Absorption and Distribution

Galantamine is rapidly and completely absorbed with time to peak concentration about one hour. Bioavailability of the tablet was the same as the bioavailability of an oral solution. Food did not affect the AUC of galantamine but Cmax decreased by 25% and Tmax was delayed by 1.5 hours. The mean volume of distribution of galantamine is 175 L.

The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations. In whole blood, galantamine is mainly distributed to blood cells (52.7%). The blood to plasma concentration ratio of galantamine is 1.2.

Metabolism and Elimination

Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly (see PRECAUTIONS: Drug-Drug Interactions). O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.

In studies of oral 3H-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39% to 77% of the total radioactivity in the plasma, and galantamine glucuronide for 14% to 24%. By 7 days, 93% to 99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.

After i.v. or oral administration, about 20% of the dose was excreted as unchanged galantamine in the urine in 24 hours, representing a renal clearance of about 65 mL/min, about 20% to 25% of the total plasma clearance of about 300 mL/min.

Galantamine hydrobromide 24 mg extended-release capsules administered once daily under fasting conditions are bioequivalent to galantamine hydrobromide tablets 12 mg twice daily with respect to AUC24h and Cmin. The Cmax and Tmax of the extended-release capsules were lower and occurred later, respectively, compared with the immediate-release tablets, with Cmax about 25% lower and median Tmax occurring about 4.5 to 5 hours after dosing. Dose proportionality is observed for galantamine hydrobromide extended-release capsules over the range of 8 mg to 24 mg daily and steady-state is achieved within a week. There was no effect of age on the pharmacokinetics of galantamine hydrobromide extended-release capsules. CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers.

There are no appreciable differences in pharmacokinetic parameters when galantamine hydrobromide extended-release capsules are given with food compared to when they are given in the fasted state.

CYP2D6 Poor Metabolizers

Approximately 7% of the normal population has a genetic variation that leads to reduced levels of activity of CYP2D6 isozyme. Such individuals have been referred to as poor metabolizers. After a single oral dose of 4 mg or 8 mg galantamine, CYP2D6 poor metabolizers demonstrated a similar Cmax and about 35% AUC∞ increase of unchanged galantamine compared to extensive metabolizers.

A total of 356 patients with Alzheimer’s disease enrolled in two Phase 3 studies were genotyped with respect to CYP2D6 (n = 210 hetero-extensive metabolizers, 126 homo-extensive metabolizers, and 20 poor metabolizers). Population pharmacokinetic analysis indicated that there was a 25% decrease in median clearance in poor metabolizers compared to extensive metabolizers. Dosage adjustment is not necessary in patients identified as poor metabolizers as the dose of drug is individually titrated to tolerability.

Hepatic Impairment

Following a single 4 mg dose of galantamine tablets, the pharmacokinetics of galantamine in subjects with mild hepatic impairment (n = 8; Child-Pugh score of 5 to 6) were similar to those in healthy subjects. In patients with moderate hepatic impairment (n = 8; Child-Pugh score of 7 to 9), galantamine clearance was decreased by about 25% compared to normal volunteers. Exposure would be expected to increase further with increasing degree of hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Impairment

Following a single 8 mg dose of galantamine tablets, AUC increased by 37% and 67% in moderate and severely renal-impaired patients compared to normal volunteers (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Elderly

Data from clinical trials in patients with Alzheimer’s disease indicate that galantamine concentrations are 30% to 40% higher than in healthy young subjects.

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of galantamine, but a population pharmacokinetic analysis indicates (n = 539 males and 550 females) that galantamine clearance is about 20% lower in females than in males (explained by lower body weight in females) and race (n = 1,029 White, 24 Black, 13 Asian and 23 other) did not affect the clearance of galantamine.

(A) Effect of Other Drugs on the Metabolism of Galantamine

Drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC of galantamine. Multiple dose pharmacokinetic studies demonstrated that the AUC of galantamine increased 30% and 40%, respectively, during coadministration of ketoconazole and paroxetine. As coadministered with erythromycin, another CYP3A4 inhibitor, the galantamine AUC increased only 10%. Population PK analysis with a database of 852 patients with Alzheimer’s disease showed that the clearance of galantamine was decreased about 25% to 33% by concurrent administration of amitriptyline (n = 17), fluoxetine (n = 48), fluvoxamine (n = 14), and quinidine (n = 7), known inhibitors of CYP2D6.

Concurrent administration of H2-antagonists demonstrated that ranitidine did not affect the pharmacokinetics of galantamine, and cimetidine increased the galantamine AUC by approximately16%.

A multiple-dose pharmacokinetic study with concurrent administration of memantine, an N-methyl D-aspartate (NMDA) receptor antagonist, demonstrated that coadministration of memantine in a dose of 10 mg BID did not affect the pharmacokinetic profile of galantamine (16 mg daily) at steady-state.

(B) Effect of Galantamine on the Metabolism of Other Drugs

In vitro studies show that galantamine did not inhibit the metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6 and CYP2E1. This indicated that the inhibitory potential of galantamine towards the major forms of cytochrome P450 is very low. Multiple doses of galantamine (24 mg/day) had no effect on the pharmacokinetics of digoxin and warfarin (R- and S- forms). Galantamine had no effect on the increased prothrombin time induced by warfarin.

