Sulmetin Solution

Magnesium Gluconate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Sulmetin Solution (Magnesium Gluconate) reviews

Sulmetin Solution (Magnesium Gluconate) Sulfate

Injection, USP

Ansyr Plastic Syringe

Rx only

Hospira Logo

DESCRIPTION

Sulmetin Solution (Magnesium Gluconate) Sulfate Injection, USP is a sterile solution of Sulmetin Solution (Magnesium Gluconate) 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.

Sulmetin Solution (Magnesium Gluconate) 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

Sulmetin Solution (Magnesium Gluconate) (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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate). While there are large stores of Sulmetin Solution (Magnesium Gluconate) present intracellularly and in the bones of adults, these stores often are not mobilized sufficiently to maintain plasma levels. Parenteral Sulmetin Solution (Magnesium Gluconate) therapy repairs the plasma deficit and causes deficiency symptoms and signs to cease.

Sulmetin Solution (Magnesium Gluconate) prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) levels range from 1.5 to 2.5 mEq/liter.

As plasma Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate). Serum Sulmetin Solution (Magnesium Gluconate) concentrations in excess of 12 mEq/L may be fatal.

Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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. Sulmetin Solution (Magnesium Gluconate) is excreted solely by the kidneys at a rate proportional to the plasma concentration and glomerular filtration.

INDICATIONS AND USAGE

Sulmetin Solution (Magnesium Gluconate) Sulfate Injection, USP is suitable for replacement therapy in Sulmetin Solution (Magnesium Gluconate) deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those observed in hypocalcemia. In such cases, the serum Sulmetin Solution (Magnesium Gluconate) (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), Sulmetin Solution (Magnesium Gluconate) sulfate may be added to the nutrient admixture to correct or prevent hypomagnesemia which can arise during the course of therapy.

Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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. Sulmetin Solution (Magnesium Gluconate) sulfate should be used during pregnancy only if clearly needed. If Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate), their dosage should be adjusted with caution because of additive CNS depressant effects of Sulmetin Solution (Magnesium Gluconate).

Because Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) should be given until they return. Serum Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) intoxication in eclampsia.

50% Sulmetin Solution (Magnesium Gluconate) 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

Sulmetin Solution (Magnesium Gluconate) sulfate injection should not be given unless hypomagnesemia has been confirmed and the serum concentration of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate), their dosage should be adjusted with caution because of additive CNS depressant effects of Sulmetin Solution (Magnesium Gluconate). CNS depression and peripheral transmission defects produced by Sulmetin Solution (Magnesium Gluconate) may be antagonized by calcium.

Neuromuscular Blocking Agents - Excessive neuromuscular block has occurred in patients receiving parenteral Sulmetin Solution (Magnesium Gluconate) sulfate and a neuromuscular blocking agent; these drugs should be administered concomitantly with caution.

Cardiac Glycosides - Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) toxicity.

Pregnancy

Teratogenic Effects

Pregnancy Category D (See WARNINGS and PRECAUTIONS )

See WARNINGS and PRECAUTIONS .

Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate for more than 5 to 7 days.^1-10 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) toxicity, including neuromuscular or respiratory depression (See OVERDOSAGE ).

Labor and Delivery

Continuous administration of Sulmetin Solution (Magnesium Gluconate) sulfate is an unapproved treatment for preterm labor. The safety and efficacy of such use have not been established. The administration of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) is distributed into milk during parenteral Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) should be monitored in such patients.

ADVERSE REACTIONS

The adverse effects of parenterally administered Sulmetin Solution (Magnesium Gluconate) usually are the result of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate therapy for eclampsia has been reported.

OVERDOSAGE

Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) intoxication. In the event of overdosage, artificial ventilation must be provided until a calcium salt can be injected intravenously to antagonize the effects of Sulmetin Solution (Magnesium Gluconate).

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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) Deficiency

In the treatment of mild Sulmetin Solution (Magnesium Gluconate) deficiency, the usual adult dose is 1 gram, equivalent to 8.12 mEq of Sulmetin Solution (Magnesium Gluconate) (2 mL of the 50% solution) injected intramuscularly every six hours for four doses (equivalent to a total of 32.5 mEq of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate is 20 grams/48 hours and frequent serum Sulmetin Solution (Magnesium Gluconate) concentrations must be obtained. Continuous use of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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, Sulmetin Solution (Magnesium Gluconate) 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

Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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

Sulmetin Solution (Magnesium Gluconate) Sulfate Injection, USP is supplied in single-dose containers as follows:

