MEMANTINE AND DONEPEZIL HYDROCHLORIDES

Brand names: MEMANTINE AND DONEPEZIL HYDROCHLORIDES

Warnings

5 WARNINGS AND PRECAUTIONS • Memantine and donepezil hydrochlorides extended-release capsules are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. ( 5.1 ) • Memantine and donepezil hydrochlorides extended-release capsules may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block. ( 5.2 ) • Monitor patients for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers. ( 5.3 ) • Memantine and donepezil hydrochlorides extended-release capsules can cause diarrhea, nausea, and vomiting. ( 5.4 ) • Memantine and donepezil hydrochlorides extended-release capsules may cause bladder outflow obstructions. ( 5.5 ) • Conditions that raise urine pH may decrease the urinary elimination of memantine, resulting in increased plasma levels of memantine. ( 5.5 , 7.1 ) 5.1 Anesthesia Donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules. 5.3 Peptic Ulcer Disease and Gastrointestinal Bleeding Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Clinical studies of donepezil hydrochloride in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Patients treated with memantine and donepezil hydrochlorides extended-release capsules should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). 5.4 Nausea and Vomiting Donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, when initiated, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil hydrochloride, patients should be observed closely at the initiation of treatment. 5.5 Genitourinary Conditions Although not observed in clinical trials of donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, cholinomimetics may cause bladder outflow obstruction. Conditions that raise urine pH may decrease the urinary elimination of memantine, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, resulting in increased plasma levels of memantine [see Drug Interactions ( 7.1 )]. 5.6 Seizures Cholinomimetics, including donepezil hydrochloride, an active ingredient in memantine and donepezil hydrochlorides extended-release capsules, are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease. 5.7 Pulmonary Conditions Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Contraindications

4 CONTRAINDICATIONS Memantine and donepezil hydrochlorides extended-release capsules are contraindicated in patients with known hypersensitivity to memantine hydrochloride, donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation. Memantine and donepezil hydrochlorides extended-release capsules are contraindicated in patients with known hypersensitivity to memantine hydrochloride, donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation. ( 4 )

Overdose

10 OVERDOSAGE Memantine hydrochloride and donepezil hydrochloride are the two active ingredients of memantine and donepezil hydrochlorides extended-release capsules. No specific antidote for memantine hydrochloride overdose is known; however, elimination of memantine can be increased by acidification of the urine. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride overdose. In managing cases of overdose, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for the latest recommendation. In general, supportive measures should be utilized, and treatment should be symptomatic. Memantine Hydrochloride Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered. One patient participating in a memantine hydrochloride extended-release clinical trial unintentionally took 112 mg of memantine hydrochloride extended-release daily for 31 days and experienced elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count. No fatalities have been noted with overdoses of memantine alone. A fatal outcome has very rarely been reported when memantine has been ingested as part of overdosing with multiple drugs; in those instances, the relationship between memantine and a fatal outcome has been unclear. Donepezil Hydrochloride Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation, and lower body surface temperature.

Drug interactions

7 DRUG INTERACTIONS • Combined use with NMDA antagonists: use with caution. ( 7.2 ) • Memantine and donepezil hydrochlorides extended-release capsules may interfere with anticholinergic medications. ( 7.4 ) • Concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists may lead to synergistic effect. ( 7.5 ) 7.1 Use of Memantine with 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 reactions. 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 of Memantine 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. 7.3 Effect of Other Drugs on the Metabolism of Donepezil Inhibitors of CYP3A4 (e.g., ketoconazole) and CYP2D6 (e.g., quinidine), inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. Inducers of CYP3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of donepezil. 7.4 Use of Donepezil with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors, including donepezil hydrochloride, have the potential to interfere with the activity of anticholinergic medications. 7.5 Use of Donepezil with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors, including donepezil hydrochloride, are given concurrently with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol.

Uses

1 INDICATIONS AND USAGE Memantine and donepezil hydrochlorides extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on 10 mg of donepezil hydrochloride once daily. Memantine and donepezil hydrochlorides extended-release capsules are a combination of memantine hydrochloride, an NMDA receptor antagonist, and donepezil hydrochloride, an acetylcholinesterase inhibitor, indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients stabilized on 10 mg of donepezil hydrochloride once daily. ( 1 )

Dosage forms & strengths

CAPSULE, EXTENDED RELEASE
MEMANTINE HYDROCHLORIDE 21 mg/1 DONEPEZIL HYDROCHLORIDE 10 mg/1

2 DOSAGE AND ADMINISTRATION • For patients on donepezil hydrochloride 10 mg only, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg, taken once daily in the evening. The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg/10 mg. The minimum recommended interval between dose increases is one week. ( 2.1 ) • Patients on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched to memantine and donepezil hydrochlorides extended-release capsules 28 mg/10 mg, taken once daily in the evening. ( 2.1 ) • Memantine and donepezil hydrochlorides extended-release capsules can be taken with or without food, whole or sprinkled on applesauce; do not divide, chew, or crush. ( 2.2 ) • Severe renal impairment: the recommended maintenance dose for memantine and donepezil hydrochlorides extended-release capsules is 14 mg/10 mg once daily in the evening. ( 2.3 ) 2.1 Recommended Dosing The recommended dose of memantine and donepezil hydrochlorides extended-release capsules is 28 mg/10 mg once daily. For patients stabilized on donepezil and not currently on memantine: For patients stabilized on donepezil hydrochloride 10 mg and not currently on memantine hydrochloride, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg, taken once a day in the evening. The dose should be increased in 7 mg increments of the memantine hydrochloride component to the recommended maintenance dose of 28 mg/10 mg once daily. The minimum recommended interval between dose increases is one week. The dose should only be increased if the previous dose has been well tolerated. The maximum dose is 28 mg/10 mg once daily. For patients stabilized on both donepezil and memantine: Patients stabilized on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched to memantine and donepezil hydrochlorides extended-release capsules 28 mg/10 mg, taken once a day in the evening. Patients should start memantine and donepezil hydrochlorides extended-release capsules the day following the last dose of memantine hydrochloride and donepezil hydrochloride administered separately. If a patient misses a single dose of memantine and donepezil hydrochlorides extended-release capsules, the next dose should be taken as scheduled, without doubling up the dose. 2.2 Administration Information Memantine and donepezil hydrochlorides extended-release capsules can be taken with or without food. Memantine and donepezil hydrochlorides extended-release capsules can be taken intact or may be opened, sprinkled on applesauce, and swallowed without chewing. The entire contents of each memantine and donepezil hydrochlorides extended-release capsule should be consumed; the dose should not be divided. Except when opened and sprinkled on applesauce, as described above, memantine and donepezil hydrochlorides extended-release capsules should be swallowed whole. Memantine and donepezil hydrochlorides extended-release capsules should not be divided, chewed, or crushed. 2.3 Dosing in Patients with Severe Renal Impairment For patients stabilized on donepezil and not currently on memantine: For patients with severe renal impairment (creatinine clearance 5-29 mL/min, based on the Cockcroft-Gault equation) stabilized on donepezil hydrochloride 10 mg once daily and not currently on memantine hydrochloride, the recommended starting dose of memantine and donepezil hydrochlorides extended-release capsules is 7 mg/10 mg taken once a day in the evening. The dose should be increased to the recommended maintenance dose of 14 mg/10 mg once daily in the evening after a minimum of one week [see Use in Specific Populations ( 8.6 )] . For patients stabilized on both donepezil and memantine: Patients with severe renal impairment, stabilized on memantine hydrochloride (5 mg twice daily or 14 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily, can be switched to memantine and donepezil hydrochlorides extended-release capsules 14 mg/10 mg, taken once daily in the evening.

All identified pills

Side effects

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling. • Cardiovascular Conditions [see Warnings and Precautions ( 5.2 )] • Peptic Ulcer Disease and Gastrointestinal Bleeding [see Warnings and Precautions ( 5.3 )] • Nausea and Vomiting [see Warnings and Precautions ( 5.4 )] • Genitourinary Conditions [ see Warnings and Precautions ( 5.5 )] • Seizures [see Warnings and Precautions ( 5.6 )] • Pulmonary Conditions [see Warnings and Precautions ( 5.7 )] • The most common adverse reactions occurring at a frequency of at least 5% and greater than placebo with memantine hydrochloride extended-release 28 mg/day were headache, diarrhea, and dizziness. ( 6.1 ) • The most common adverse reactions occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, include diarrhea, anorexia, vomiting, nausea, and ecchymosis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 practice. Memantine Hydrochloride Memantine hydrochloride extended-release was evaluated in a double-blind, placebo-controlled trial in 676 patients with moderate to severe dementia of the Alzheimer's type (341 patients treated with memantine 28 mg/day dose and 335 patients treated with placebo) for a treatment period up to 24 weeks. Of the patients randomized, 236 treated with memantine 28 mg/day and 227 treated with placebo were on a stable dose of donepezil for 3 months prior to screening. Adverse Reactions Leading to Discontinuation with Memantine Hydrochloride In the placebo-controlled clinical trial of memantine hydrochloride extended-release, the proportion of patients in the memantine hydrochloride extended-release 28 mg/day dose group and in the placebo group who discontinued treatment due to adverse reactions was 10% and 6%, respectively. The most common adverse reaction in the memantine hydrochloride extended-release treated group that led to treatment discontinuation was dizziness, at a rate of 1.5%. Most Common Adverse Reactions with Memantine Hydrochloride The most common adverse reactions with memantine hydrochloride extended-release in patients with moderate to severe Alzheimer's disease, defined as those occurring at a frequency of at least 5% in the memantine hydrochloride extended-release group and at a higher frequency than placebo, were headache, diarrhea, and dizziness. Table 1 lists adverse reactions that occurred at an incidence of ≥ 2% in the memantine hydrochloride extended-release treated group and occurred at a rate greater than placebo. Table 1: Adverse reactions with memantine hydrochloride extended-release in patients with moderate to severe Alzheimer's disease Adverse Reaction Placebo (n=335) % Memantine hydrochloride extended-release 28 mg (n=341) % Gastrointestinal Disorders Diarrhea 4 5 Constipation 1 3 Abdominal pain 1 2 Vomiting 1 2 Infections and Infestations Influenza 3 4 Investigations Increased weight 1 3 Musculoskeletal and Connective Tissue Disorders Back pain 1 3 Nervous System Disorders Headache 5 6 Dizziness 1 5 Somnolence 1 3 Psychiatric Disorders Anxiety 3 4 Depression 1 3 Aggression 1 2 Renal and Urinary Disorders Urinary incontinence 1 2 Vascular Disorders Hypertension 2 4 Hypotension 1 2 Donepezil hydrochloride Adverse Reactions Leading to Discontinuation with Donepezil Hydrochloride In controlled clinical trials of donepezil hydrochloride, the rate of discontinuation due to adverse reactions for patients treated with donepezil hydrochloride was approximately 12%, compared to 7% for patients treated with placebo. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at twice or more the incidence seen with placebo, were anorexia (2%), nausea (2%), diarrhea (2%) and urinary tract infection (2%). Most Common Adverse Reactions with Donepezil Hydrochloride The most common adverse reactions reported with donepezil hydrochloride in controlled clinical trials in patients with severe Alzheimer's disease, defined as those occurring at a frequency of at least 5% in the donepezil hydrochloride group and at twice or more the placebo rate, were diarrhea, anorexia, vomiting, nausea, and ecchymosis. The most common adverse reactions reported with donepezil hydrochloride in controlled clinical trials in patients with mild to moderate Alzheimer's disease were insomnia, muscle cramp, and fatigue. Table 2 lists adverse reactions that occurred at an incidence of ≥ 2% in the donepezil hydrochloride group and at a rate greater than placebo in controlled trials in patients with severe Alzheimer's disease. Table 2: Adverse reactions with donepezil hydrochloride in patients with severe Alzheimer’s disease Body System/Adverse Event Placebo (n=392) % Donepezil hydrochloride 10 mg/day (n=501) % Percent of Patients with any Adverse Event 73 81 Body as a Whole Accident 12 13 Infection 9 11 Headache 3 4 Pain 2 3 Back pain 2 3 Fever 1 2 Chest pain <1 2 Cardiovascular System Hypertension 2 3 Hemorrhage 1 2 Syncope 1 2 Digestive System Diarrhea 4 10 Vomiting 4 8 Anorexia 4 8 Nausea 2 6 Hemic and Lymphatic System Ecchymosis 2 5 Metabolic and Nutritional Systems Increased creatine phosphokinase 1 3 Dehydration 1 2 Hyperlipemia <1 2 Nervous System Insomnia 4 5 Hostility 2 3 Nervousness 2 3 Hallucinations 1 3 Somnolence 1 2 Dizziness 1 2 Depression 1 2 Confusion 1 2 Emotional lability 1 2 Personality disorder 1 2 Skin and Appendages Eczema 2 3 Urogenital System Urinary incontinence 1 2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of memantine hydrochloride and donepezil hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Memantine Hydrochloride Acute renal failure, agranulocytosis, cardiac failure congestive, hepatitis, leukopenia (including neutropenia), pancreatitis, pancytopenia, Stevens Johnson Syndrome, suicidal ideation, thrombocytopenia, and thrombotic thrombocytopenic purpura. Donepezil Hydrochloride Abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.

Official source

DailyMed