FDA Label for Memantine Hydrochloride

Other

Memantine hydrochloride is indicated for the treatment of moderate to severe dementia of the Alzheimer's type.

The recommended starting dose of memantine hydrochloride tablet is 5 mg once daily. The dose should be increased in 5 mg increments to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg as separate doses), and 20 mg/day (10 mg twice daily). The minimum recommended interval between dose increases is one week. The dosage shown to be effective in controlled clinical trials is 20 mg/day.

Memantine hydrochloride tablets can be taken with or without food. If a patient misses a single dose of memantine hydrochloride tablets, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take memantine hydrochloride tablet for several days, dosing may need to be resumed at lower doses and retitrated as described above.

Special Populations

Renal Impairment

A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL/min based on the Cockroft-Gault equation).

Hepatic Impairment

Memantine hydrochloride tablets should be administered with caution to patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].

Memantine hydrochloride tablet USP, 5 mg: Tan coloured, capsule-shaped, biconvex, film-coated tablets, debossed with 'LU' on one side and 'W01' on the other side.

Memantine hydrochloride tablet USP, 10 mg: Grey coloured, capsule shaped, biconvex, film-coated tablets, debossed with 'LU' on one side and 'W02' on the other side.

Memantine hydrochloride tablet is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.

Patient Information

Memantine Hydrochloride (me-MAN-teen HYE-droe-KLOR-ide)

Tablets USP

Read this Patient Information that comes with memantine hydrochloride tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is Memantine Hydrochloride?

Memantine hydrochloride is a prescription medicine used for the treatment of moderate to severe dementia in people with Alzheimer's disease. Memantine hydrochloride belongs to a class of medicines called NMDA (N-methyl-D-aspartate) inhibitors.

It is not known if memantine hydrochloride is safe and effective in children.

Who should not take Memantine Hydrochloride Tablets?

Do not take memantine hydrochloride tablets if you are allergic to memantine or any of the ingredients in memantine hydrochloride tablets. See the end of this leaflet for a complete list of ingredients in memantine hydrochloride tablets.

What should I tell my doctor before taking Memantine Hydrochloride Tablets?

Before you take memantine hydrochloride tablets, tell your doctor if you:

• have or have had seizures
• have or have had problems passing urine
• have or have had bladder or kidney problems
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if memantine hydrochloride will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if memantine hydrochloride passes into your breast milk. You and your doctor should decide if you will take memantine hydrochloride or breastfeed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Taking memantine hydrochloride tablets with certain other medicines may affect each other. Taking memantine hydrochloride tablets with other medicines can cause serious side effects.

Especially tell your doctor if you take:

• other NMDA antagonists such as amantadine, ketamine, and dextromethorphan
• medicines that make your urine alkaline such as carbonic anhydrase inhibitors and sodium bicarbonate

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

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

How should I take Memantine Hydrochloride Tablet?

• Your doctor will tell you how much memantine hydrochloride tablets to take and when to take it.
• Your doctor may change your dose if needed.
• Memantine hydrochloride tablets can be taken with food or without food.
• Do not use any tablets of memantine hydrochloride that are damaged or show signs of tampering.
• If you forget to take one dose of memantine hydrochloride tablet, do not double up on the next dose. You should take only the next dose as scheduled.
• If you have forgotten to take memantine hydrochloride tablets for several days, you should not take the next dose until you talk to your doctor.
• If you take too much memantine hydrochloride tablets, call your doctor or poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.

What are the possible side effects of Memantine Hydrochloride Tablets?

Memantine Hydrochloride Tablets may cause side effects, including:

The most common side effects of memantine hydrochloride tablets include:

• dizziness
• headache
• confusion
• constipation

These are not all the possible side effects of memantine hydrochloride tablets. For more information, ask your doctor or pharmacist.

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 Memantine Hydrochloride Tablets?

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

What are the ingredients in Memantine Hydrochloride Tablets?

Active ingredients: memantine hydrochloride

Inactive ingredients: croscarmellose sodium, magnesium stearate, silicified microcrystalline cellulose and talc. In addition the following inactive ingredients are also present as components of the film coat: hypromellose, titanium dioxide, polyethylene glycol, FD&C Yellow No. 6 Aluminium Lake and FD&C Blue No. 2 Aluminium Lake (5 mg tablets), and hypromellose, titanium dioxide, polyethylene glycol and iron oxide black (10 mg tablets).

Keep Memantine Hydrochloride Tablets and all medicines out of the reach of children.

General information about the safe and effective use of Memantine Hydrochloride Tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take memantine hydrochloride tablets for a condition for which it was not prescribed. Do not give memantine hydrochloride tablets to other people, even if they have the same condition. It may harm them.

This Patient Information leaflet summarizes the most important information about memantine hydrochloride tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about memantine hydrochloride tablets that was written for healthcare professionals.

For more information, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or www.lupinpharmaceuticals.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

This Patient Information has been approved by the U.S. Food and Drug Administration.

5.1 Genitourinary Conditions

Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see DRUG INTERACTIONS (7.1)].

