Migrafin

Aspirin Lysine:

• Pharmacological action
• Pharmacokinetics
• Why is Migrafin prescribed?
• Dosage and administration
• Migrafin (Aspirin Lysine) side effects, adverse reactions
• Migrafin contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Precautionary measures
• Migrafin (Aspirin Lysine) drug interactions
• Migrafin in case of emergency / overdose
• Migrafin (Aspirin Lysine) reviews

Pharmacological action

Migrafin is a NSAIDs. It has anti-inflammatory, analgesic and antipyretic effect, and inhibits platelet aggregation. The mechanism of action is associated with inhibition of COX activity - the main enzyme metabolism of arachidonic acid which is a precursor of prostaglandins which play a major role in the pathogenesis of inflammation, pain and fever. Reduction of prostaglandins (mainly E1) in the thermoregulation center leads to a decrease in body temperature due to expansion of blood vessels of the skin and increase perspiration. Analgesic effect of Migrafin (Aspirin Lysine) is due to both central and peripheral effects. Reduces aggregation, platelet adhesion and thrombus formation through suppression of synthesis of thromboxane A2 in platelets.

Reduces mortality and risk of myocardial infarction in unstable stenocardia. It is effective in primary prevention of cardio-vascular system and secondary prevention of myocardial infarction. At a daily dose of 6 g or more inhibits the synthesis of prothrombin in the liver and increases the prothrombin time. Migrafin (Aspirin Lysine) increases fibrinolytic activity of plasma and reduces the concentration of vitamin K-dependent coagulation factors (II, VII, IX, X). Increases the rate of hemorrhagic complications in carrying out surgical procedures, increases the risk of bleeding during therapy with anticoagulants. It stimulates the excretion of uric acid (violating its reabsorption in the renal tubules) but in high doses. The blockade of COX-1 in the mucosa of the stomach leads to inhibition of gastroprotective prostaglandins, which may lead to ulceration of the mucous membrane and subsequent bleeding.

Pharmacokinetics

When administered orally Migrafin (Aspirin Lysine) is rapidly absorbed mainly from the proximal small intestine and to a lesser extent from the stomach. The presence of food in the stomach significantly affects the absorption of acetylsalicylic acid.

Metabolised in the liver by hydrolysis with the formation of salicylic acid with subsequent conjugation with glycine or two drugs. The concentration of salicylates in blood plasma is variable.

About 80% of salicylic acid binds to plasma proteins. Salicylates easily penetrate into many tissues and body fluids, including the cerebrospinal, peritoneal and synovial fluid. In small quantities salicylates are found in brain tissue, traces - in bile, sweat and feces. Quickly penetrates the placental barrier in small amounts excreted in breast milk.

For newborns salicylates may displace bilirubin from its association with albumin and promote bilirubin encephalopathy.

Penetration into the joint cavity is accelerated in the presence of hyperemia and edema, and slows down in the proliferative phase of inflammation.

If you have acidosis most of salicylate becomes unionized acid, good penetration into the tissue, including in the brain.

Migrafin (Aspirin Lysine) withdraws mainly by active secretion in the tubules of the kidneys in unchanged form (60%) and in the form of metabolites. The withdraw of unchanged salicylate is dependent on the pH of urine (for alkalinization of urine increases ionized salicylates, worsening their reabsorption and increases excretion). T1/2 of acetylsalicylic acid is approximately 15 minutes. T1/2 of salicylate at a reception in low doses is 2-3 h, with an increase in dose may increase to 15-30 hours. Newborns' elimination of salicylate is much slower than in adults.

Why is Migrafin prescribed?

Rheumatism, rheumatoid arthritis, infectious-allergic myocarditis, fever during infectious and inflammatory diseases, pain syndrome, weak and medium intensity of various origins (including neuralgia, myalgia, headache); based prevention of thrombosis and embolism, primary and secondary prevention of myocardial infarction, prevention of violations of cerebral circulation by ischemic type.

In the clinical immunology and allergy: a gradually increasing doses for a prolonged "aspirin" desensitization and the formation of stable tolerance to NSAIDs in patients with "aspirin asthma" and "aspirin triad."

