Meclomid

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Meclomid uses


1 INDICATIONS AND USAGE

Meclomid tablets are indicated for the:


Limitations of Use:

Meclomid 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 ) ].

Meclomid tablets are indicated for the:


Limitations of Use:

Meclomid 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


Acute and Recurrent Diabetic Gastroparesis (2.3)


Dosage Adjustment in Specific Populations (2.2, 2.3)

2.1 Important Administration Instructions

Avoid treatment with Meclomid 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

Meclomid 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 Meclomid 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, 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 Meclomid in single dose up to 20 mg prior to the provoking situation. Consider dosage reductions for the populations and situations in Table 1.


Recommended Dosage


Maximum Recommended Daily Dosage


Adult patients


10 to 15 mg four times daily (thirty minutes before each meal and at bedtime)


60 mg


Mild hepatic impairment (Child-Pugh A)


Elderly patients [see Use in Specific Populations (8.5)]


5 mgElderly patients may be more sensitive to the therapeutic or adverse effects of Meclomid; therefore, consider a lower starting dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 to 15 mg four times daily based upon response and tolerability. four times daily (thirty minutes before each meal and at bedtime)


Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations (8.7)]


5 mg four times daily (thirty minutes before each meal and at bedtime), or

10 mg taken three times daily


30 mg


CYP2D6 poor metabolizers [see Use in Specific Populations (8.9)]


Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions (7.1)]


Moderate or severe renal impairment (creatinine clearance less than or equal to 60 mL/minute) [see Use in Specific Populations (8.6)]


Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]


5 mg four times daily (thirty minutes before each meal and at bedtime) or 10 mg twice daily


20 mg

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


Recommended Dosage


Maximum Recommended Daily Dosage


Adult Patients


10 mg four times daily (30 minutes before each meal and at bedtime)


40 mg


Mild hepatic impairment (Child-Pugh A)


Elderly patients [see Use in Specific Populations (8.5)]


5 mgElderly patients may be more sensitive to the therapeutic or adverse effects of Meclomid; therefore, consider a lower dosage of 5 mg four times daily with titration to the recommended adult dosage of 10 mg four time daily based upon response and tolerability. four times daily (30 minutes before each meal and at bedtime)


Moderate or severe hepatic impairment (Child-Pugh B or C) [see Use in Specific Populations (8.7)]


5 mg four times daily (30 minutes before each meal and at bedtime)


20 mg


CYP2D6 poor metabolizers [see Use in Specific Populations (8.9)]


Concomitant use with strong CYP2D6 inhibitors (e.g., quinidine, bupropion, fluoxetine, and paroxetine) [see Drug Interactions (7.1)]


Moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Use in Specific Populations (8.6)]


Patients with End-Stage Renal Disease (ESRD) including those treated with hemodialysis and continuous ambulatory peritoneal dialysis [see Use in Specific Populations (8.6)]


5 mg twice daily


10 mg

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3 DOSAGE FORMS AND STRENGTHS

Tablets:


Tablets: 5 mg and 10 mg Meclomid (3)

4 CONTRAINDICATIONS

Meclomid is contraindicated:

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5 WARNINGS AND PRECAUTIONS

5.1 Tardive Dyskinesia

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

Discontinue Meclomid 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 Meclomid is withdrawn.

Meclomid 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. Meclomid is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Meclomid in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).

5.2 Other Extrapyramidal Symptoms

In addition to TD, Meclomid may cause other extrapyramidal symptoms, parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Meclomid.

5.3 Neuroleptic Malignant Syndrome

Meclomid may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with Meclomid overdosage and concomitant treatment with another drug associated with NMS. Avoid Meclomid 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:

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 Meclomid use in patients with a history of depression.

5.5 Hypertension

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

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

5.6 Fluid Retention

Because Meclomid 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 Meclomid if any of these adverse reactions occur.

5.7 Hyperprolactinemia

As with other dopamine D2 receptor antagonists, Meclomid 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 Meclomid.

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 ].

5.8 Effects of the Ability to Drive and Operate Machinery

Meclomid 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 Meclomid or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].

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6 ADVERSE REACTIONS

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


The following adverse reactions have been identified from clinical studies or postmarketing reports of Meclomid. 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 Meclomid four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of Meclomid administration.

Adverse reactions, especially those involving the nervous system, occurred after stopping Meclomid including dizziness, nervousness, and headaches.

Central Nervous System Disorders


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 Meclomid 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


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.

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7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Meclomid

Table 3 displays the effects of other drugs on Meclomid.


Antipsychotics


Clinical Impact


Potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS).


Intervention


Avoid concomitant use [see Warnings and Precautions (5.1, 5.2, 5.3)].


Strong CYP2D6 Inhibitors, not Included in Antipsychotic Category Above


Clinical Impact


Increased plasma concentrations of Meclomid; risk of exacerbation of extrapyramidal symptoms [see Clinical Pharmacology (12.3)].


