RAZADYNE (galantamine hydrobromide 12 mg) Dailymed

Precautions

Information for Patients and Caregivers:

Caregivers should be instructed about the recommended dosage and administration of RAZADYNE^® ER/RAZADYNE^® (galantamine hydrobromide). RAZADYNE^® ER Extended-Release Capsules should be administered once daily in the morning, preferably with food (although not required). RAZADYNE^® Tablets and Oral Solution should be administered twice per day, preferably with the morning and evening meals. Dose escalation (dose increases) should follow a 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 RAZADYNE^® 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 RAZADYNE^® Oral Solution. Caregivers should direct questions about the administration of the solution to either their physician or pharmacist.

Deaths in Subjects with Mild Cognitive Impairment (MCI)

In two randomized placebo controlled trials of 2 years duration in subjects with mild cognitive impairment (MCI), a total of 13 subjects on RAZADYNE^® (n=1026) and 1 subject on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the RAZADYNE^® deaths appeared to result from various vascular causes (myocardial infarction, stroke, and sudden death).

Although the difference in mortality between RAZADYNE^® and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of RAZADYNE^®. Specifically, in these two MCI studies, the mortality rate in the placebo-treated subjects was markedly lower than the rate in placebo-treated patients in trials of RAZADYNE^® in Alzheimer's disease or other dementias (0.7 per 1000 person years compared to 22-61 per 1000 person years, respectively). Although the mortality rate in the RAZADYNE^®-treated MCI subjects was also lower than that observed in RAZADYNE^®-treated patients in Alzheimer's disease and other dementia trials (10.2 per 1000 person years compared to 23-31 per 1000 person years, respectively), the relative difference was much less. When the Alzheimer's disease and other dementia studies were pooled (n=6000), the mortality rate in the placebo group numerically exceeded that in the RAZADYNE^® group. Furthermore, in the MCI studies, no subjects in the placebo group died after 6 months, a highly unexpected finding in this population.

Individuals with mild cognitive impairment demonstrate isolated memory impairment greater than expected for their age and education, but do not meet current diagnostic criteria for Alzheimer's disease.

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 RAZADYNE^® 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 (CL_cr < 9 mL/min) the use of RAZADYNE^® is not recommended.

Drug-Drug Interactions

(see also CLINICAL PHARMACOLOGY, Drug-Drug Interactions )

Use With Anticholinergics

RAZADYNE^® 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%.

Memantine: 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.

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 2^nd and 3^rd 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 RAZADYNE^® in pregnant women. RAZADYNE^® 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. RAZADYNE^® 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 RAZADYNE^® in children is not recommended.

Pre-Marketing Clinical Trial Experience:

The specific adverse event data described in this section are based on studies of the immediate-release tablet formulation. In clinical trials, once-daily treatment with RAZADYNE^® ER (galantamine hydrobromide) Extended-Release Capsules was well tolerated and adverse events were similar to those seen with RAZADYNE^® Tablets.

Adverse Events Leading to Discontinuation:

In two large scale, placebo-controlled trials of 6 months duration in which patients were titrated weekly from 8 to 16 to 24, and to 32 mg/day, the risk of discontinuation because of an adverse event in the galantamine group exceeded that in the placebo group by about threefold. In contrast, in a 5-month trial with escalation of the dose by 8 mg/day every 4 weeks, the overall risk of discontinuation because of an adverse event was 7%, 7%, and 10% for the placebo, galantamine 16 mg/day, and galantamine 24 mg/day groups, respectively, with gastrointestinal adverse effects the principle reason for discontinuing galantamine. Table 1 shows the most frequent adverse events leading to discontinuation in this study.

Table 1: Most Frequent Adverse Events Leading to Discontinuation in a Placebo-Controlled, Double-Blind Trial With a 4-Week Dose Escalation Schedule

4-Week Escalation
	Placebo	16 mg/day	24 mg/day
Adverse Event	N=286	N=279	N=273
Nausea	<1%	2%	4%
Vomiting	0%	1%	3%
Anorexia	<1%	1%	<1%
Dizziness	<1%	2%	1%
Syncope	0%	0%	1%

Adverse Events Reported in Controlled Trials:

The reported adverse events in trials using RAZADYNE^® (galantamine hydrobromide) Tablets reflect experience gained under closely monitored conditions in a highly selected patient population. In actual practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior and the types of patients treated may differ.

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^® with food, the use of anti-emetic medication, and ensuring adequate fluid intake may reduce the impact of these events.

The most frequent adverse events, defined as those occurring at a frequency of at least 5% and at least twice the rate on placebo with the recommended maintenance dose of either 16 or 24 mg/day of RAZADYNE^® under conditions of every 4-week dose-escalation for each dose increment of 8 mg/day, are shown in Table 2 . These events were primarily gastrointestinal and tended to be less frequent with the 16 mg/day recommended initial maintenance dose.

Table 2: The Most Frequent Adverse Events in the Placebo-Controlled Trial With Dose Escalation Every 4 Weeks Occurring in at Least 5% of Patients Receiving RAZADYNE^® and at Least Twice the Rate on Placebo.