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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate tocolysis. Acta Obstet Gynecol Scan. 2006;85(9):1099-103.
• Malaeb SN, Rassi A, Haddad MC. Bone mineralization in newborns whose mothers received Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate therapy on neonatal calcium metabolism and bone mineral content. Gynecol Obstet Invest. 1997;43(4):236-41.
• Santi MD, Henry GW, Douglas GL. Sulmetin Solution (Magnesium Gluconate) 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. Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) sulfate infusion for tocolysis. J Pediatr. 1988; 113(6):1078-82.
• McGuinness GA, Weinstein MM, Cruikshank DP, et al. Effects of Sulmetin Solution (Magnesium Gluconate) 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 Sulmetin Solution (Magnesium Gluconate) 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% Sulmetin Solution (Magnesium Gluconate) Sulfate 5 g/10 mL (500 mg/mL)

Rx only

NDC 0409-1754-10

10 mL Single-dose syringe

50% Sulmetin Solution (Magnesium Gluconate) 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

Metoclopramide Hydrochloride:

• 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
• How supplied/storage and handling
• Patient counseling information
• Sulmetin Solution (Metoclopramide Hydrochloride) reviews

1 INDICATIONS AND USAGE

Sulmetin Solution (Metoclopramide Hydrochloride) tablets are indicated for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy.
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis.

Limitations of Use:

Sulmetin Solution (Metoclopramide Hydrochloride) tablets are not recommended for use in pediatric patients due to the risk of developing tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates [see Use in Specific Populations ( 8.4 ) ].

Sulmetin Solution (Metoclopramide Hydrochloride) tablets are indicated for the:

• Treatment for 4 to 12 weeks of symptomatic, documented gastroesophageal reflux in adults who fail to respond to conventional therapy. (1)
• Relief of symptoms in adults with acute and recurrent diabetic gastroparesis. (1)

Limitations of Use:

Sulmetin Solution (Metoclopramide Hydrochloride) tablets are not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. (1, 8.4)

2 DOSAGE AND ADMINISTRATION

Gastroesophageal Reflux

• Administer Sulmetin Solution (Metoclopramide Hydrochloride) continuously or intermittently:
  • Continuous: Administer 10 to 15 mg, 30 minutes before each meal and at bedtime (maximum of 60 mg per day) for 4 to 12 weeks.
  • Intermittent: Single doses up to 20 mg prior to provoking situation.

Acute and Recurrent Diabetic Gastroparesis (2.3)

• Administer 10 mg, 30 minutes before each meal and at bedtime (maximum of 40 mg per day) for 2 to 8 weeks

Dosage Adjustment in Specific Populations (2.2, 2.3)

• For gastroesophageal reflux and acute and recurrent diabetic gastroparesis, see Full Prescribing Information for recommended dosage reductions for elderly patients, in patients with moderate or severe hepatic or renal impairment, and cytochrome P450 2D6 (CYP2D6) poor metabolizers.

2.1 Important Administration Instructions

Avoid treatment with Sulmetin Solution (Metoclopramide Hydrochloride) for longer than 12 weeks because of the increased risk of developing TD with longer-term use [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

2.2 Dosage for Gastroesophageal Reflux

Sulmetin Solution tablets may be administered continuously or intermittently in patients with symptomatic gastroesophageal reflux who fail to respond to conventional therapy:

Continuous Dosing

The recommended adult dosage of Sulmetin Solution (Metoclopramide Hydrochloride) is 10 to 15 mg four times daily for 4 to 12 weeks. The treatment duration is determined by endoscopic response. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 60 mg.

Table 1 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

Intermittent Dosing

If symptoms only occur intermittently or at specific times of the day, administer Sulmetin Solution (Metoclopramide Hydrochloride) in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1.

2.3 Dosage for Acute and Recurrent Diabetic Gastroparesis

The recommended adult dosage for the treatment of acute and recurrent diabetic gastroparesis is 10 mg four times daily for 2 to 8 weeks, depending on symptomatic response. Avoid Sulmetin Solution (Metoclopramide Hydrochloride) treatment for greater than 12 weeks [see Warnings and Precautions (5.1)]. Administer the dosage thirty minutes before each meal and at bedtime. The maximum recommended daily dosage is 40 mg.

Table 2 displays the recommended daily dosage and maximum daily dosage for adults and dosage adjustments for patients with moderate or severe hepatic impairment (Child-Pugh B or C), in patients with creatinine clearance less than 60 mL/minute, in cytochrome P450 2D6 (CYP2D6) poor metabolizers, and with concomitant use with strong CYP2D6 inhibitors.

If patients with diabetic gastroparesis have severe nausea or vomiting and are unable to take oral Sulmetin Solution (Metoclopramide Hydrochloride) tablets, consider starting therapy with Sulmetin Solution (Metoclopramide Hydrochloride) injection given intramuscularly or intravenously for up to 10 days injection). After patients are able to take oral therapy, switch to Sulmetin Solution (Metoclopramide Hydrochloride) tablets.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 5 mg Sulmetin Solution (Metoclopramide Hydrochloride): white, round, unscored, debossed “TV” on one side and “2204” on the other side.
• 10 mg Sulmetin Solution (Metoclopramide Hydrochloride): white, round, scored, debossed “TEVA” on one side and “2203” above the score on the other side.