Intervention


Reduce the Meclomid dosage [see Dosage and Administration (2.2, 2.3)].


Examples


quinidine, bupropion, fluoxetine, and paroxetine


Monoamine Oxidase Inhibitors


Clinical Impact


Increased risk of hypertension [see Warnings and Precautions (5.5)].


Intervention


Avoid concomitant use.


Central Nervous System (CNS) Depressants


Clinical Impact


Increased risk of CNS depression [see Warnings and Precautions (5.8)].


Intervention


Avoid Meclomid or the interacting drug, depending on the importance of the drug to the patient.


Examples


alcohol, sedatives, hypnotics, opiates and anxiolytics


Drugs that Impair Gastrointestinal Motility


Clinical Impact


Decreased systemic absorption of Meclomid.


Intervention


Monitor for reduced therapeutic effect.


Examples


antiperistaltic antidiarrheal drugs, anticholinergic drugs, and opiates


Dopaminergic Agonists and Other Drugs that Increase Dopamine Concentrations


Clinical Impact


Decreased therapeutic effect of Meclomid due to opposing effects on dopamine.


Intervention


Monitor for reduced therapeutic effect.


Examples


apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine

7.2 Effects of Meclomid on Other Drugs

Table 4 displays the effects of Meclomid on other drugs.


Dopaminergic Agonists and Drugs Increasing Dopamine Concentrations


Clinical Impact


Opposing effects of Meclomid and the interacting drug on dopamine. Potential exacerbation of symptoms (e.g., parkinsonian symptoms).


Intervention


Avoid concomitant use [see Warnings and Precautions (5.2)].


Examples


Apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, rotigotine


Succinylcholine, Mivacurium


Clinical Impact


Meclomid inhibits plasma cholinesterase leading to enhanced neuromuscular blockade.


Intervention


Monitor for signs and symptoms of prolonged neuromuscular blockade


Drugs with Absorption Altered due to Increased Gastrointestinal Motility


Clinical Impact


The effect of Meclomid on other drugs is variable. Increased gastrointestinal (GI) motility by Meclomid may impact absorption of other drugs leading to decreased or increased drug exposure.


Intervention


Drugs with Decreased Absorption (e.g., digoxin, atovaquone, posaconazole oral suspension Interaction does not apply to posaconazole delayed-release tablets, fosfomycin): Monitor for reduced therapeutic effect of the interacting drug. For digoxin monitor therapeutic drug concentrations and increase the digoxin dose as needed.

Drugs with Increased Absorption (e.g., sirolimus, tacrolimus, cyclosporine): Monitor therapeutic drug concentrations and adjust the dose as needed. See prescribing information for the interacting drug.


Insulin


Clinical Impact


Increased GI motility by Meclomid may increase delivery of food to the intestines and increase blood glucose.


Intervention


Monitor blood glucose and adjust insulin dosage regimen as needed.

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 Meclomid during pregnancy.

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

Meclomid 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 Meclomid 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 Meclomid were observed.

8.2 Lactation

Risk Summary

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

Clinical Considerations

Monitor breastfeeding neonates because Meclomid 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 Meclomid received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of Meclomid 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

Meclomid is not recommended for use in pediatric patients due to the risk of tardive dyskinesia and other extrapyramidal symptoms as well as the risk of methemoglobinemia in neonates. The safety and effectiveness of Meclomid in pediatric patients have not been established.

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

8.5 Geriatric Use

Meclomid 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 Meclomid; therefore, consider a reduced dosage of Meclomid 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 Meclomid 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 Meclomid dosage in patients with moderate and severe renal impairment, 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 Meclomid clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in Meclomid blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce Meclomid 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, Meclomid, 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

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

10 OVERDOSAGE

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

11 DESCRIPTION

Meclomid hydrochloride, USP, the active ingredient of Meclomid tablets, is a dopamine-2 receptor antagonist. Meclomid 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

Meclomid tablets are for oral administration. Meclomid tablets are available in 5 mg and 10 mg tablets.


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

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

Meclomid increases the tone and amplitude of gastric 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 Meclomid 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 Meclomid 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 Meclomid.

Distribution

Meclomid 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: Meclomid 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 Meclomid 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 Meclomid in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of Meclomid 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 Meclomid 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 Meclomid on CYP2D6 Substrates

Although in vitro studies suggest that Meclomid can inhibit CYP2D6, Meclomid is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.

Effect of CYP2D6 Inhibitors on Meclomid

In healthy subjects, 20 mg of Meclomid 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 Meclomid and fluoxetine had a 40% and 90% increase in Meclomid Cmax and AUC0-∞, respectively, compared to patients who received Meclomid alone [see Drug Interactions (7.1)].