U.S. Twenty-One-Week Fixed-Dose Study

In a study of 21 weeks duration, 978 patients were randomized to doses of 8 mg, 16 mg or 24 mg of galantamine per day, or to placebo, each given in two divided doses. Treatment was initiated at 8 mg/day for all patients randomized to galantamine, and increased by 8 mg/day every 4 weeks. Therefore, the maximum titration phase was 8 weeks and the minimum maintenance phase was 13 weeks (in patients randomized to 24 mg/day of galantamine).

Effects on the ADAS-cog

Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all four dose groups over the 21 weeks of the study. At 21 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 1.7 units, 3.3 units and 3.6 units for the 8 mg/day, 16 mg/day or 24 mg/day treatments, respectively. The 16 mg/day and 24 mg/day treatments were statistically significantly superior to placebo and to the 8 mg/day treatment. There was no statistically significant difference between the 16 mg/day and 24 mg/day dose groups.

Figure 1: Time-Course of the Change from Baseline in ADAS-cog Score for Patients Completing 21 Weeks (5 Months) of Treatment

Figure 2 illustrates the cumulative percentages of patients from each of the four treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvements.

Figure 2: Cumulative Percentage of Patients Completing 21 Weeks of Double-Blind Treatment with Specified Changes from Baseline in ADAS-cog Scores. The Percentages of Randomized Patients who Completed the Study were: Placebo 84%, 8 mg/day 77%, 16 mg/day 78% and 24 mg/day 78%.

Change in ADAS-cog
Treatment	-10	-7	-4	0
Placebo	3.6%	7.6%	19.6%	41.8%
8 mg/day	5.9%	13.9%	25.7%	46.5%
16 mg/day	7.2%	15.9%	35.6%	65.4%
24 mg/day	10.4%	22.3%	37%	64.9%

Effects on the CIBIC-plus

Figure 3 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the four treatment groups who completed 21 weeks of treatment. The galantamine-placebo differences for these groups of patients in mean rating were 0.15 units, 0.41 units and 0.44 units for the 8 mg/day, 16 mg/day and 24 mg/day treatments, respectively. The 16 mg/day and 24 mg/day treatments were statistically significantly superior to placebo. The differences versus the 8 mg/day treatment for the 16 mg/day and 24 mg/day treatments were 0.26 and 0.29, respectively. There were no statistically significant differences between the 16 mg/day and 24 mg/day dose groups.

Figure 3: Distribution of CIBIC-plus Ratings at Week 21

U.S. Twenty-Six-Week Fixed-Dose Study

In a study of 26 weeks duration, 636 patients were randomized to either a dose of 24 mg or 32 mg of galantamine per day, or to placebo, each given in two divided doses. The 26-week study was divided into a 3-week dose titration phase and a 23-week maintenance phase.

Effects on the ADAS-cog

Figure 4 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 3.9 units and 3.8 units for the 24 mg/day and 32 mg/day treatments, respectively. Both treatments were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 4: Time-Course of the Change from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment

Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon, or shifted to the right of the curve for placebo, respectively.

Figure 5: Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment with Specified Changes from Baseline in ADAS-cog Scores. The Percentages of Randomized Patients who Completed the Study were: Placebo 81%, 24 mg/day 68%, and 32 mg/day 58%.

Change in ADAS-cog
Treatment	-10	-7	-4	0
Placebo	2.1%	5.7%	16.6%	43.9%
24 mg/day	7.6%	18.3%	33.6%	64.1%
32 mg/day	11.1%	19.7%	33.3%	58.1%

Effects on the CIBIC-plus

Figure 6 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 26 weeks of treatment. The mean galantamine-placebo differences for these groups of patients in the mean rating were 0.28 units and 0.29 units for 24 mg/day and 32 mg/day of galantamine, respectively. The mean ratings for both groups were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 6: Distribution of CIBIC-plus Ratings at Week 26

International 26-Week Fixed-Dose Study

In a study of 26 weeks duration identical in design to the U.S. 26-Week Fixed-Dose Study, 653 patients were randomized to either a dose of 24 mg or 32 mg of galantamine per day, or to placebo, each given in two divided doses. The 26-week study was divided into a 3-week dose titration phase and a 23-week maintenance phase.

Effects on the ADAS-cog

Figure 7 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean differences in the ADAS-cog change scores for the galantamine-treated patients compared to the patients on placebo were 3.1 units and 4.1 units for the 24 mg/day and 32 mg/day treatments, respectively. Both treatments were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 7: Time-Course of the Change from Baseline in ADAS-cog Score for Patients Completing 26 Weeks of Treatment

Figure 8 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine groups are more likely to show the greater improvement.

Figure 8: Cumulative Percentage of Patients Completing 26 Weeks of Double-Blind Treatment with Specified Changes from Baseline in ADAS-cog Scores. The Percentages of Randomized Patients who Completed the Study Were: Placebo 87%, 24 mg/day 80%, and 32 mg/day 75%.

