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DRUGS & SUPPLEMENTS
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How often in a day do you take medicine? How many times? |
Acumel tablets are indicated for the:
Acumel 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 ) ].
Acumel tablets are indicated for the:
Limitations of Use:
Acumel 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)
Gastroesophageal Reflux
Acute and Recurrent Diabetic Gastroparesis (2.3)
Dosage Adjustment in Specific Populations (2.2, 2.3)
Avoid treatment with Acumel 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)].
Acumel 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 Acumel 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 Acumel 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 mg | |
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 |
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 Acumel 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 Acumel tablets, consider starting therapy with Acumel injection given intramuscularly or intravenously for up to 10 days. After patients are able to take oral therapy, switch to Acumel 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 mg | |
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 |
Tablets:
Tablets: 5 mg and 10 mg Acumel (3)
Acumel is contraindicated:
Acumel 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 Acumel for longer than 12 weeks and reduce the dosage in elderly patients [see Dosage and Administration (2.2, 2.3)].
Discontinue Acumel 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 Acumel is withdrawn.
Acumel 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. Acumel is contraindicated in patients with a history of TD [see Contraindications (4)]. Avoid Acumel in patients receiving other drugs that are likely to cause TD (e.g., antipsychotics).
In addition to TD, Acumel may cause other extrapyramidal symptoms, parkinsonian symptoms, and motor restlessness. Advise patients to seek immediate medical attention if such symptoms occur and to discontinue Acumel.
Acumel may cause a potentially fatal symptom complex called neuroleptic malignant syndrome (NMS). NMS has been reported in association with Acumel overdosage and concomitant treatment with another drug associated with NMS. Avoid Acumel 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:
Depression has occurred in metoclopramide-treated patients with and without a history of depression. Symptoms have included suicidal ideation and suicide. Avoid Acumel use in patients with a history of depression.
Acumel may elevate blood pressure. In one study in hypertensive patients, intravenously administered Acumel 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. Acumel is contraindicated in patients with pheochromocytoma or other catecholamine-releasing paragangliomas [see Contraindications (4)]. Discontinue Acumel in any patient with a rapid rise in blood pressure.
Because Acumel 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 Acumel if any of these adverse reactions occur.
As with other dopamine D2 receptor antagonists, Acumel 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 Acumel.
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 ].
Acumel 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 Acumel or the interacting drug, depending on the importance of the drug to the patient [see Drug Interactions (7.1)].
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 Acumel. 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 Acumel four times daily) were restlessness, drowsiness, fatigue, and lassitude. In general, the incidence of adverse reactions correlated with the dosage and duration of Acumel administration.
Adverse reactions, especially those involving the nervous system, occurred after stopping Acumel 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 Acumel 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.
Table 3 displays the effects of other drugs on Acumel.
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 Acumel; risk of exacerbation of extrapyramidal symptoms [see Clinical Pharmacology (12.3)]. |
Intervention | Reduce the Acumel 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 Acumel 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 Acumel. |
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 Acumel due to opposing effects on dopamine. |
Intervention | Monitor for reduced therapeutic effect. |
Examples | apomorphine, bromocriptine, cabergoline, levodopa, pramipexole, ropinirole, and rotigotine |
Table 4 displays the effects of Acumel on other drugs.
Dopaminergic Agonists and Drugs Increasing Dopamine Concentrations | |
Clinical Impact | Opposing effects of Acumel 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 | Acumel 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 Acumel on other drugs is variable. Increased gastrointestinal (GI) motility by Acumel 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 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 Acumel may increase delivery of food to the intestines and increase blood glucose. |
Intervention | Monitor blood glucose and adjust insulin dosage regimen as needed. |
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 Acumel during pregnancy.
There are potential risks to the neonate following exposure in utero to Acumel during delivery [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed with oral administration of Acumel 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
Acumel 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 Acumel 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 Acumel were observed.
Risk Summary
Limited published data report the presence of Acumel in human milk in variable amounts. Breastfed infants exposed to Acumel have experienced gastrointestinal adverse reactions, including intestinal discomfort and increased intestinal gas formation [see Data]. Acumel 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 Acumel and any potential adverse effects on the breastfed child from Acumel or from the underlying maternal condition.
Clinical Considerations
Monitor breastfeeding neonates because Acumel 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 Acumel received by the breastfed infant was less than 10% of the maternal weight-adjusted dose. In one study, the estimated daily amount of Acumel 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.
Acumel 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 Acumel in pediatric patients have not been established.
Dystonias and other extrapyramidal symptoms associated with Acumel 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 Acumel use in neonates [see Use in Specific Populations (8.8)].
Acumel 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 Acumel; therefore, consider a reduced dosage of Acumel in elderly patients [see Boxed Warning, Dosage and Administration (2.2, 2.3), Warnings and Precautions (5.1)].
The clearance of Acumel 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 Acumel 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)].
Patients with severe hepatic impairment (Child-Pugh C) have reduced systemic Acumel clearance (by approximately 50%) compared to patients with normal hepatic function. The resulting increase in Acumel blood concentrations increases the risk of adverse reactions. There is no pharmacokinetic data in patients with moderate hepatic impairment (Child-Pugh B). Reduce Acumel 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, Acumel, 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.
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)].
Acumel is a substrate of CYP2D6. The elimination of Acumel 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 Acumel [see Clinical Pharmacology (12.3)]. Reduce the Acumel dosage in patients who are poor CYP2D6 metabolizers [see Dosage and Administration (2.2, 2.3)].
Manifestations of Acumel overdosage included drowsiness, disorientation, extrapyramidal reactions, other adverse reactions associated with Acumel use (including, e.g., methemoglobinemia), and sometimes death. Neuroleptic malignant syndrome (NMS) has been reported in association with Acumel 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 Acumel 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 Acumel.
Acumel hydrochloride, USP, the active ingredient of Acumel tablets, is a dopamine-2 receptor antagonist. Acumel 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
Acumel tablets are for oral administration. Acumel 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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Acumel stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. The exact mechanism of action of Acumel 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 Acumel on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.
Acumel 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.
Gastroesophageal Reflux
In patients with gastroesophageal reflux and low lower esophageal sphincter pressure (LESP), single oral doses of Acumel 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.
Absorption
Relative to an intravenous dose of 20 mg, the absolute bioavailability of oral Acumel 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 Acumel.
Distribution
Acumel 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: Acumel 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 Acumel 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 Acumel in patients with moderate to severe renal impairment was about 2-fold the AUC in subjects with normal renal function. The AUC of Acumel 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 Acumel 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 Acumel on CYP2D6 Substrates
Although in vitro studies suggest that Acumel can inhibit CYP2D6, Acumel is unlikely to interact with CYP2D6 substrates in vivo at therapeutically relevant concentrations.
Effect of CYP2D6 Inhibitors on Acumel
In healthy subjects, 20 mg of Acumel 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 Acumel and fluoxetine had a 40% and 90% increase in Acumel Cmax and AUC0-∞, respectively, compared to patients who received Acumel alone [see Drug Interactions (7.1)].
Parameter | Acumel alone (mean SD) | Acumel 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 |
Carcinogenesis
A 77-week study was conducted in rats with oral Acumel doses up to 40 mg/kg/day (about six times the maximum recommended human dose on body surface area basis). Acumel elevated prolactin levels and the elevation persisted during chronic administration. An increase in mammary neoplasms was found in rodents after chronic administration of Acumel [see Warnings and Precautions (5.7)]. In a rat model for assessing the tumor promotion potential, a 2-week oral treatment with Acumel 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
Acumel 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
Acumel 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.
Each white, round, unscored, debossed “TV” on one side and “2204” on the other side, compressed Acumel tablet, USP contains Acumel hydrochloride, USP equivalent to 5 mg Acumel. 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 Acumel tablet, USP contains Acumel hydrochloride, USP equivalent to 10 mg Acumel. 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.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients or their caregivers that Acumel can cause serious adverse reactions. Instruct patients to discontinue Acumel 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 Acumel.
Inform patients or their caregivers that Acumel 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 Acumel TABLETS, USP (MET-oh-KLOE-pra-mide), oral use |
Read this Medication Guide before you start taking Acumel tablets and each time you get a refill. There may be new information. If you take another product that contains Acumel (such as Acumel injection, Acumel orally disintegrating tablets, or Acumel 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 Acumel tablets? Acumel 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 Acumel tablets. There is no treatment for tardive dyskinesia, but symptoms may decrease or go away over time after you stop taking Acumel tablets. Your chances for getting tardive dyskinesia increase:
It is not possible for your healthcare provider to know if you will get tardive dyskinesia if you take Acumel tablets. Call your healthcare provider right away if you get movements you cannot stop or control, such as:
See the section “What are the possible side effects of Acumel tablets?” for more information about side effects. |
What are Acumel tablets? Acumel tablets are a prescription medicine used in adults:
Acumel tablets are not recommended for use in children. |
Do not take Acumel tablets if you:
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Before taking Acumel tablets, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Acumel tablets may affect the way other medicines work, and other medicines may affect how Acumel tablets work. Tell your healthcare provider before you start or stop other medicines. Especially tell your healthcare provider if you take:
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 Acumel tablets?
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What should I avoid while taking Acumel tablets?
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What are the possible side effects of Acumel tablets?
Call your healthcare provider and get medical help right away if you:
The most common side effects of Acumel tablets include:
You may have more side effects the longer you take Acumel tablets and the more Acumel tablets you take. You may still have side effects after stopping Acumel tablets. You may have symptoms from stopping Acumel 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 Acumel 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 Acumel tablets?
Keep Acumel tablets and all medicines out of the reach of children. |
General information about the safe and effective use of Acumel tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Acumel tablets for a condition for which they were not prescribed. Do not give Acumel 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 Acumel tablets that is written for health professionals. For more information, call 1-888-838-2872. |
What are the ingredients in Acumel tablets, USP? Active ingredient: Acumel 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
Acumel
Tablets, USP
5mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
Rx only
100 TABLETS
TEVA
NDC 0093-2203-01
Acumel
Tablets, USP
10 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
Rx only
100 TABLETS
TEVA
Depending on the reaction of the Acumel after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Acumel 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 Acumel 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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The information was verified by Dr. Rachana Salvi, MD Pharmacology