INDICATIONS AND USAGE
RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide) is indicated
for the treatment of mild to moderate dementia of the Alzheimer's type.
CONTRAINDICATIONS
RAZADYNE® ER/RAZADYNE® (galantamine hydrobromide) is
contraindicated in patients with known hypersensitivity to galantamine
hydrobromide or to any excipients used in the formulation.
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 was rarely severe and 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 RAZADYNE® (galantamine hydrobromide)
have shown no increase, relative to placebo, in the incidence of either
peptic ulcer disease or gastrointestinal bleeding.
RAZADYNE® ER/RAZADYNE®, 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 RAZADYNE®
ER/RAZADYNE®, 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 RAZADYNE®
ER/RAZADYNE®, 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 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 placebotreated
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 (CLcr < 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.
6
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-desmethylgalantamine.
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 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 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.
ADVERSE REACTIONS
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 doseescalation
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
7
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.
RAZADYNE® RAZADYNE®
Placebo 16 mg/day 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 listed
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 Placebo RAZADYNE® 1
Adverse Event (N=801) (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%
1 Adverse events in patients treated with 16 or 24 mg/day of
RAZADYNE® in four placebo-controlled trials are included.
Adverse events occurring with an incidence of at least 2% in placebotreated
patients that was either equal to or greater than with
RAZADYNE® 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. There were 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 listed elsewhere in labeling, WHO
terms too general to be informative, or events unlikely to be drug caused.
Events are classified by body system and listed 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)
8
Psychiatric Disorders: aggression
Gastrointestinal System Disorders: upper and lower GI bleeding
Hepatobiliary Disorders: elevated liver enzymes, hepatitis
Metabolic & Nutritional Disorders: hypokalemia
These adverse events may or may not be causally related to the drug.
OVERDOSAGE
Because strategies for the management of overdose are continually
evolving, it is advisable to contact a poison control center to determine
the latest recommendations for the management of an overdose of any
drug.
As in any case of overdose, general supportive measures should be
utilized. Signs and symptoms of significant overdosing of galantamine
are predicted to be similar to those of overdosing of other
cholinomimetics. These effects generally involve the central nervous
system, the parasympathetic nervous system, and the neuromuscular
junction. In addition to muscle weakness or fasciculations, some or all of
the following signs of cholinergic crisis may develop: severe nausea,
vomiting, gastrointestinal cramping, salivation, lacrimation, urination,
defecation, 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
RAZADYNE® (galantamine hydrobromide) overdosage. Intravenous
atropine sulfate titrated to effect is recommended at an initial dose of 0.5
to 1.0 mg i.v. with subsequent doses based upon clinical response.
Atypical responses in blood pressure and heart rate have been reported
with other cholinomimetics when coadministered with quaternary
anticholinergics. It is not known whether RAZADYNE® and/or its
metabolites can be removed by dialysis (hemodialysis, peritoneal
dialysis, or hemofiltration). Dose-related signs of toxicity in animals
included hypoactivity, tremors, clonic convulsions, salivation, lacrimation,
chromodacryorrhea, mucoid feces, and dyspnea.
In one postmarketing report, one patient who had been taking 4 mg of
galantamine daily for a week inadvertently ingested eight 4 mg tablets
(32 mg total) on a single day. Subsequently, she developed bradycardia,
QT prolongation, ventricular tachycardia and torsades de pointes
accompanied by a brief loss of consciousness for which she required
hospital treatment. Two additional cases of accidental ingestion of 32 mg
(nausea, vomiting, and dry mouth; nausea, vomiting, and substernal
chest pain) and one of 40 mg (vomiting), resulted in brief hospitalizations
for observation with full recovery.
One patient, who was prescribed
24 mg/day and had a history of hallucinations over the previous two
years, mistakenly received 24 mg twice daily for 34 days and developed
hallucinations requiring hospitalization. Another patient, who was
prescribed 16 mg/day of oral solution, inadvertently ingested 160 mg
(40 mL) and experienced sweating, vomiting, bradycardia, and nearsyncope
one hour later, which necessitated hospital treatment. His
symptoms resolved within 24 hours.
DOSAGE AND ADMINISTRATION
RAZADYNE® ER Extended-Release Capsules
The dosage of RAZADYNE® ER (galantamine hydrobromide) Extended-
Release Capsules shown to be effective in a controlled clinical trial is 16-
24 mg/day.
The recommended starting dose of RAZADYNE® ER is 8 mg/day. The
dose should be increased to the initial maintenance dose of 16 mg/day
after a minimum of 4 weeks. A further increase to 24 mg/day should be
attempted after a minimum of 4 weeks at 16 mg/day. Dose increases
should be based upon assessment of clinical benefit and tolerability of
the previous dose.
RAZADYNE® ER should be administered once daily in the morning,
preferably with food.
Patients currently being treated with RAZADYNE® tablets can convert to
RAZADYNE® ER by taking their last dose of RAZADYNE® tablets in the
evening and starting RAZADYNE® ER once daily treatment the next
morning. Converting from RAZADYNE® to RAZADYNE® ER should occur
at the same total daily dose.
RAZADYNE® Immediate-Release Tablets and Oral Solution
The dosage of RAZADYNE® Tablets shown to be effective in controlled
clinical trials is 16-32 mg/day given as twice daily dosing. As the dose of
32 mg/day is less well tolerated than lower doses and does not provide
increased effectiveness, the recommended dose range is 16-24 mg/day
given in a BID regimen. The dose of 24 mg/day did not provide a
statistically significant greater clinical benefit than 16 mg/day. It is
possible, however, that a daily dose of 24 mg of RAZADYNE® might
provide additional benefit for some patients.
The recommended starting dose of RAZADYNE® Tablets and Oral
Solution is 4 mg twice a day (8 mg/day). The dose should be increased
to the initial maintenance dose of 8 mg twice a day (16 mg/day) after a
minimum of 4 weeks. A further increase to 12 mg twice a day (24
mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice
a day (16 mg/day). Dose increases should be based upon assessment
of clinical benefit and tolerability of the previous dose.
RAZADYNE® Tablets and Oral Solution should be administered twice a
day, preferably with morning and evening meals.
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.
The abrupt withdrawal of RAZADYNE® ER/RAZADYNE® in those
patients who had been receiving doses in the effective range was not
associated with an increased frequency of adverse events in comparison
with those continuing to receive the same doses of that drug. The
beneficial effects of RAZADYNE® ER/RAZADYNE® are lost, however,
when the drug is discontinued.
Doses in Special Populations
Galantamine plasma concentrations may be increased in patients with
moderate to severe hepatic impairment. In patients with moderately
impaired hepatic function (Child-Pugh score of 7-9), the total daily dose
should generally not exceed 16 mg/day. The use of RAZADYNE®
ER/RAZADYNE® in patients with severe hepatic impairment (Child-Pugh
score of 10-15) is not recommended.For patients with moderate renal
impairment the dose should generally not exceed 16 mg/day. In patients
with severe renal impairment (creatinine clearance < 9 mL/min), the use
of RAZADYNE® ER/RAZADYNE® is not recommended.
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