Tablets: 5 mg and 10 mg Sulmetin Solution (Metoclopramide Hydrochloride) (3)

4 CONTRAINDICATIONS

Sulmetin Solution (Metoclopramide Hydrochloride) is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to Sulmetin Solution (Metoclopramide Hydrochloride) [see Warnings and Precautions ( 5.1, 5.2 ) ].
• When stimulation of gastrointestinal motility might be dangerous (e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation).
• In patients with pheochromocytoma or other catecholamine-releasing paragangliomas. Sulmetin Solution (Metoclopramide Hydrochloride) may cause a hypertensive/pheochromocytoma crisis, probably due to release of catecholamines from the tumor [see Warnings and Precautions (5.5)].
• In patients with epilepsy. Sulmetin Solution (Metoclopramide Hydrochloride) may increase the frequency and severity of seizures [see Adverse Reactions (6)].
• In patients with hypersensitivity to Sulmetin Solution (Metoclopramide Hydrochloride). Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6)].

• History of TD or dystonic reaction to Sulmetin Solution (Metoclopramide Hydrochloride) (4)
• When stimulation of gastrointestinal motility might be dangerous (4)
• Pheochromocytoma, catecholamine-releasing paragangliomas (4)
• Epilepsy (4)
• Hypersensitivity to Sulmetin Solution (Metoclopramide Hydrochloride) (4)

5 WARNINGS AND PRECAUTIONS

• Tardive Dyskinesia, Other Extrapyramidal Symptoms (EPS), and Neuroleptic Malignant Syndrome (NMS): Avoid concomitant use of other drugs known to cause TD/EPS/NMS and avoid use in patients with Parkinson’s Disease. If symptoms occur, discontinue Sulmetin Solution (Metoclopramide Hydrochloride) and seek immediate medical attention. (5.1, 5.2, 5.3, 7.1, 7.2)
• Depression and suicidal ideation/suicide: Avoid use. (5.4)

5.1 Tardive Dyskinesia

Sulmetin Solution (Metoclopramide Hydrochloride) can cause tardive dyskinesia (TD), a syndrome of potentially irreversible and disfiguring involuntary movements of the face or tongue, and sometimes of the trunk and/or extremities. Movements may be choreoathetotic in appearance. The risk of developing TD and the likelihood that TD will become irreversible increases with duration of treatment and total cumulative dosage. Additionally, the risk of developing TD is increased among the elderly, especially elderly women [see Use in Specific Populations (8.5)], and in patients with diabetes mellitus. Due to the risk of developing TD, avoid treatment with Sulmetin Solution (Metoclopramide Hydrochloride) for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].

Discontinue Sulmetin Solution (Metoclopramide Hydrochloride) immediately in patients who develop signs and symptoms of TD. There is no known effective treatment for established cases of TD, although in some patients TD may remit, partially or completely, within several weeks to months after Sulmetin Solution (Metoclopramide Hydrochloride) is withdrawn.

Sulmetin Solution (Metoclopramide Hydrochloride) itself may suppress, or partially suppress, the signs of TD, thereby masking the underlying disease process. The effect of this symptomatic suppression upon the long-term course of TD is unknown. Sulmetin Solution (Metoclopramide Hydrochloride) is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Sulmetin Solution (Metoclopramide Hydrochloride) in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).

5.2 Other Extrapyramidal Symptoms

In addition to TD, Sulmetin Solution may cause other extrapyramidal symptoms (EPS), parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Sulmetin Solution (Metoclopramide Hydrochloride).

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with Sulmetin Solution (Metoclopramide Hydrochloride) dosages of 30 mg to 40 mg daily. Such reactions occurred more frequently in adults less than 30 years of age and at higher than recommended dosages. EPS occurred more frequently in pediatric patients compared to adults (metoclopramide is not approved for use in pediatric patients). Symptoms can occur in the first 24 to 48 hours after starting Sulmetin Solution (Metoclopramide Hydrochloride). Symptoms included involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus. Rarely, dystonic reactions were present as stridor and dyspnea, possibly due to laryngospasm. Diphenhydramine hydrochloride or benztropine mesylate may be used to treat these adverse reactions. Avoid Sulmetin Solution (Metoclopramide Hydrochloride) in patients receiving other drugs that can cause EPS (e.g., antipsychotics).
• Parkinsonian symptoms (bradykinesia, tremor, cogwheel rigidity, mask-like facies) have occurred after starting Sulmetin Solution (Metoclopramide Hydrochloride), more commonly within the first 6 months, but also after longer periods. Symptoms generally have subsided within 2 to 3 months after discontinuation of Sulmetin Solution (Metoclopramide Hydrochloride). Avoid Sulmetin Solution (Metoclopramide Hydrochloride) in patients with Parkinson’s disease and other patients being treated with antiparkinsonian drugs due to potential exacerbation of symptoms. Avoid treatment with Sulmetin Solution (Metoclopramide Hydrochloride) for more than 12 weeks [see Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].
• Motor restlessness (akathisia) has developed and consisted of feelings of anxiety, agitation, jitteriness, and insomnia, as well as inability to sit still, pacing, and foot tapping. If symptoms resolve, consider restarting at a lower dosage.