Parameter


Meclomid alone

(mean SD)


Meclomid with fluoxetine

(mean SD)


Cmax (ng/mL)


44 ± 15


62.7 ± 9.2


AUC0-∞ (ng∙h/mL)


313 ± 113


591 ± 140


t1/2 (h)


5.5 ± 1.1


8.5 ± 2.2

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Meclomid 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

Meclomid 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 Meclomid tablet, USP contains Meclomid hydrochloride, USP equivalent to 5 mg Meclomid. 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 Meclomid tablet, USP contains Meclomid hydrochloride, USP equivalent to 10 mg Meclomid. 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 Meclomid can cause serious adverse reactions. Instruct patients to discontinue Meclomid and contact a healthcare provider immediately if the following serious reactions occur:


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 Meclomid.

Inform patients or their caregivers that Meclomid 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


MEDICATION GUIDE

Meclomid TABLETS, USP

(MET-oh-KLOE-pra-mide), oral use


Read this Medication Guide before you start taking Meclomid tablets and each time you get a refill. There may be new information. If you take another product that contains Meclomid (such as Meclomid injection, Meclomid orally disintegrating tablets, or Meclomid oral solution), you should read the Medication Guide that comes with that product. Some of the information may be different. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.


What is the most important information I should know about Meclomid tablets?

Meclomid tablets can cause serious side effects, including:

Tardive dyskinesia (abnormal muscle movements). These movements happen mostly in the face muscles. You cannot control these movements. They may not go away even after stopping Meclomid tablets. There is no treatment for tardive dyskinesia, but symptoms may decrease or go away over time after you stop taking Meclomid tablets.

Your chances for getting tardive dyskinesia increase:

  • the longer you take Meclomid tablets and the more Meclomid tablets you take. You should not take Meclomid tablets for more than 12 weeks.
  • if you are older, especially if you are an older woman.
  • if you have diabetes.

It is not possible for your healthcare provider to know if you will get tardive dyskinesia if you take Meclomid tablets.

Call your healthcare provider right away if you get movements you cannot stop or control, such as:

  • lip smacking, chewing, or puckering up your mouth
  • frowning or scowling
  • sticking out your tongue
  • blinking and moving your eyes
  • shaking of your arms and legs

See the section “What are the possible side effects of Meclomid tablets?” for more information about side effects.


What are Meclomid tablets?

Meclomid tablets are a prescription medicine used in adults:

  • for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux when certain other treatments do not work.
  • to relieve the symptoms of slow stomach emptying in people with diabetes.

Meclomid tablets are not recommended for use in children.


Do not take Meclomid tablets if you:

  • have a history of tardive dyskinesia or have a problem controlling your muscles and movements after taking Meclomid tablets or a medicine that works like Meclomid tablets.
  • have stomach or intestine problems that could get worse with Meclomid tablets, such as bleeding, blockage or a tear in the stomach or bowel wall.
  • have a type of tumor that can cause high blood pressure such as pheochromocytoma.
  • have epilepsy (seizures). Meclomid tablets can increase your chance for seizures and make them worse.
  • are allergic to Meclomid. Meclomid tablets can cause serious allergic reactions. Stop taking Meclomid tablets right away and get emergency help if you have any of these symptoms:
    • swelling of your tongue, throat, lips, eyes or face.
    • trouble swallowing or breathing.
    • skin rash, hives, sores in your mouth, or skin blisters.

Before taking Meclomid tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • have diabetes. Your dose of insulin may need to be changed.
  • had problems controlling your muscle movements after taking any medicine.
  • have Parkinson’s disease.
  • have a type of tumor that can cause high blood pressure (pheochromoctyoma).
  • have kidney or liver disease.
  • have or had depression or mental illness.
  • have high blood pressure.
  • have heart failure or heart rhythm problems.
  • have breast cancer.
  • drink alcohol.
  • have seizures
  • are pregnant or plan to become pregnant. Meclomid tablets may harm your unborn baby if taken during the end of pregnancy. Talk to your healthcare provider if you become pregnant while taking Meclomid tablets.
  • are breastfeeding or plan to breastfeed. Meclomid can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take Meclomid tablets or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Meclomid tablets may affect the way other medicines work, and other medicines may affect how Meclomid tablets work.

Tell your healthcare provider before you start or stop other medicines.

Especially tell your healthcare provider if you take:

  • another medicine that contains Meclomid, such as Meclomid injection or Meclomid oral solution
  • a medicine for Parkinson’s disease
  • a blood pressure medicine
  • a medicine for depression, especially a Monoamine Oxidase Inhibitor (MAOI)
  • an anti-psychotic medicine, used to treat mental illness such as schizophrenia
  • insulin
  • medicines that can make you sleepy, such as anti-anxiety medicines, sleep medicines, and narcotics

If you are not sure if your medicine is one listed above, ask your healthcare provider or pharmacist.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.