6.1 Clinical Trials Experience

Memantine hydrochloride was evaluated in eight double-blind placebo-controlled trials involving a total of 1862 dementia (Alzheimer's disease, vascular dementia) patients (940 patients treated with memantine hydrochloride and 922 patients treated with placebo) for a treatment period up to 28 weeks.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Events Leading to Discontinuation

In placebo-controlled trials in which dementia patients received doses of memantine hydrochloride up to 20 mg/day, the likelihood of discontinuation because of an adverse reaction was the same in the memantine hydrochloride group (10.1%) as in the placebo group (11.5%). No individual adverse reaction was associated with the discontinuation of treatment in 1% or more of memantine hydrochloride-treated patients and at a rate greater than placebo.

Most Common Adverse Reactions

In double-blind placebo-controlled trials involving dementia patients, the most common adverse reactions (incidence ≥ 5% and higher than placebo) in patients treated with memantine hydrochloride were dizziness, headache, confusion and constipation. Table 1 lists all adverse reactions that occurred in at least 2% of patients treated with memantine hydrochloride and at an incidence greater than placebo.

The overall profile of adverse reactions and the incidence rates for individual adverse reactions in the subpopulation of patients with moderate to severe Alzheimer's disease were not different from the profile and incidence rates described above for the overall dementia population.

Seizures

Memantine hydrochloride has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine hydrochloride, seizures occurred in 0.2% of patients treated with memantine hydrochloride and 0.5% of patients treated with placebo.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of memantine. 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. These reactions include:

Blood and Lymphatic System Disorders - agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombotic thrombocytopenic purpura.

Cardiac Disorders - cardiac failure congestive.

Gastrointestinal Disorders - pancreatitis.

Hepatobiliary Disorders - hepatitis.

Psychiatric Disorders - suicidal ideation.

Renal and Urinary Disorders - acute renal failure (including increased creatinine and renal insufficiency).

Skin Disorders - Stevens Johnson syndrome.

7.1 Drugs That Make The Urine Alkaline

The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.

7.2 Use With Other N-Methyl-D-Aspartate (Nmda) Antagonists

The combined use of memantine hydrochloride with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of memantine in pregnant women. Memantine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose [MRHD] on a mg/m² basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the postpartum period. The no-effect dose for these effects was 6 mg/kg, which is 3 times the MRHD on a mg/m² basis.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine hydrochloride is administered to a nursing mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

The majority of people with Alzheimer's disease are 65 years and older. In the clinical studies of memantine hydrochloride the mean age of patients was approximately 76; over 90% of patients were 65 years and older, 60% were 75 years and older, and 12% were at or above 85 years of age. The efficacy and safety data presented in the clinical trial sections were obtained from these patients. There were no clinically meaningful differences in most adverse events reported by patient groups ≥65 years old and <65 year old.

8.6 Renal Impairment

No dosage adjustment is needed in patients with mild or moderate renal impairment. A dosage reduction is recommended in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION (2) and CLINICAL PHARMACOLOGY (12.3)].

8.7 Hepatic Impairment

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine hydrochloride should be administered with caution to patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION (2) and CLINICAL PHARMACOLOGY (12.3)].

12.1 Mechanism Of Action

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.

12.2 Pharmacodynamics

Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca²⁺, Na⁺ or K⁺ channels. Memantine also showed antagonistic effects at the 5HT₃ receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

12.3 Pharmacokinetics

Absorption

Following oral administration memantine is highly absorbed with peak concentrations reached in about 3 to 7 hours. Memantine has linear pharmacokinetics over the therapeutic dose range. Food has no effect on the absorption of memantine.

Distribution

The mean volume of distribution of memantine is 9 to 11 L/kg and the plasma protein binding is low (45%).

Metabolism

Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.

Elimination

Memantine is excreted predominantly (about 48%) unchanged in urine and has a terminal elimination half-life of about 60 to 80 hours.

The remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitrosodeaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.

Pharmacokinetics in Specific Populations

Gender:

Following multiple dose administration of memantine hydrochloride 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.

Elderly:

The pharmacokinetics of memantine hydrochloride in young and elderly subjects are similar.

Renal Impairment:

Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, >50 to 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 to 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 to 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC_0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.

No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment [see DOSAGE AND ADMINISTRATION (2)].

Hepatic Impairment:

Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on C_max and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.

Drug-Drug Interactions:

Use with Cholinesterase Inhibitors

Coadministration of memantine with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. Furthermore, memantine did not affect AChE inhibition by donepezil. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with a combination of memantine hydrochloride and donepezil was similar to that of donepezil alone.

Effect of Memantine Hydrochloride on the Metabolism of Other Drugs

In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.

Pharmacokinetic studies evaluated the potential of memantine for interaction with warfarin, and buproprion. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate buproprion or its metabolite hydroxybuproprion. Furthermore, memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin as assessed by the prothrombin INR.

Effect of Other Drugs on Memantine

Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the metabolism of memantine.

Drugs Eliminated via Renal Mechanisms

Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of memantine hydrochloride and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance^® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance^®, indicating the absence of a pharmacodynamic interaction.

Drugs Highly Bound to Plasma Proteins

Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (10 times the maximum recommended human dose [MRHD] on a mg/m² basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (20 and 10 times the MRHD on a mg/m² basis, respectively) through 128 weeks.

Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (9 times the MRHD on a mg/m² basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

13.2 Animal Toxicology And/Or Pharmacology

Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose of 20 mg/day on a mg/m² basis.

In acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.

The relevance of these findings to humans is unknown.