5.3 Neuroleptic Malignant Syndrome

Sulmetin Solution (Metoclopramide Hydrochloride) may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with Sulmetin Solution (Metoclopramide Hydrochloride) overdosage and concomitant treatment with another drug associated with NMS. Avoid Sulmetin Solution (Metoclopramide Hydrochloride) in patients receiving other drugs associated with NMS, including typical and atypical antipsychotics.

Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and manifestations of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Patients with such symptoms should be evaluated immediately.

In the diagnostic evaluation, consider the presence of other serious medical conditions (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever, serotonin syndrome, and primary central nervous system pathology.

Management of NMS includes:

• Immediate discontinuation of Sulmetin Solution (Metoclopramide Hydrochloride) and other drugs not essential to concurrent therapy [see Drug Interactions (7.1)].
• Intensive symptomatic treatment and medical monitoring.
• Treatment of any concomitant serious medical problems for which specific treatments are available.

5.4 Depression

Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid Sulmetin Solution use in patients with a history of depression.

5.5 Hypertension

Sulmetin Solution (Metoclopramide Hydrochloride) may elevate blood pressure. In one study in hypertensive patients, intravenously administered Sulmetin Solution (Metoclopramide Hydrochloride) was shown to release catecholamines; hence, avoid use in patients with hypertension or in patients taking monoamine oxidase inhibitors [see Drug Interactions (7.1)].

There are also clinical reports of hypertensive crises in patients with undiagnosed pheochromocytoma. Sulmetin Solution (Metoclopramide Hydrochloride) is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue Sulmetin Solution (Metoclopramide Hydrochloride) in any patient with a rapid rise in blood pressure.

5.6 Fluid Retention

Because Sulmetin Solution produces a transient increase in plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of developing fluid retention and volume overload. Discontinue Sulmetin Solution (Metoclopramide Hydrochloride) if any of these adverse reactions occur.

5.7 Hyperprolactinemia

As with other dopamine D₂ receptor antagonists, Sulmetin Solution (Metoclopramide Hydrochloride) elevates prolactin levels.

Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating drugs, including Sulmetin Solution (Metoclopramide Hydrochloride).

Hyperprolactinemia may potentially stimulate prolactin-dependent breast cancer. However, some clinical studies and epidemiology studies have not shown an association between administration of dopamine D₂ receptor antagonists and tumorigenesis in humans [see Nonclinical Toxicology ( 13.1 ) ].

5.8 Effects of the Ability to Drive and Operate Machinery

Sulmetin Solution (Metoclopramide Hydrochloride) may impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle. Concomitant use of central nervous system (CNS) depressants or drugs associated with EPS may increase this effect (e.g., alcohol, sedatives, hypnotics, opiates, and anxiolytics). Avoid Sulmetin Solution (Metoclopramide Hydrochloride) or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].

6 ADVERSE REACTIONS

The following adverse reactions are described, or described in greater detail, in other sections of the labeling:

• Tardive dyskinesia [see Boxed Warning and Warnings and Precautions (5.1)]
• Other extrapyramidal effects [see Warnings and Precautions (5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Depression [see Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Fluid retention [see Warnings and Precautions (5.6)]
• Hyperprolactinemia [see Warnings and Precautions (5.7)]
• Effects on the ability to drive and operate machinery [see Warnings and Precautions (5.8)]

The following adverse reactions have been identified from clinical studies or postmarketing reports of Sulmetin Solution (Metoclopramide Hydrochloride). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most common adverse reactions (in approximately 10% of patients receiving 10 mg of Sulmetin Solution (Metoclopramide Hydrochloride) four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of Sulmetin Solution (Metoclopramide Hydrochloride) administration.

Adverse reactions, especially those involving the nervous system, occurred after stopping Sulmetin Solution (Metoclopramide Hydrochloride) including dizziness, nervousness, and headaches.

Central Nervous System Disorders

• Tardive dyskinesia, acute dystonic reactions, drug-induced parkinsonism, akathisia, and other extrapyramidal symptoms
• Convulsive seizures
• Hallucinations
• Restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurred less frequently.
• Neuroleptic malignant syndrome, serotonin syndrome (in combination with serotonergic agents).