Change in ADAS-cog
Treatment	-10	-7	-4	0
Placebo	1.2%	5.8%	15.2%	39.8%
24 mg/day	4.5%	15.4%	30.8%	65.4%
32 mg/day	7.9%	19.7%	34.9%	63.8%

Effects on the CIBIC-plus

Figure 9 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 26 weeks of treatment. The mean galantamine-placebo differences for these groups of patients in the mean rating of change from baseline were 0.34 and 0.47 for 24 mg/day and 32 mg/day of galantamine, respectively. The mean ratings for the galantamine groups were statistically significantly superior to placebo, but were not significantly different from each other.

Figure 9: Distribution of CIBIC-plus Rating at Week 26

International Thirteen-Week Flexible-Dose Study

In a study of 13 weeks duration, 386 patients were randomized to either a flexible dose of 24 to 32 mg/day of galantamine or to placebo, each given in two divided doses. The 13-week study was divided into a 3-week dose titration phase and a 10-week maintenance phase. The patients in the active treatment arm of the study were maintained at either 24 mg/day or 32 mg/day at the discretion of the investigator.

Effects on the ADAS-cog

Figure 10 illustrates the time course for the change from baseline in ADAS-cog scores for both dose groups over the 13 weeks of the study. At 13 weeks of treatment, the mean difference in the ADAS-cog change scores for the treated patients compared to the patients on placebo was 1.9. Galantamine at a dose of 24 to 32 mg/day was statistically significantly superior to placebo.

Figure 10: Time-Course of the Change from Baseline in ADAS-cog Score for Patients Completing 13 Weeks of Treatment

Figure 11 illustrates the cumulative percentages of patients from each of the two treatment groups who had attained at least the measure of improvement in ADAS-cog score shown on the X-axis. Three change scores (10-point, 7-point and 4-point reductions) and no change in score from baseline have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.

The curves demonstrate that both patients assigned to galantamine and placebo have a wide range of responses, but that the galantamine group is more likely to show the greater improvements.

Figure 11: Cumulative Percentage of Patients Completing 13 Weeks of Double-Blind Treatment with Specified Changes from Baseline in ADAS-cog Scores. The Percentages of Randomized Patients who Completed the Study Were: Placebo 90%, 24 to 32 mg/day 67%.

Change in ADAS-cog
Treatment	-10	-7	-4	0
Placebo	1.9%	5.6%	19.4%	50%
24 mg or 32 mg/day	7.1%	18.8%	32.9%	65.3%

Effects on the CIBIC-plus

Figure 12 is a histogram of the percentage distribution of CIBIC-plus scores attained by patients assigned to each of the two treatment groups who completed 13 weeks of treatment. The mean galantamine-placebo differences for the group of patients in the mean rating of change from baseline was 0.37 units. The mean rating for the 24 to 32 mg/day group was statistically significantly superior to placebo.

Figure 12: Distribution of CIBIC-plus Ratings at Week 13

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 galantamine, compared to placebo.

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 galantamine (n = 1,026) and one subject on placebo (n = 1,022) died. The deaths were due to various causes which could be expected in an elderly population; about half of the galantamine deaths appeared to result from various vascular causes (myocardial infarction, stroke and sudden death).

Although the difference in mortality between galantamine and placebo-treated groups in these two studies was significant, the results are highly discrepant with other studies of galantamine. 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 galantamine in Alzheimer’s disease or other dementias (0.7 per 1,000 person years compared to 22 to 61 per 1,000 person years, respectively). Although the mortality rate in the galantamine-treated MCI subjects was also lower than that observed in galantamine-treated patients in Alzheimer’s disease and other dementia trials (10.2 per 1,000 person years compared to 23 to 31 per 1,000 person years, respectively), the relative difference was much less. When the Alzheimer’s disease and other dementia studies were pooled (n = 6,000), the mortality rate in the placebo group numerically exceeded that in the galantamine 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.

Hepatic Impairment

In patients with moderately impaired hepatic function, dose titration should proceed cautiously (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). The use of galantamine 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 galantamine is not recommended.

Use With Anticholinergics

Galantamine 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.

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

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

Teratogenic Effects. 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 mg/kg/day 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 galantamine in pregnant women. Galantamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 mg/day 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.

Adverse Events Reported in Controlled Trials

The reported adverse events in trials using galantamine 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 to 7 days.

Administration of galantamine 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 mg/day or 24 mg/day of galantamine 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 3: The most common adverse events (adverse events occurring with an incidence of at least 2% with galantamine 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 mg/day or 24 mg/day of galantamine.

Adverse events occurring with an incidence of at least 2% in placebo-treated patients that was either equal to or greater than with galantamine 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

Galantamine hydrobromide tablets were administered to 3,055 patients with Alzheimer’s disease. A total of 2,357 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 1,000 patients received galantamine for at least one year and approximately 200 patients received galantamine for 2 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 1/1,000 patients; rare adverse events - those occurring in fewer than 1/1,000 patients. These adverse events are not necessarily related to galantamine 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