Dosage and administration

Individual. For oral administration dosing of Migrafin regimen depends on indication for use. Usual adult dose when used as antipyretic and analgesic is 500-1000 mg / day (up to 3 g) were divided into 3 admission.

In myocardial infarction, as well as for secondary prevention in patients after myocardial infarction - 40-325 mg 1 time a day (usually 160 mg). As an inhibitor of platelet aggregation - a dose of 300-325 mg / day, for a long time. At the dynamic circulatory disorders in men, cerebral thromboembolism, including to prevent a recurrence - 325 mg / day with gradual increase to a maximum of 1 g / day. For prevention of thrombosis or occlusion of the aortic shunt - by 325 mg every 7 h after intranasal gastric tube set, and then - through the mouth to 325 mg 3 times a day (usually in combination with dipyridamole, which abolished after 1 week, continuing the long-term treatment with acetylsalicylic acid).

Migrafin (Aspirin Lysine) side effects, adverse reactions

Digestive system: nausea, vomiting, anorexia, epigastric pain, diarrhea; rarely - occurrence of erosive and ulcerative lesions, bleeding from the gastrointestinal tract, abnormal liver function.

Central nervous system: long-term use may be dizziness, headache, reversible visual disturbances, tinnitus, aseptic meningitis.

Hemopoietic system: rarely - thrombocytopenia, anemia.

Blood coagulation system: rarely - haemorrhagic syndrome, prolongation of bleeding time.

Urinary system: rarely - renal dysfunction, with prolonged use - acute kidney failure, nephrotic syndrome.

Allergic reactions: rarely - skin rash, Quincke's edema, bronchospasm, "aspirin triad" (a combination of bronchial asthma, recurrent nasal polyposis, and paranasal sinuses and intolerance of acetylsalicylic acid and medicines pirazolonic series).

Other: in some cases - Reye syndrome, long-term use - increased symptoms of chronic heart failure.

Migrafin contraindications

Exacerbation phase of erosive-ulcerative lesions in the gastrointestinal tract, gastro-intestinal bleeding, "aspirin triad", a history of indications urticaria, rhinitis, caused by taking aspirin and other NSAIDs, hemophilia, hemorrhagic diathesis, gipoprotrombinemii, dissecting aneurysm of the aorta, portal hypertension, deficiency of vitamin K, liver and / or renal failure, deficiency of glucose-6-phosphate dehydrogenase, Reye syndrome, children's age (under 15 years - the risk of developing Reye syndrome in children with hyperthermia on a background of viral diseases), I and III trimester of pregnancy, lactation, hypersensitivity to aspirin and other salicylates.

Using during pregnancy and breastfeeding

Aspirin is contraindicated in I and III trimester of pregnancy. In pregnancy trimester II can a one-off reception on the strict condition.

This medication has a teratogenic effect: when used in the I trimester leads to top palatoschisis, in the III trimester - cause inhibition of labor (inhibition of prostaglandin synthesis), premature closure of the ductus arteriosus in the fetus, pulmonary vascular hyperplasia and hypertension in the pulmonary circulation.

aspirin (acetylsalicylic acid) is excreted in breast milk, which increases the risk of bleeding in a child due to dysfunction of platelets, and therefore should not be applied acetylsalicylic acid in the mother during lactation.

Special instructions

Migrafin (Aspirin Lysine) with caution used in patients with liver diseases and kidney, bronchial asthma, erosive and ulcerative lesions, and bleeding from the digestive tract in history, with increased bleeding or while holding anticoagulant therapy, decompensated congestive heart failure.

Acetylsalicylic acid even in small doses reduces the excretion of uric acid from the organism that can cause an acute attack of gout in predisposed patients. When conducting long-term therapy and / or use of aspirin in high doses required medical supervision and regular monitoring of hemoglobin levels.

The use of acetylsalicylic acid as anti-inflammatory drugs in a daily dose of 5-8 g is limited due to the high probability of adverse effects from the gastrointestinal tract.

Before surgery to reduce bleeding during surgery and postoperative period should stop taking salicylates for 5-7 days.

During prolonged therapy is necessary to conduct a general analysis of blood and study of occult blood.

The use of acetylsalicylic acid is contraindicated in pediatrics, as in the case of viral infection in children under the influence of acetylsalicylic acid increases the risk of developing Reye syndrome. Symptoms of Reye syndrome are prolonged vomiting, acute encephalopathy, liver enlargement.