Endocrine Disorders: Fluid retention secondary to transient elevation of aldosterone. Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia

Cardiovascular Disorders: Acute congestive heart failure, possible atrioventricular block, hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention

Gastrointestinal Disorders: Nausea, bowel disturbances (primarily diarrhea)

Hepatic Disorders: Hepatotoxicity, characterized by, e.g., jaundice and altered liver function tests, when Sulmetin Solution (Metoclopramide Hydrochloride) was administered with other drugs with known hepatotoxic potential

Renal and Urinary Disorders: Urinary frequency, urinary incontinence

Hematologic Disorders: Agranulocytosis, neutropenia, leukopenia, methemoglobinemia, sulfhemoglobinemia

Hypersensitivity Reactions: Bronchospasm (especially in patients with a history of asthma), urticaria; rash; angioedema, including glossal or laryngeal edema

Eye Disorders: Visual disturbances

Metabolism Disorders: Porphyria

• Most common adverse reactions (> 10%) are restlessness, drowsiness, fatigue, and lassitude. (6)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

• Antipsychotics: Potential for additive effects, including TD, EPS, and NMS; avoid concomitant use.
• CNS depressants: Increased risk of CNS depression. Avoid concomitant use and monitor for adverse reactions. (7.1)
• Strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine): See Full Prescribing Information for recommended dosage reductions. (2.2, 2.3, 7.1)
• MAO inhibitors: Increased risk of hypertension; avoid concomitant use. (5.5, 7.1)
• Additional drug interactions: See Full Prescribing Information. (7.1, 7.2)

7.1 Effects of Other Drugs on Sulmetin Solution (Metoclopramide Hydrochloride)

Table 3 displays the effects of other drugs on Sulmetin Solution (Metoclopramide Hydrochloride).

7.2 Effects of Sulmetin Solution on Other Drugs

Table 4 displays the effects of Sulmetin Solution (Metoclopramide Hydrochloride) on other drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published studies, including retrospective cohort studies, national registry studies, and meta-analyses, do not report an increased risk of adverse pregnancy-related outcomes with use of Sulmetin Solution during pregnancy.

There are potential risks to the neonate following exposure in utero to Sulmetin Solution (Metoclopramide Hydrochloride) during delivery [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of Sulmetin Solution (Metoclopramide Hydrochloride) to pregnant rats and rabbits at exposures about 6 and 12 times the maximum recommended human dose (MRHD) [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Sulmetin Solution (Metoclopramide Hydrochloride) crosses the placental barrier and may cause extrapyramidal signs and methemoglobinemia in neonates with maternal administration during delivery. Monitor neonates for extrapyramidal signs [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)].

Data

Animal Data

Reproduction studies have been performed following administration of oral Sulmetin Solution (Metoclopramide Hydrochloride) during organogenesis in pregnant rats at about 6 times the MRHD calculated on body surface area and in pregnant rabbits at about 12 times the MRHD calculated on body surface area. No evidence of adverse developmental effects due to Sulmetin Solution (Metoclopramide Hydrochloride) were observed.

8.2 Lactation

Risk Summary

Limited published data report the presence of Sulmetin Solution (Metoclopramide Hydrochloride) in human milk in variable amounts. Breastfed infants exposed to Sulmetin Solution (Metoclopramide Hydrochloride) have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data]. Sulmetin Solution (Metoclopramide Hydrochloride) elevates prolactin levels [see Warnings and Precautions (5.7)]; however, the published data are not adequate to support drug effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sulmetin Solution (Metoclopramide Hydrochloride) and any potential adverse effects on the breastfed child from Sulmetin Solution (Metoclopramide Hydrochloride) or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding neonates because Sulmetin Solution (Metoclopramide Hydrochloride) may cause extrapyramidal signs (dystonias) and methemoglobinemia [see Warnings and Precautions (5.1, 5.2), Use in Specific Populations (8.4)].

Data

In published clinical studies, the estimated amount of Sulmetin Solution (Metoclopramide Hydrochloride) received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of Sulmetin Solution (Metoclopramide Hydrochloride) received by infants from breast milk ranged from 6 to 24 mcg/kg/day in early puerperium (3 to 9 days postpartum) and from 1 to 13 mcg/kg/day at 8 to 12 weeks postpartum.

8.4 Pediatric Use

Sulmetin Solution is not recommended for use in pediatric patients due to the risk of tardive dyskinesia (TD) and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of Sulmetin Solution (Metoclopramide Hydrochloride) in pediatric patients have not been established.