	Placebo	RAZADYNE® 16 mg/day	RAZADYNE® 24 mg/day
Adverse Event	N=286	N=279	N=273
Nausea	5%	13%	17%
Vomiting	1%	6%	10%
Diarrhea	6%	12%	6%
Anorexia	3%	7%	9%
Weight decrease	1%	5%	5%

Table 3 : The most common adverse events (adverse events occurring with an incidence of at least 2% with RAZADYNE^® treatment and in which the incidence was greater than with placebo treatment) are uled in Table 3 for four placebo-controlled trials for patients treated with 16 or 24 mg/day of RAZADYNE^®.

Table 3: Adverse Events Reported in at Least 2% of Patients With Alzheimer's Disease Administered RAZADYNE^® and at a Frequency Greater Than With Placebo

Body System    Adverse Event	Placebo(N=801)	RAZADYNE® Adverse events in patients treated with 16 or 24 mg/day of RAZADYNE® in four placebo-controlled trials are included. (N=1040)
Body as a whole - general disorders
Fatigue	3%	5%
Syncope	1%	2%
Central & peripheral nervous system disorders
Dizziness	6%	9%
Headache	5%	8%
Tremor	2%	3%
Gastrointestinal system disorders
Nausea	9%	24%
Vomiting	4%	13%
Diarrhea	7%	9%
Abdominal pain	4%	5%
Dyspepsia	2%	5%
Heart rate and rhythm disorders
Bradycardia	1%	2%
Metabolic and nutritional disorders
Weight decrease	2%	7%
Psychiatric disorders
Anorexia	3%	9%
Depression	5%	7%
Insomnia	4%	5%
Somnolence	3%	4%
Red blood cell disorders
Anemia	2%	3%
Respiratory system disorders
Rhinitis	3%	4%
Urinary system disorders
Urinary tract infection	7%	8%
Hematuria	2%	3%

Adverse events occurring with an incidence of at least 2% in RAZADYNE-treated patients that was either equal to or greater than with placebo treatment were constipation, agitation, confusion, anxiety, hallucination, injury, back pain, peripheral edema, asthenia, chest pain, urinary incontinence, upper respiratory tract infection, bronchitis, coughing, hypertension, fall, and purpura.

There were no important differences in adverse event rates related to dose or sex. Therewere too few non-Caucasian patients to assess the effects of race on adverse event rates.

No clinically relevant abnormalities in laboratory values were observed.

Other Adverse Events Observed During Clinical Trials

RAZADYNE^® Tablets were administered to 3055 patients with Alzheimer's disease. A total of 2357 patients received galantamine in placebo-controlled trials and 761 patients with Alzheimer's disease received galantamine 24 mg/day, the maximum recommended maintenance dose. About 1000 patients received galantamine for at least one year and approximately 200 patients received galantamine for two years.

To establish the rate of adverse events, data from all patients receiving any dose of galantamine in 8 placebo-controlled trials and 6 open-label extension trials were pooled. The methodology to gather and codify these adverse events was standardized across trials, using WHO terminology. All adverse events occurring in approximately 0.1% are included, except for those already uled elsewhere in labeling, WHO terms too general to be informative, or events unlikely to be drug caused. Events are classified by body system and uled using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients; rare adverse events - those occurring in fewer than 1/1000 patients. These adverse events are not necessarily related to RAZADYNE^® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Additional adverse events observed in other clinical trials are also included below.

Body As a Whole – General Disorders: Frequent: chest pain, asthenia, fever, malaise

Cardiovascular System Disorders: Infrequent: postural hypotension, hypotension, dependent edema, cardiac failure, myocardial ischemia or infarction

Central & Peripheral Nervous System Disorders: Infrequent : vertigo, hypertonia, convulsions, involuntary muscle contractions, paresthesia, ataxia, hypokinesia, hyperkinesia, apraxia, aphasia, leg cramps, tinnitus, transient ischemic attack or cerebrovascular accident

Gastrointestinal System Disorders: Frequent: flatulence; Infrequent: gastritis, melena, dysphagia, rectal hemorrhage, dry mouth, saliva increased, diverticulitis, gastroenteritis, hiccup; Rare: esophageal perforation

Heart Rate & Rhythm Disorders: Infrequent: AV block, palpitation, atrial arrhythmias including atrial fibrillation and supraventricular tachycardia, QT prolonged, bundle branch block, T-wave inversion, ventricular tachycardia; Rare: severe bradycardia

Metabolic& Nutritional Disorders: Infrequent : hyperglycemia, alkaline phosphatase increased

Platelet, Bleeding& Clotting Disorders: Infrequent : purpura, epistaxis, thrombocytopenia

Psychiatric Disorders: Infrequent: apathy, paroniria, paranoid reaction, libido increased, delirium; Rare: suicidal ideation, suicide

Urinary System Disorders: Frequent: incontinence; Infrequent: hematuria, micturition frequency, cystitis, urinary retention, nocturia, renal calculi

Post-Marketing Experience:

Other adverse events from post-approval controlled and uncontrolled clinical trials and post-marketing experience observed in patients treated with RAZADYNE^® include:

Body as a Whole – General Disorders: dehydration (including rare, severe cases leading to renal insufficiency and renal failure)

Psychiatric Disorders: aggression

Gastrointestinal System Disorders: upper and lower GI bleeding, stomach discomfort, abdominal discomfort

Hepatobiliary Disorders:elevated liver enzymes, hepatitis

Metabolic& Nutritional Disorders: hypokalemia

Nervous System Disorders: lethargy, dysgeusia, hypersomnia

Eye disorders: vision blurred

These adverse events may or may not be causally related to the drug.