Memantine and Donepezil Hydrochlorides Extended-release

MEMANTINE AND DONEPEZIL HYDROCHLORIDES EXTENDED-RELEASE- memantine hydrochloride and donepezil hydrochloride capsule, extended release
Amneal Pharmaceuticals LLC

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.

2 DOSAGE AND ADMINISTRATION

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 and donepezil hydrochlorides extended-release 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 to 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 14 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.

3 DOSAGE FORMS AND STRENGTHS

Memantine and donepezil hydrochlorides extended-release capsules:

  • 14 mg memantine hydrochloride extended-release/10 mg donepezil hydrochloride capsules: Two-piece hard gelatin capsules with green opaque cap and green opaque body filled with white to off-white pellets. Imprinted in white ink AN on the cap and imprinted in white ink 1248 on the body.
  • 28 mg memantine hydrochloride extended-release/10 mg donepezil hydrochloride capsules: Two-piece hard gelatin capsules with yellow opaque cap and yellow opaque body filled with white to off-white pellets. Imprinted in black ink AN on the cap and imprinted in black ink 1247 on the body.

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.

5 WARNINGS AND PRECAUTIONS

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 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, 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed below and elsewhere in the labeling.

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