Galantamine Hydrobromide

1 INDICATIONS AND USAGE Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. Galantamine is a cholinesterase inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer’s type. ( 1 )

2 DOSAGE AND ADMINISTRATION • Galantamine Oral Solution: Recommended starting dosage is 4 mg (1 mL) twice daily; increase dose to initial maintenance dosage of 8 mg (2 mL) twice daily after a minimum of 4 weeks. Based on clinical benefit and tolerability, dosage may be increased to 12 mg (3 mL) twice daily after a minimum of 4 weeks at 8 mg (2 mL) twice daily. ( 2.2 ) • Take with meals; ensure adequate fluid intake during treatment. ( 2.2 ) • Hepatic Impairment: should not exceed 16 mg (4 mL)/day for moderate hepatic impairment; do not use in patients with severe hepatic impairment. ( 2.3 ) • Renal Impairment: should not exceed 16 mg (4 mL)/day for creatinine clearance 9 mL to 59 mL/min; do not use in patients with creatinine clearance less than 9 mL/min. ( 2.4 ) 2.2 Galantamine Oral Solution The dosage of galantamine tablets shown to be effective in controlled clinical trials is 16 mg to 32 mg/day given as twice daily dosing. As the dosage of 32 mg/day is less well tolerated than lower dosages and does not provide increased effectiveness, the recommended dosage range is 16 mg to 24 mg/day given twice daily. The dosage of 24 mg/day did not provide a statistically significant greater clinical benefit than 16 mg/day. It is possible, however, that a daily dosage of 24 mg of galantamine might provide additional benefit for some patients. The recommended starting dosage of galantamine oral solution is 4 mg (1 mL) twice a day (8 mg (2 mL)/day). The dosage should be increased to the initial maintenance dosage of 8 mg (2 mL) twice a day (16 mg (4 mL)/day) after a minimum of 4 weeks. A further increase to 12 mg (3 mL) twice a day (24 mg (6 mL)/day) should be attempted after a minimum of 4 weeks at 8 mg (2 mL) twice a day (16 mg (4 mL)/day). Dosage increases should be based upon assessment of clinical benefit and tolerability of the previous dose. Galantamine 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 more than three days, the patient should be restarted at the lowest dosage and the dosage escalated to the current dose. The abrupt withdrawal of galantamine in those patients who had been receiving dosages in the effective range was not associated with an increased frequency of adverse events in comparison with those continuing to receive the same dosages of that drug. The beneficial effects of galantamine are lost, however, when the drug is discontinued. 2.3 Dosage in Patients with Hepatic Impairment In patients with moderate hepatic impairment (Child-Pugh score of 7 to 9), the dosage should generally not exceed 16 mg (4 mL)/day. The use of galantamine in patients with severe hepatic impairment (Child-Pugh score of 10 to 15) is not recommended [see Clinical Pharmacology (12.3) ]. 2.4 Dosage in Patients with Renal Impairment In patients with creatinine clearance of 9 mL to 59 mL/min, the dosage should generally not exceed 16 mg (4 mL)/day. In patients with creatinine clearance less than 9 mL/min, the use of galantamine is not recommended [see Clinical Pharmacology (12.3) ] .

5 WARNINGS AND PRECAUTIONS • Serious Skin Reactions: discontinue at first appearance of skin rash. ( 5.1 ) • All patients should be considered at risk for adverse effects on cardiac conduction, including bradycardia and AV block, due to vagotonic effects on sinoatrial and atrioventricular nodes. ( 5.3 ) • Active or Occult Gastrointestinal Bleeding: monitor, especially those with an increased risk for developing ulcers. ( 5.4 ) • Cholinomimetics may cause bladder outflow obstruction. ( 5.5 ) • Monitor for respiratory adverse events in patients with a history of severe asthma or obstructive pulmonary disease. ( 5.7 ) 5.1 Serious Skin Reactions Serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis) have been reported in patients receiving galantamine. Inform patients and caregivers that the use of galantamine should be discontinued at the first appearance of a skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a serious skin reaction, use of this drug should not be resumed and alternative therapy should be considered. 5.2 Anesthesia Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia. 5.3 Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block. Bradycardia and all types of heart block have been reported in patients both with and without known underlying cardiac conduction abnormalities [see Adverse Reactions (6.1 , 6.2) ] . Therefore, all patients should be considered at risk for adverse effects on cardiac conduction. 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 twice daily 0.4% [3/692]; 8 mg twice daily 1.3% [7/552]; 12 mg twice daily 2.2% [6/273]). 5.4 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 galantamine have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Galantamine, as a predictable consequence of its pharmacological properties, has been shown to produce nausea, vomiting, diarrhea, anorexia, and weight loss. During therapy, the patient’s weight should be monitored. 5.5 Genitourinary Conditions Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction. 5.6 Neurological Conditions Seizures: Cholinesterase inhibitors are believed to have some potential to cause generalized convulsions [see Adverse Reactions (6.2) ] . Seizure activity may also be a manifestation of Alzheimer’s disease. Patients with Alzheimer’s disease should be monitored closely for seizures while taking galantamine. 5.7 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. Respiratory function should be monitored closely for the occurrence of respiratory adverse effects. 5.8 Deaths in Subjects with Mild Cognitive Impairment (MCI) In two randomized placebo controlled trials of 2 years duration in patients with mild cognitive impairment (MCI), a total of 13 patients on galantamine (n=1026) and 1 patient on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population; a…

