WARNINGS
ANESTHESIA
Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.
CARDIOVASCULAR CONDITIONS
Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. These actions may be particularly important to patients with supraventricular cardiac conduction disorders or to patients taking other drugs concomitantly that significantly slow heart rate. Postmarketing surveillance of marketed anticholinesterase inhibitors has shown, however, that bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities. Therefore all patients should be considered at risk for adverse effects on cardiac conduction.
In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but rarely led to treatment discontinuation. The overall frequency of this event was 2-3% for galantamine doses up to 24 mg/day compared with <1% for placebo. No increased incidence of heart block was observed at the recommended doses.
Patients treated with galantamine up to 24 mg/day using the recommended dosing schedule showed a dose-related increase in risk of syncope (placebo 0.7% [2/286]; 4 mg BID 0.4% [3/692]; 8 mg BID 1.3% [7/552]; 12 mg BID 2.2% [6/273]).
GASTROINTESTINAL CONDITIONS
Through their primary action, cholinomimetics may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those with an increased risk for developing ulcers, e.g., those with a history of ulcer disease or patients using concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Clinical studies of REMINYL® (galantamine hydrobromide) have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
REMINYL®, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss (see ADVERSE REACTIONS).
GENITOURINARY
Although this was not observed in clinical trials with REMINYL®, cholinomimetics may cause bladder outflow obstruction.
NEUROLOGICAL CONDITIONS
Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease. In clinical trials, there was no increase in the incidence of convulsions with REMINYL® compared to placebo.
PULMONARY CONDITIONS
Because of its cholinomimetic action, galantamine should be prescribed with care to patients with a history of severe asthma or obstructive pulmonary disease.
PRECAUTIONS
Information for Patients and Caregivers: Caregivers should be instructed in the recommended administration (twice per day, preferably with morning and evening meal) and dose escalation (dose increases should follow minimum of four weeks at prior dose).
Patients and caregivers should be advised that the most frequent adverse events associated with use of the drug can be minimized by following the recommended dosage and administration.
Patients and caregivers should be advised to ensure adequate fluid intake during treatment. If therapy has been interrupted for several days or longer, the patient should be restarted at the lowest dose and the dose escalated to the current dose.
Caregivers should be instructed in the correct procedure for administering REMINYL® (galantamine hydrobromide) Oral Solution. In addition, they should be informed of the existence of an Instruction Sheet (included with the product) describing how the solution is to be administered. They should be urged to read this sheet prior to administering REMINYL® Oral Solution. Caregivers should direct questions about the administration of the solution to either their physician or pharmacist.
SPECIAL POPULATIONS
HEPATIC IMPAIRMENT
In patients with moderately impaired hepatic function, dose titration should proceed cautiously (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). The use of REMINYL® in patients with severe hepatic impairment is not recommended.
RENAL IMPAIRMENT
In patients with moderately impaired renal function, dose titration should proceed cautiously (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). In patients with severely impaired renal function (CLcr< 9 mL/min) the use of REMINYL® is not recommended.
DRUG-DRUG INTERACTIONS
USE WITH ANTICHOLINERGICS
REMINYL® has the potential to interfere with the activity of anticholinergic medications.
USE WITH CHOLINOMIMETICS AND OTHER CHOLINESTERASE INHIBITORS
A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.
A) EFFECT OF OTHER DRUGS ON GALANTAMINE
In vitro
CYP3A4 and CYP2D6 are the major enzymes involved in the metabolism of galantamine. CYP3A4 mediates the formation of galantamine-N-oxide; CYP2D6 leads to the formation of O-desmethyl-galantamine. Because galantamine is also glucuronidated and excreted unchanged, no single pathway appears predominant. In vivo Cimetidine and Ranitidine: Galantamine was administered as a single dose of 4 mg on day 2 of a 3-day treatment with either cimetidine (800 mg daily) or ranitidine (300 mg daily). Cimetidine increased the bioavailability of galantamine by approximately 16%. Ranitidine had no effect on the PK of galantamine. Ketoconazole: Ketoconazole, a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6, at a dose of 200 mg BID for 4 days, increased the AUC of galantamine by 30%. Erythromycin: Erythromycin, a moderate inhibitor of CYP3A4, at a dose of 500 mg QID for 4 days, affected the AUC of galantamine minimally (10% increase).
Paroxetine: Paroxetine, a strong inhibitor of CYP2D6, at 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%.
B) EFFECT OF GALANTAMINE ON OTHER DRUGS
In vitro
Galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 or CYP2E1. This indicates that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. In vivo Warfarin: Galantamine at 24 mg/day had no effect on the pharmacokinetics of R-and-S-warfarin (25 mg single dose) or on the prothrombin time. The protein binding of warfarin was unaffected by galantamine. Digoxin: Galantamine at 24 mg/day had no effect on the steady-state pharmacokinetics of digoxin (0.375 mg once daily) when they were coadministered. In this study, however, one healthy subject was hospitalized for 2nd and 3rd degree heart block and bradycardia.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY
In a 24-month oral carcinogenicity study in rats, a slight increase in endometrial adenocarcinomas was observed at 10 mg/kg/day (4 times the Maximum Recommended Human Dose [MRHD] on a mg/m2 basis or 6 times on an exposure [AUC] basis and 30 mg/kg/day (12 times MRHD on a mg/m2 basis or 19 times on an AUC basis). No increase in neoplastic changes was observed in females at 2.5 mg/kg/day (equivalent to the MRHD on a mg/m2 basis or 2 times on an AUC basis) or in males up to the highest dose tested of 30 mg/kg/day (12 times the MRHD on a mg/m2 and AUC basis).
Galantamine was not carcinogenic in a 6-month oral carcinogenicity study in transgenic (P 53-deficient) mice up to 20 mg/kg/day, or in a 24-month oral carcinogenicity study in male and female mice up to 10 mg/kg/day (2 times the MRHD on a mg/m2 basis and equivalent on an AUC basis).
Galantamine produced no evidence of genotoxic potential when evaluated in the in vitro Ames S. typhimurium or E. coli reverse mutation assay, in vitro mouse lymphoma assay, in vivo micronucleus test in mice, or in vitro chromosome aberration assay in Chinese hamster ovary cells.
No impairment of fertility was seen in rats given up to 16 mg/kg/day (7 times the MRHD on a mg/m2 basis) for 14 days prior to mating in females and for 60 days prior to mating in males.
PREGNANCY
Pregnancy Category B: In a study in which rats were dosed from day 14 (females) or day 60 (males) prior to mating through the period of organogenesis, a slightly increased incidence of skeletal variations was observed at doses of 8 mg/kg/day (3 times the Maximum Recommended Human Dose [MRHD] on a mg/m2 basis) and 16 mg/kg/day. In a study in which pregnant rats were dosed from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at 8 and 16 mg/kg/day, but no adverse effects on other postnatal developmental parameters were seen. The doses causing the above effects in rats produced slight maternal toxicity. No major malformations were caused in rats given up to 16 mg/kg/day. No drug related teratogenic effects were observed in rabbits given up to 40 mg/kg/day (32 times the MRHD on a mg/m2 basis) during the period of organogenesis.
There are no adequate and well-controlled studies of REMINYL® in pregnant women. REMINYL® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS
It is not known whether galantamine is excreted in human breast milk. REMINYL® has no indication for use in nursing mothers.
PEDIATRIC USE
There are no adequate and well-controlled trials documenting the safety and efficacy of galantamine in any illness occurring in children. Therefore, use of REMINYL® in children is not recommended.
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