., Lockey,R.F., Turkeltaub,P.C., Platts-Mills,T.A.E., Survey of fatalities from skin testing and immunotherapy 1985-1989. Journal of Allergy Clin. Immunol. 92 (1): 6-15, July 1993.

5. Murray, A.B., Ferguson, A., Morrison, B., The frequency and severity of cat allergy vs dog allergy in atopic children. J. Allergy Clin. Immunolo: 72, 145-9, 1983.

6. Lockey, R.F., Bukantz, S.C., Allergen Immunotherapy. New York,NY: Marcel Dekker Inc., 1991.

CONTAINER LABELING

Sodium Glycerophosphate:


1 INDICATIONS AND USAGE

Sanatogen nitrite is indicated for sequential use with Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) Nitrite Injection is indicated for sequential use with Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen 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, Sanatogen (Sodium Glycerophosphate) Nitrite Injection and Sanatogen (Sodium Glycerophosphate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) thiosulfate, simultaneously with Sanatogen (Sodium Glycerophosphate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Sanatogen (Sodium Glycerophosphate) thiosulfate, with Sanatogen (Sodium Glycerophosphate) 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 Sanatogen Nitrite and Sanatogen (Sodium Glycerophosphate) Thiosulfate
Adults
  • Sanatogen (Sodium Glycerophosphate) Nitrite -10 mL of Sanatogen (Sodium Glycerophosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Sanatogen (Sodium Glycerophosphate) Thiosulfate - 50 mL of Sanatogen (Sodium Glycerophosphate) thiosulfate immediately following administration of Sanatogen (Sodium Glycerophosphate) nitrite.
Children
  • Sanatogen (Sodium Glycerophosphate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sanatogen (Sodium Glycerophosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sanatogen (Sodium Glycerophosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sanatogen (Sodium Glycerophosphate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite, followed by Sanatogen (Sodium Glycerophosphate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate.

Sanatogen (Sodium Glycerophosphate) nitrite injection and Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) nitrite should be administered first, followed immediately by Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) Nitrite and Sanatogen (Sodium Glycerophosphate) Thiosulfate
Adults
  • Sanatogen (Sodium Glycerophosphate) Nitrite -10 mL of Sanatogen (Sodium Glycerophosphate) nitrite at the rate of 2.5 to 5 mL/minute
  • Sanatogen (Sodium Glycerophosphate) Thiosulfate - 50 mL of Sanatogen (Sodium Glycerophosphate) thiosulfate immediately following administration of Sanatogen (Sodium Glycerophosphate) nitrite.
Children
  • Sanatogen (Sodium Glycerophosphate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Sanatogen (Sodium Glycerophosphate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Sanatogen (Sodium Glycerophosphate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Sanatogen (Sodium Glycerophosphate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Sanatogen (Sodium Glycerophosphate) 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 Sanatogen 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 Sanatogen (Sodium Glycerophosphate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Sanatogen (Sodium Glycerophosphate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Sanatogen (Sodium Glycerophosphate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Sanatogen (Sodium Glycerophosphate) thiosulfate and Sanatogen (Sodium Glycerophosphate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Sanatogen (Sodium Glycerophosphate) Nitrite Injection consists of:

  • One vial of Sanatogen (Sodium Glycerophosphate) 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: Sanatogen 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 Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Sanatogen (Sodium Glycerophosphate) nitrite whenever possible. When Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite administered to an adult. Sanatogen (Sodium Glycerophosphate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Sanatogen 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen 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 Sanatogen (Sodium Glycerophosphate) nitrite.

5.7 Use with Other Drugs

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite.

The medical literature has reported the following adverse events in association with Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Sanatogen 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. Sanatogen (Sodium Glycerophosphate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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, Sanatogen (Sodium Glycerophosphate) 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, Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Sanatogen (Sodium Glycerophosphate) 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, Sanatogen 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 Sanatogen (Sodium Glycerophosphate) nitrite is excreted in human milk. Because Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Sanatogen (Sodium Glycerophosphate) nitrite. In studies conducted with Long-Evans rats, Sanatogen (Sodium Glycerophosphate) 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 Sanatogen nitrite in conjunction with Sanatogen (Sodium Glycerophosphate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Sanatogen (Sodium Glycerophosphate) 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.

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) nitrite has the chemical name nitrous acid Sanatogen (Sodium Glycerophosphate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Sanatogen (Sodium Glycerophosphate) Nitrite

Sanatogen (Sodium Glycerophosphate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Sanatogen (Sodium Glycerophosphate) nitrite injection.

Sanatogen (Sodium Glycerophosphate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Sanatogen (Sodium Glycerophosphate) nitrite in 10 mL solution (30 mg/mL). Sanatogen (Sodium Glycerophosphate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

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 Sanatogen nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Sanatogen (Sodium Glycerophosphate) Nitrite

Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite. It has been suggested that Sanatogen (Sodium Glycerophosphate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Sanatogen (Sodium Glycerophosphate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) Nitrite

When 4 mg/kg Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Sanatogen (Sodium Glycerophosphate) Nitrite

Sanatogen (Sodium Glycerophosphate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Sanatogen (Sodium Glycerophosphate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) 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 Sanatogen nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Sanatogen (Sodium Glycerophosphate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) 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. Sanatogen (Sodium Glycerophosphate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Sanatogen (Sodium Glycerophosphate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Sanatogen (Sodium Glycerophosphate) nitrite or 1 g/kg Sanatogen (Sodium Glycerophosphate) thiosulfate alone or in sequence immediately after subcutaneous injection of Sanatogen (Sodium Glycerophosphate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Sanatogen (Sodium Glycerophosphate) nitrite and/or 0.5 g/kg Sanatogen (Sodium Glycerophosphate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Sanatogen (Sodium Glycerophosphate) cyanide required to cause death, and when administered together, Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Sanatogen (Sodium Glycerophosphate) nitrite and Sanatogen (Sodium Glycerophosphate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Sanatogen (Sodium Glycerophosphate) nitrite, with or without Sanatogen (Sodium Glycerophosphate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) thiosulfate report its use in conjunction with Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) 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 Sanatogen (Sodium Glycerophosphate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Sanatogen (Sodium Glycerophosphate) nitrite injection 30 mg/mL (containing 300 mg of Sanatogen (Sodium Glycerophosphate) 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: Sanatogen (Sodium Glycerophosphate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Sanatogen 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

Sanatogen (Sodium Glycerophosphate) 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

Sanatogen (Sodium Glycerophosphate) 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

Sanatogen pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Sanatogen available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Sanatogen destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Sanatogen Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Sanatogen pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."CASEIN INJECTION, SOLUTION COWS MILK INJECTION, SOLUTION GOATS MILK INJECTION, SOLUTION [NELCO LABORATORIES, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Casein". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  3. "Casein - DrugBank". http://www.drugbank.ca/drugs/DB1051... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Sanatogen?

Depending on the reaction of the Sanatogen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Sanatogen 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 Sanatogen 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.

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sdrugs.com conducted a study on Sanatogen, 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 Sanatogen 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.

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