4 CONTRAINDICATIONS Galantamine is contraindicated in patients with known hypersensitivity to galantamine hydrobromide or to any excipients used in the formulation. Known hypersensitivity to galantamine hydrobromide or any excipients. ( 4 )

7 DRUG INTERACTIONS • Potential to interfere with the activity of anticholinergic medications. ( 7.1 ) • Synergistic effect expected when given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents, or cholinergic agonists. ( 7.2 ) 7.1 Use with Anticholinergics Galantamine has the potential to interfere with the activity of anticholinergic medications [see Clinical Pharmacology (12.3) ] . 7.2 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 (12.3) ] .

8.1 Pregnancy There are no adequate and well-controlled studies in pregnant women. In studies conducted in animals, administration of galantamine during pregnancy resulted in developmental toxicity (increased incidence of morphological abnormalities and decreased growth in offspring) at doses similar to or greater than those used clinically. Galantamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats, administration of galantamine (oral doses of 2 mg, 8 mg, or 16 mg/kg/day), from day 14 (females) or day 60 (males) prior to mating and continuing in females through the period of organogenesis, resulted in an increased incidence of fetal skeletal variations at the two highest doses. The no-effect dose for embryo-fetal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the maximum recommended human dose (MRHD of 24 mg/day) on a body surface area (mg/m 2 ) basis. When galantamine (oral doses of 4 mg, 12 mg, 28 mg, or 48 mg/kg/day) was administered to pregnant rabbits throughout the period of organogenesis, small increases in fetal visceral malformations and skeletal variations were observed at the highest dose. The no-effect dose for embryo-fetal developmental toxicity in rabbits (28 mg/kg/day) is approximately 20 times the MRHD on a mg/m 2 basis. In a study in which pregnant rats were orally dosed with galantamine (2 mg, 8 mg, or 16 mg/kg/day) from the beginning of organogenesis through day 21 post-partum, pup weights were decreased at birth and during the lactation period at the two highest doses. The no-effect dose for pre- and postnatal developmental toxicity in rats (2 mg/kg/day) is approximately equal to the MRHD on a mg/m 2 basis.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when galantamine is administered to a nursing woman.

6 ADVERSE REACTIONS Serious adverse reactions are discussed in more detail in the following sections of the labeling: • Serious Skin Reactions [see Warnings and Precautions (5.1) ] • Cardiovascular Conditions [see Warnings and Precautions (5.3) ] • Gastrointestinal Conditions [see Warnings and Precautions (5.4) ] • Genitourinary Conditions [see Warnings and Precautions (5.5) ] • Neurological Conditions [see Warnings and Precautions (5.6) ] • Pulmonary Conditions [see Warnings and Precautions (5.7) ] • Deaths in Subjects with Mild cognitive impairment (MCI) [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 patients from double-blind clinical trials (≥5%) were nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. The most common adverse reactions associated with discontinuation (≥1%) in galantamine-treated patients from double-blind clinical trials were nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%). The safety of the extended-release capsule and immediate-release tablet formulations of galantamine was evaluated in 3956 galantamine-treated patients who participated in 8 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. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Table 1 lists the adverse reactions reported in ≥1% of galantamine-treated patients in 8 placebo-controlled, double-blind clinical trials. Table 1: Adverse Reactions Reported by ≥1% of Galantamine-Treated Patients in Pooled Placebo-Controlled, Double-Blind Clinical Trials System/Organ Class Adverse Reaction Galantamine (n=3956) % Placebo (n=2546) % Metabolism and Nutrition Disorders Decreased Appetite 7.4 2.1 Psychiatric Disorders Depression 3.6 2.3 Nervous System Disorders Headache 7.1 5.5 Dizziness 7.5 3.4 Tremor 1.6 0.7 Somnolence 1.5 0.8 Syncope 1.4 0.6 Lethargy 1.3 0.4 Cardiac Disorders Bradycardia 1.0 0.3 Gastrointestinal Disorders Nausea 20.7 5.5 Vomiting 10.5 2.3 Diarrhea 7.4 4.9 Abdominal Discomfort 2.1 0.7 Abdominal Pain 3.8 2.0 Dyspepsia 1.5 1.0 Musculoskeletal and Connective Tissue Disorders Muscle Spasms 1.2 0.5 General Disorders and Administration Site Conditions Fatigue 3.5 1.8 Asthenia 2.0 1.5 Malaise 1.1 0.5 Investigations Decreased Weight 4.7 1.5 Injury, Poisoning and Procedural Complications Fall 3.9 3.0 Laceration 1.1 0.5 The majority of these adverse reactions occurred during the dose-escalation period. In those patients who experienced the most frequent adverse reaction, nausea, the median duration of the nausea was 5 to 7 days. Other Adverse Reactions Observed in Clinical Trials of Galantamine: The following adverse reactions occurred in <1% of all galantamine-treated patients (n=3956) 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 patients (n=1454) who participated in open-label studies. Adverse reactions listed in Table 1 above were not included below: Metabolism a…