Duration of treatment (without consulting a doctor) with Migrafin (Aspirin Lysine) should not exceed 7 days when administered as analgesic and more than 3 days as an antipyretic.

During treatment the patient should abstain from alcohol.

Precautionary measures

Undesirable combined use with other NSAIDs and glucocorticoids. For 5-7 days before surgery should stop taking.

The probability of NSAID-gastropathy decreases in the appointment after a meal, use of tablets with buffer additives or coated with a special enteric-soluble shell. The risk of hemorrhagic complications is minimal when used in doses less than 100 mg / day.

Note that in predisposed patients acetylsalicylic acid (even in small doses) reduces the excretion of uric acid from the body and can cause the development of acute attack of gout.

During prolonged therapy should regularly carry out the analysis of blood and to investigate faeces for occult blood. In connection with the observed cases hepatogenic encephalopathy is not recommended for relief of fever syndrome in children.

Migrafin (Aspirin Lysine) drug interactions

With simultaneous use of antacids containing magnesium and / or aluminum hydroxide, slow down and reduce the absorption of acetylsalicylic acid.

With simultaneous use of calcium channel blockers, means limiting intake of calcium or increasing the excretion of calcium from the body, increases the risk of bleeding.

With simultaneous use with acetylsalicylic acid enhances the action of heparin and indirect anticoagulants, hypoglycemic funds derived sulfonylureas, insulin, methotrexate, phenytoin, valproic acid.

With simultaneous use of Migrafin (Aspirin Lysine) with SCS increases the risk of ulcerogenic effect and occurrence of gastrointestinal bleeding.

With simultaneous use of decreasing the effectiveness of diuretics (spironolactone, furosemide).

With simultaneous use of other NSAIDs increases the risk of side effects. Acetylsalicylic acid may reduce plasma concentrations indomethacin, piroxicam.

With simultaneous use of gold drugs acetylsalicylic acid can induce liver damage.

With simultaneous use decreases effectiveness of uricosuric medications (including probenecid, sulfinpirazon, benzbromarone).

With simultaneous use of acetylsalicylic acid and alendronate sodium may develop severe esophagitis.

With simultaneous use of griseofulvin may be in breach Absorption of acetylsalicylic acid.

There is one case of spontaneous hemorrhage in the iris while taking Ginkgo Biloba extract on the background of prolonged use of aspirin in a dose of 325 mg / day. It is believed that this may be due to additive inhibitory effect on platelet aggregation.

With simultaneous use of dipyridamole may increase C_max of salicylate in plasma and AUC.

When applied simultaneously with acetylsalicylic acid increased concentration of digoxin, barbiturates and lithium salts in the blood plasma.

With simultaneous use of salicylates in high doses with carbonic anhydrase inhibitors can intoxication salicylates.

Acetylsalicylic acid in doses of less than 300 mg have little effect on the effectiveness of captopril and enalapril. When aspirin (acetylsalicylic acid) is admistered in high doses may decrease the effectiveness of captopril and enalapril.

With simultaneous application of caffeine increases the rate of absorption, plasma concentrations and bioavailability of acetylsalicylic acid.

With simultaneous use of Migrafin (Aspirin Lysine) with metoprolol may increase C_max of salicylate in blood plasma.

In the application of pentazocine on the background of long-term use of aspirin in high doses there is a risk of severe adverse reactions in the kidneys.

With simultaneous application phenylbutazone reduces uricosuria caused by acetylsalicylic acid.

With simultaneous application of ethanol may exacerbate the effects of acetylsalicylic acid on the gastrointestinal tract.

Migrafin in case of emergency / overdose

May occur after receiving a single large dose or prolonged use. If a single dose of less than 150 mg / kg, acute poisoning feel light, 150-300 mg / kg - moderate, when using higher doses - heavy.

Symptoms: salicylism syndrome (nausea, vomiting, tinnitus, blurred vision, dizziness, severe headache, malaise, fever - a poor prognostic sign in adults). More severe poisoning - stupor, convulsions and coma, noncardiogenic pulmonary edema, abrupt dehydration, violations ABE (initially - respiratory alkalosis, then - metabolic acidosis), renal failure and shock.

