"Today, the U.S. Food and Drug Administration issued a proposal designed to assist companies developing new treatments for patients in the early stages of Alzheimer's disease, before the onset of noticeable (overt) dementia.
The following are discussed in more detail in other sections of the labeling:
- Anesthesia [see WARNINGS AND PRECAUTIONS]
- Cardiovascular conditions [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal conditions [see WARNINGS AND PRECAUTIONS]
- Genitourinary conditions [see WARNINGS AND PRECAUTIONS]
- Neurological conditions [see WARNINGS AND PRECAUTIONS]
- Pulmonary conditions [see WARNINGS AND PRECAUTIONS]
- Deaths in subjects with mild cognitive impairment (MCI) [see WARNINGS AND PRECAUTIONS]
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.
The most common adverse reactions in galantamine-treated subjects from double-blind clinical trials ( ≥ 5%) were nausea, vomiting, diarrhea, dizziness, headache, decreased appetite, and weight decreased.
The most common adverse reactions associated with discontinuation ( ≥ 1%) in galantamine-treated subjects from double-blind clinical trials were nausea (7.7%), vomiting (4.1%), decreased appetite (1.9%), and dizziness (1.6%).
The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 2932 galantamine-treated subjects who participated in 7 placebo-controlled clinical studies and 1454 subjects in 5 open-label clinical studies with mild to moderate dementia of the Alzheimer's type. In clinical studies, the safety profile of once-daily treatment with extended-release galantamine was similar in frequency and nature to that seen with tablets. The information presented in this section was derived from pooled double-blind studies and from pooled open-label data.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of galantamine based on the comprehensive assessment of the available adverse event information. A causal relationship with galantamine cannot be reliably established in individual cases.
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials
Table 1 lists the adverse drug reactions reported in ≥ 1% of galantamine-treated subjects in 7 placebo-controlled, double-blind clinical trials.
Table 1: Adverse Drug Reactions Reported by ≥ 1%
of Galantamine-Treated Subjects in 7 Placebo-Controlled, Double-Blind Clinical
|Metabolism and Nutrition Disorders|
|Nervous System Disorders|
|Abdominal pain upper||2.0||1.4|
|Skin and Subcutaneous Tissue Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|General Disorders and Administration Site Conditions|
The majority of these adverse events occurred during the dose-escalation period. In those patients who experienced the most frequent adverse event, nausea, the median duration of the nausea was 5-7 days.
Administration of RAZADYNE® ER and RAZADYNE® with food, the use of anti-emetic medication, and ensuring adequate fluid intake may reduce the impact of these events [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].
Other Adverse Reactions Observed in Clinical Trials of Galantamine
The following adverse reactions occurred in < 1% of all galantamine-treated subjects (N=2932) in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes all adverse reactions reported at any frequency rate in subjects (N=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below:
Metabolism and Nutrition Disorders: Dehydration
Nervous System Disorders: Dysgeusia, Hypersomnia, Paresthesia
Eye Disorders: Vision blurred
Vascular Disorders: Flushing, Hypotension
Gastrointestinal Disorders: Retching
Musculoskeletal and Connective Tissue Disorders: Muscular weakness
Injury, Poisoning and Procedural Complications: Fall
Discontinuations Due to Adverse Reactions
In the 7 placebo-controlled studies of adults, 379 (12.9%) galantamine-treated patients (N=2932) and 42 (2.8%) placebo patients (N=1525) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% in the galantamine-treated patients included nausea (225, 7.7%), vomiting (119, 4.1%), decreased appetite (56, 1.9%), dizziness (48, 1.6%), diarrhea (27, 0.9%), headache (26, 0.9%) weight decreased (24, 0.8%), and abdominal pain (15, 0.5%). Those events with an incidence of ≥ 0.5% in placebo patients included nausea (14, 0.9%) and dizziness (8, 0.5%).
In the 5 open-label studies, 103 (7.1%) patients (N=1454) discontinued due to an adverse reaction. Those events with an incidence of ≥ 0.5% included nausea (43, 3.0%), vomiting (23, 1.6%), decreased appetite (13, 0.9%), headache (12, 0.8%), weight decreased (9, 0.6%), dizziness (8, 0.6%), and diarrhea (7, 0.5%).
The following additional adverse reactions have been identified during post-approval use of RAZADYNE® ER and RAZADYNE®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:
Immune System Disorders: Hypersensitivity
Psychiatric Disorders: Hallucination, Hallucination visual, Hallucination auditory
Ear and Labyrinth Disorders: Tinnitus
Vascular Disorders: Hypertension
Read the Razadyne ER (galantamine hbr er) Side Effects Center for a complete guide to possible side effects
Use with Anticholinergics
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 [see CLINICAL PHARMACOLOGY].
Effect of Other Drugs on Galantamine
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 [see CLINICAL PHARMACOLOGY].
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 pharmacokinetics of galantamine.
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%.
Paroxetine, a strong inhibitor of CYP2D6, at 20 mg/day for 16 days, increased the oral bioavailability of galantamine by about 40%.
Memantine, an N-methyl-D-aspartate receptor antagonist, at a dose of 10 mg BID, had no effect on the pharmacokinetics of galantamine (16 mg/day) at steady state.
Effect of Galantamine on Other Drugs
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 [see CLINICAL PHARMACOLOGY].
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.
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.
Read the Razadyne ER Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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