Dystonias and other extrapyramidal symptoms associated with Sulmetin Solution (Metoclopramide Hydrochloride) are more common in pediatric patients than in adults [see Warnings and Precautions (5.1, 5.2)]. In addition, neonates have reduced levels of NADH-cytochrome b₅ reductase, making them more susceptible to methemoglobinemia, a possible adverse reaction of Sulmetin Solution (Metoclopramide Hydrochloride) use in neonates [see Use in Specific Populations (8.8)].

8.5 Geriatric Use

Sulmetin Solution (Metoclopramide Hydrochloride) is known to be substantially excreted by the kidney, and the risk of adverse reactions, including tardive dyskinesia (TD), may be greater in patients with impaired renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Elderly patients are more likely to have decreased renal function and may be more sensitive to the therapeutic or adverse effects of Sulmetin Solution (Metoclopramide Hydrochloride); therefore, consider a reduced dosage of Sulmetin Solution (Metoclopramide Hydrochloride) in elderly patients [see Boxed Warning, Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].

8.6 Renal Impairment

The clearance of Sulmetin Solution is decreased and the systemic exposure is increased in patients with moderate to severe renal impairment compared to patients with normal renal function, which may increase the risk of adverse reactions. Reduce the Sulmetin Solution (Metoclopramide Hydrochloride) dosage in patients with moderate and severe renal impairment (creatinine clearance less than or equal to 60 mL/minute), including those receiving hemodialysis and continuous ambulatory peritoneal dialysis [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic Sulmetin Solution (Metoclopramide Hydrochloride) clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in Sulmetin Solution (Metoclopramide Hydrochloride) blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce Sulmetin Solution (Metoclopramide Hydrochloride) dosage in patients with moderate or severe (Child-Pugh B or C) hepatic impairment [see Dosage and Administration (2.2, 2.3)]. There is no dosage adjustment required for patients with mild hepatic impairment (Child-Pugh A).

In addition, Sulmetin Solution (Metoclopramide Hydrochloride), by producing a transient increase in plasma aldosterone, may increase the risk of fluid retention in patients with hepatic impairment [see Warnings and Precautions (5.6)].

Monitor patients with hepatic impairment for the occurrence of fluid retention and volume overload.

8.8 NADH-Cytochrome b₅ Reductase Deficiency

Metoclopramide-treated patients with NADH-cytochrome b₅ reductase deficiency are at an increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. For patients with glucose-6-phosphate dehydrogenase deficiency with metoclopramide-induced methemoglobinemia, methylene blue treatment is not recommended. Methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal [see Overdosage (10)].

8.9 CYP2D6 Poor Metabolizers

Sulmetin Solution (Metoclopramide Hydrochloride) is a substrate of CYP2D6. The elimination of Sulmetin Solution (Metoclopramide Hydrochloride) may be slowed in patients who are CYP2D6 poor metabolizers (compared to patients who are CYP2D6 intermediate, extensive, or ultra-rapid metabolizers); possibly increasing the risk of dystonic and other adverse reactions to Sulmetin Solution (Metoclopramide Hydrochloride) [see Clinical Pharmacology (12.3)]. Reduce the Sulmetin Solution (Metoclopramide Hydrochloride) dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].

10 OVERDOSAGE

Manifestations of Sulmetin Solution (Metoclopramide Hydrochloride) overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with Sulmetin Solution (Metoclopramide Hydrochloride) use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with Sulmetin Solution (Metoclopramide Hydrochloride) overdose and concomitant treatment with another drug associated with NMS [see Warnings and Precautions (5.1, 5.2, 5.3)].

There are no specific antidotes for Sulmetin Solution (Metoclopramide Hydrochloride) overdosage. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However, methylene blue may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may be fatal.

Hemodialysis and continuous ambulatory peritoneal dialysis do not remove significant amounts of Sulmetin Solution (Metoclopramide Hydrochloride).

11 DESCRIPTION

Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride, USP, the active ingredient of Sulmetin Solution (Metoclopramide Hydrochloride) tablets, is a dopamine-2 receptor antagonist. Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride (metoclopramide monohydrochloride monohydrate) is a white or practically white, crystalline, odorless or practically odorless powder. It is very soluble in water, freely soluble in alcohol, sparingly soluble in chloroform and practically insoluble in ether. Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide monohydrochloride monohydrate. Its structural formula is as follows:

C₁₄H₂₂ClN₃O₂-HCl-H₂O M.W. 354.3

Sulmetin Solution (Metoclopramide Hydrochloride) tablets are for oral administration. Sulmetin Solution (Metoclopramide Hydrochloride) tablets are available in 5 mg and 10 mg tablets.

• Each Sulmetin Solution (Metoclopramide Hydrochloride) tablet, 5 mg contains 5 mg Sulmetin Solution (Metoclopramide Hydrochloride) (equivalent to 5.91 mg of Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride, USP).
• Each Sulmetin Solution (Metoclopramide Hydrochloride) tablet, 10 mg contains 10 mg Sulmetin Solution (Metoclopramide Hydrochloride) (equivalent to 11.82 mg of Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride, USP).