In chronic overdose concentration determined in plasma are poorly correlated with the severity of intoxication. The greatest risk of chronic intoxication is found among elderly people at reception for a few days more than 100 mg / kg / day. In children and elderly patients the initial signs of salicylism are not always visible, and therefore desirable to periodically determine the concentration of salicylates in the blood. Level above 70 mg% indicates moderate or severe poisoning; above 100 mg% - on extremely heavy, a poor prognosis. If poisoning moderate require hospitalization for at least 24 hours.

Treatment: the provocation of vomiting, the appointment of activated charcoal and laxatives, monitoring ABE and electrolyte balance, depending on the state of metabolism - the introduction of sodium bicarbonate, solution of sodium citrate or sodium lactate. Raising reserve alkalinity increases the excretion of acetylsalicylic acid by alkalinization of urine. Alkalinization of urine is shown at the level of salicylates above 40 mg%, is provided in / by infusion of sodium bicarbonate - 88 mEq in 1 liter of 5% glucose solution, the rate of 10-15 ml / kg / h. Restoring BCC and induction of diuresis (achieved by introducing a bicarbonate in the same dose and dilution, repeat 2-3 times); should be aware that intense infusion fluid elderly patients may lead to pulmonary edema. Not recommended the use of acetazolamide for alkalinization of urine (may cause acidemia and enhance the toxic effect of salicylates). Hemodialysis is shown at the level of salicylates over 100-130 mg%, and in patients with chronic poisoning - 40 mg% or lower in the presence of witnesses (refractory acidosis, progressive deterioration, severe damage of the CNS, pulmonary edema and renal failure). When pulmonary edema - a mixture of artificial ventilation, oxygen enriched, in the mode of positive end-expiratory pressure, to treat cerebral edema apply hyperventilation and osmotic diuresis.

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
• Migrafin (Metoclopramide Hydrochloride) reviews

1 INDICATIONS AND USAGE

Migrafin (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:

Migrafin (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 ) ].

Migrafin (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:

Migrafin (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 Migrafin (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 Migrafin (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

Migrafin 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 Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride) tablets, consider starting therapy with Migrafin (Metoclopramide Hydrochloride) injection given intramuscularly or intravenously for up to 10 days injection). After patients are able to take oral therapy, switch to Migrafin (Metoclopramide Hydrochloride) tablets.

3 DOSAGE FORMS AND STRENGTHS

Tablets:

• 5 mg Migrafin (Metoclopramide Hydrochloride): white, round, unscored, debossed “TV” on one side and “2204” on the other side.
• 10 mg Migrafin (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 Migrafin (Metoclopramide Hydrochloride) (3)

4 CONTRAINDICATIONS

Migrafin (Metoclopramide Hydrochloride) is contraindicated:

• In patients with a history of tardive dyskinesia (TD) or a dystonic reaction to Migrafin (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. Migrafin (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. Migrafin (Metoclopramide Hydrochloride) may increase the frequency and severity of seizures [see Adverse Reactions (6)].
• In patients with hypersensitivity to Migrafin (Metoclopramide Hydrochloride). Reactions have included laryngeal and glossal angioedema and bronchospasm [see Adverse Reactions (6)].

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

Migrafin (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 Migrafin (Metoclopramide Hydrochloride) for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].

Discontinue Migrafin (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 Migrafin (Metoclopramide Hydrochloride) is withdrawn.

Migrafin (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. Migrafin (Metoclopramide Hydrochloride) is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Migrafin (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, Migrafin 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 Migrafin (Metoclopramide Hydrochloride).

• Extrapyramidal symptoms (EPS), such as acute dystonic reactions, occurred in patients treated with Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride). Avoid Migrafin (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 Migrafin (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

Migrafin (Metoclopramide Hydrochloride) may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with Migrafin (Metoclopramide Hydrochloride) overdosage and concomitant treatment with another drug associated with NMS. Avoid Migrafin (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 Migrafin (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 Migrafin use in patients with a history of depression.

5.5 Hypertension

Migrafin (Metoclopramide Hydrochloride) may elevate blood pressure. In one study in hypertensive patients, intravenously administered Migrafin (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. Migrafin (Metoclopramide Hydrochloride) is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue Migrafin (Metoclopramide Hydrochloride) in any patient with a rapid rise in blood pressure.