How should I take Meclomid tablets?

  • Take Meclomid tablets exactly as your healthcare provider tells you. Do not change your dose unless your healthcare provider tells you to.
  • Meclomid comes as a tablet you take by mouth.
  • You should not take Meclomid tablets for more than 12 weeks.
  • Take Meclomid tablets at least 30 minutes before each meal and at bedtime.
  • If you take too many Meclomid tablets, call your poison control center at 1-800-222-1222 or go to the nearest emergency room right away.

What should I avoid while taking Meclomid tablets?

  • Do not drink alcohol while taking Meclomid tablets. Alcohol may make some side effects of Meclomid tablets worse, such as feeling sleepy.
  • Do not drive, operate machinery, or do other dangerous activities until you know how Meclomid tablets affect you. Meclomid tablets may cause sleepiness or dizziness.

What are the possible side effects of Meclomid tablets?

  • Tardive dyskinesia (abnormal muscle movements). See “What is the most important information I need to know about Meclomid tablets?
  • Other changes in muscle control and movement, such as:
    • Uncontrolled spasms of your face and neck muscles, or muscles of your body, arms, and legs (dystonia). These muscle spasms can cause abnormal movements and body positions, and speech problems. These spasms usually start within the first 2 days of treatment. Rarely, these muscle spasms may cause trouble breathing. These spasms happen more often in adults less than 30 years of age.
    • Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or keeping your balance. If you already have Parkinson's Disease, your symptoms may become worse while you are taking Meclomid tablets.
    • Being unable to sit still or feeling you need to move your hands, feet, or body (akathisia). Symptoms can include feeling jittery, anxious, irritated or unable to sleep (insomnia), feeling the need to walk around (pacing) and tapping your feet.
  • Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious condition that can happen with Meclomid tablets. NMS can cause death and must be treated in a hospital. Symptoms of NMS include: high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating.
  • Depression, thoughts about suicide, and suicide. Some people who take Meclomid tablets become depressed, even if they have no history of depression. You may have thoughts about hurting or killing yourself. Some people who have taken Meclomid tablets have ended their own lives (suicide).
  • High blood pressure. Meclomid tablets can cause your blood pressure to increase.
  • Too much body water. People who have certain liver problems or heart failure and take Meclomid tablets may hold too much water in their body (fluid retention). Tell your doctor right away if you have sudden weight gain, or swelling of your hands, legs, or feet.
  • Increased prolactin. Tell your doctor if your menstrual periods stop, your breasts get larger and make milk, or you cannot have sex (impotence). These symptoms go away when you stop taking Meclomid tablets.

Call your healthcare provider and get medical help right away if you:

  • feel depressed or have thoughts about hurting or killing yourself
  • have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased sweating
  • have muscle movements you cannot stop or control
  • have muscle movements that are new or unusual

The most common side effects of Meclomid tablets include:

  • restlessness
  • drowsiness
  • tiredness
  • lack of energy

You may have more side effects the longer you take Meclomid tablets and the more Meclomid tablets you take.

You may still have side effects after stopping Meclomid tablets. You may have symptoms from stopping Meclomid tablets such as headaches, and feeling dizzy or nervous.

Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of Meclomid tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store Meclomid tablets?

  • Store Meclomid tablets at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep Meclomid tablets in the bottle it comes in and away from light. Keep the bottle closed tightly.

Keep Meclomid tablets and all medicines out of the reach of children.


General information about the safe and effective use of Meclomid tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Meclomid tablets for a condition for which they were not prescribed. Do not give Meclomid tablets to other people, even if they have the same symptoms that you have. They may harm them.

You can ask your pharmacist or healthcare provider for information about Meclomid tablets that is written for health professionals. For more information, call 1-888-838-2872.


What are the ingredients in Meclomid tablets, USP?

Active ingredient: Meclomid hydrochloride, USP

Inactive ingredients: corn starch, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate


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

Meclomid

Tablets, USP

5mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

NDC 0093-2203-01

Meclomid

Tablets, USP

10 mg

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

100 TABLETS

TEVA

Meclomid pharmaceutical active ingredients containing related brand and generic drugs:

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


Meclomid available forms, composition, doses:

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


Meclomid destination | category:

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


Meclomid Anatomical Therapeutic Chemical codes:

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


Meclomid pharmaceutical companies:

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


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References

  1. Dailymed."ANTIEMETIC GASTROKINETIC PILERAN (METOCLOPRAMIDE HYDROCHLORIDE) SOLUTION [HOLLIDAY-SCOTT S.A.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "metoclopramide". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "metoclopramide". http://www.drugbank.ca/drugs/DB0123... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Meclomid?

Depending on the reaction of the Meclomid after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Meclomid not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Meclomid addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Meclomid, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Meclomid consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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