Inactive Ingredients

Corn starch, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

\Client\X$\Products\Metoclopramide Tablets USP, 10 mg (ANDA 070184)\Submissions\2017-08-30 CBE-0 - AJK\Working\INSERT\Images\metoclopramide-sf1.jpg

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sulmetin Solution stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of Sulmetin Solution (Metoclopramide Hydrochloride) in the treatment of gastroesophageal reflux and acute and recurrent diabetic gastroparesis has not been fully established. It seems to sensitize tissues to the action of acetylcholine. The effect of Sulmetin Solution (Metoclopramide Hydrochloride) on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.

Sulmetin Solution (Metoclopramide Hydrochloride) increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder.

12.2 Pharmacodynamics

Gastroesophageal Reflux

In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of Sulmetin Solution (Metoclopramide Hydrochloride) produced dose-related increases in LESP. Effects began at about 5 mg and increased through 20 mg. The increase in LESP from a 5 mg dose lasted about 45 minutes and that of 20 mg lasted between 2 and 3 hours. Increased rate of stomach emptying was observed with single oral doses of 10 mg.

12.3 Pharmacokinetics

Absorption

Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral Sulmetin Solution (Metoclopramide Hydrochloride) is 80% ± 15.5% as demonstrated in a crossover study of 18 subjects. Peak plasma concentrations occurred at about 1 to 2 hours after a single oral dose. Similar time to peak was observed after individual doses at steady state.

In a single dose study of 12 subjects, the area under the drug concentration-time curve increased linearly with doses from 20 to 100 mg (5 times the maximum recommended single dose). Peak concentrations increased linearly with dose; time to peak concentrations remained the same; whole body clearance was unchanged; and the elimination rate remained the same. The mean elimination half-life in subjects with normal renal function was 5 to 6 hours. Linear kinetic processes adequately describe the absorption and elimination of Sulmetin Solution (Metoclopramide Hydrochloride).

Distribution

Sulmetin Solution (Metoclopramide Hydrochloride) is not extensively bound to plasma proteins (about 30%). The whole body volume of distribution is high (about 3.5 L/kg), which suggests extensive distribution of drug to the tissues.

Elimination

Metabolism: Sulmetin Solution (Metoclopramide Hydrochloride) undergoes enzymatic metabolism via oxidation as well as glucuronide and sulfate conjugation reactions in the liver. Monodeethylmetoclopramide, a major oxidative metabolite, is formed primarily by CYP2D6, an enzyme subject to genetic variability [see Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.9)].

Excretion: Approximately 85% of the radioactivity of an orally administered dose appeared in the urine within 72 hours. After oral administration of 10 or 20 mg, a mean of 18% and 22% of the dose, respectively, was recovered as free Sulmetin Solution (Metoclopramide Hydrochloride) in urine within 36 hours.

Specific Populations

Patients with Renal Impairment: In a study of 24 patients with varying degrees of renal impairment (moderate, severe, and end-stage renal disease (ESRD) requiring dialysis), the systemic exposure (AUC) of Sulmetin Solution (Metoclopramide Hydrochloride) in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of Sulmetin Solution (Metoclopramide Hydrochloride) in patients with ESRD on dialysis was about 3.5-fold the AUC in subjects with normal renal function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: In a group of 8 patients with severe hepatic impairment (Child-Pugh C), the average Sulmetin Solution (Metoclopramide Hydrochloride) clearance was reduced by approximately 50% compared to patients with normal hepatic function [see Dosage and Administration (2.2, 2.3) and Use in Specific Populations (8.7)].

Drug Interaction Studies

Effect of Sulmetin Solution (Metoclopramide Hydrochloride) on CYP2D6 Substrates

Although in vitro studies suggest that Sulmetin Solution (Metoclopramide Hydrochloride) can inhibit CYP2D6, Sulmetin Solution (Metoclopramide Hydrochloride) is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.

Effect of CYP2D6 Inhibitors on Sulmetin Solution (Metoclopramide Hydrochloride)

In healthy subjects, 20 mg of Sulmetin Solution (Metoclopramide Hydrochloride) and 60 mg of fluoxetine (a strong CYP2D6 inhibitor) were administered, following prior exposure to 60 mg fluoxetine orally for 8 days. The patients who received concomitant Sulmetin Solution (Metoclopramide Hydrochloride) and fluoxetine had a 40% and 90% increase in Sulmetin Solution (Metoclopramide Hydrochloride) C_max and AUC_0-∞, respectively, compared to patients who received Sulmetin Solution (Metoclopramide Hydrochloride) alone [see Drug Interactions (7.1)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 77-week study was conducted in rats with oral Sulmetin Solution (Metoclopramide Hydrochloride) doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Sulmetin Solution (Metoclopramide Hydrochloride) elevated prolactin levels and the elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic administration of Sulmetin Solution (Metoclopramide Hydrochloride) [see Warnings and Precautions (5.7)]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with Sulmetin Solution (Metoclopramide Hydrochloride) at a dose of 260 mg/kg/day (about 35 times the maximum recommended human dose based on body surface area) enhanced the tumorigenic effect of N-nitrosodiethylamine.

Mutagenesis

Sulmetin Solution (Metoclopramide Hydrochloride) was positive in the in vitro Chinese hamster lung cell/HGPRT forward mutation assay for mutagenic effects and in the in vitro human lymphocyte chromosome aberration assay for clastogenic effects. It was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis assay with rat and human hepatocytes, and the in vivo rat micronucleus assay.

Impairment of Fertility

Sulmetin Solution (Metoclopramide Hydrochloride) at intramuscular doses up to 20 mg/kg/day (about three times the maximum recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each white, round, unscored, debossed “TV” on one side and “2204” on the other side, compressed Sulmetin Solution (Metoclopramide Hydrochloride) tablet, USP contains Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 5 mg Sulmetin Solution (Metoclopramide Hydrochloride). Available in bottles of 100 (NDC 0093-2204-01) and 500 (NDC 0093-2204-05).

Each white, round, scored, debossed “TEVA” on one side and “2203” above the score on the other side, compressed Sulmetin Solution (Metoclopramide Hydrochloride) tablet, USP contains Sulmetin Solution (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 10 mg Sulmetin Solution (Metoclopramide Hydrochloride). Available in bottles of 100 (NDC 0093-2203-01), 500 (NDC 0093-2203-05), and 1000 (NDC 0093-2203-10).

Dispense in a tight, light-resistant container. Store tablets at 20° to 25°C (68° to 77°F).

This product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients or their caregivers that Sulmetin Solution (Metoclopramide Hydrochloride) can cause serious adverse reactions. Instruct patients to discontinue Sulmetin Solution (Metoclopramide Hydrochloride) and contact a healthcare provider immediately if the following serious reactions occur:

• Tardive dyskinesia and other extrapyramidal reactions [see Warnings and Precautions (5.1, 5.2)]
• Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
• Depression and/or possible suicidal ideation [see Warnings and Precautions (5.4)]

Inform patients or their caregivers that concomitant treatment with numerous other medications can precipitate or worsen serious adverse reactions such as tardive dyskinesia or other extrapyramidal reactions, neuroleptic malignant syndrome, and CNS depression [see Drug Interactions (7.1, 7.2)]. Explain that the prescriber of any other medication must be made aware that the patient is taking Sulmetin Solution (Metoclopramide Hydrochloride).

Inform patients or their caregivers that Sulmetin Solution (Metoclopramide Hydrochloride) can cause drowsiness or dizziness, or otherwise impair the mental and/or physical abilities required for the performance of hazardous tasks such as operating machinery or driving a motor vehicle [see Warnings and Precautions (5.8)].

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. Q 8/2017

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured In Croatia By:

Pliva Hrvatska d.o.o.

Zagreb, Croatia

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. D 8/2017

NDC 0093-2204-01

Sulmetin Solution (Metoclopramide Hydrochloride)

Tablets, USP

5mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

NDC 0093-2203-01

Sulmetin Solution (Metoclopramide Hydrochloride)

Tablets, USP

10 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

Sorbitol:

• Active ingredient (in each tablespoonful=15 ml )
• Purpose
• Uses
• Warnings
• Directions
• Other information
• Inactive ingredient
• Sulmetin Solution (Sorbitol) reviews

Active ingredient

Purpose

Laxative

Uses

• relieves occasional constipation and irregularity
• generally produces bowel movement in 1/4 to 1 hour when used rectally
• as a pharmaceutical aide (sweetner)
• for other uses, as your doctor
  

Warnings

• when abdominal pain, nausea, or vomiting are present
• for more than one week unless directed by a doctor
  

• are taking mineral oil
• have noticed a sudden change in bowel habits that lasts over 2 weeks
  

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children. In case of overdose, get medical help or contact a

Poison Control Center right away.

Directions

Other information

- store at room temperature 15-30C (59-86F)

- below 59F cloudiness and thickening may occur; warming will restore clarity and fluidity without affecting product quality

- do not freeze

- store in original container

- for institutional use only

Inactive ingredient

water

GERICARE

NDC 57896-435-16

Sulmetin Solution (Sorbitol) SOLUTION USP

70% W/W

LAXATIVE

TAMPER EVIDENT: Do not use this product if inner seal over mouth of bottle is missing or broken.

16 FL OZ (473 mL)