5.6 Fluid Retention

Because Migrafin 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 Migrafin (Metoclopramide Hydrochloride) if any of these adverse reactions occur.

5.7 Hyperprolactinemia

As with other dopamine D₂ receptor antagonists, Migrafin (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 Migrafin (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

Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride) administration.

Adverse reactions, especially those involving the nervous system, occurred after stopping Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride)

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

7.2 Effects of Migrafin on Other Drugs

Table 4 displays the effects of Migrafin (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 Migrafin during pregnancy.

There are potential risks to the neonate following exposure in utero to Migrafin (Metoclopramide Hydrochloride) during delivery [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of Migrafin (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

Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride) were observed.

8.2 Lactation

Risk Summary

Limited published data report the presence of Migrafin (Metoclopramide Hydrochloride) in human milk in variable amounts. Breastfed infants exposed to Migrafin (Metoclopramide Hydrochloride) have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data]. Migrafin (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 Migrafin (Metoclopramide Hydrochloride) and any potential adverse effects on the breastfed child from Migrafin (Metoclopramide Hydrochloride) or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding neonates because Migrafin (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 Migrafin (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 Migrafin (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

Migrafin 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 Migrafin (Metoclopramide Hydrochloride) in pediatric patients have not been established.

Dystonias and other extrapyramidal symptoms associated with Migrafin (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 Migrafin (Metoclopramide Hydrochloride) use in neonates [see Use in Specific Populations (8.8)].

8.5 Geriatric Use

Migrafin (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 Migrafin (Metoclopramide Hydrochloride); therefore, consider a reduced dosage of Migrafin (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 Migrafin 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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride) clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in Migrafin (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 Migrafin (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, Migrafin (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

Migrafin (Metoclopramide Hydrochloride) is a substrate of CYP2D6. The elimination of Migrafin (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 Migrafin (Metoclopramide Hydrochloride) [see Clinical Pharmacology (12.3)]. Reduce the Migrafin (Metoclopramide Hydrochloride) dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].

10 OVERDOSAGE

Manifestations of Migrafin (Metoclopramide Hydrochloride) overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with Migrafin (Metoclopramide Hydrochloride) use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride).

11 DESCRIPTION

Migrafin (Metoclopramide Hydrochloride) hydrochloride, USP, the active ingredient of Migrafin (Metoclopramide Hydrochloride) tablets, is a dopamine-2 receptor antagonist. Migrafin (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

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

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

Inactive Ingredients

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

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12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Migrafin stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of Migrafin (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 Migrafin (Metoclopramide Hydrochloride) on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.

Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride).

Distribution

Migrafin (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: Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (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 Migrafin (Metoclopramide Hydrochloride) on CYP2D6 Substrates

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

Effect of CYP2D6 Inhibitors on Migrafin (Metoclopramide Hydrochloride)

In healthy subjects, 20 mg of Migrafin (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 Migrafin (Metoclopramide Hydrochloride) and fluoxetine had a 40% and 90% increase in Migrafin (Metoclopramide Hydrochloride) C_max and AUC_0-∞, respectively, compared to patients who received Migrafin (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 Migrafin (Metoclopramide Hydrochloride) doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Migrafin (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 Migrafin (Metoclopramide Hydrochloride) [see Warnings and Precautions (5.7)]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with Migrafin (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

Migrafin (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

Migrafin (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 Migrafin (Metoclopramide Hydrochloride) tablet, USP contains Migrafin (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 5 mg Migrafin (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 Migrafin (Metoclopramide Hydrochloride) tablet, USP contains Migrafin (Metoclopramide Hydrochloride) hydrochloride, USP equivalent to 10 mg Migrafin (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 Migrafin (Metoclopramide Hydrochloride) can cause serious adverse reactions. Instruct patients to discontinue Migrafin (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 Migrafin (Metoclopramide Hydrochloride).

Inform patients or their caregivers that Migrafin (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

Migrafin (Metoclopramide Hydrochloride)

Tablets, USP

5mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

NDC 0093-2203-01

Migrafin (Metoclopramide Hydrochloride)

Tablets, USP

10 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA