Pravastatinside effects

Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant. In short-term clinical trials, the most commonly reported adverse reactions (≥2% and > placebo) regardless of causality were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. To report SUSPECTED ADVERSE REACTIONS, contact Biocon Pharma Inc. at 1-866-924-6266 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Adverse

Clinical Events Short-Term Controlled Trials In the Pravastatin Sodium placebo-controlled clinical trials database of 1313 patients (age range 20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on Pravastatin Sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness. All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1: Adverse Events in ≥2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients) Body System/Event 5 mg N=100 10 mg N=153 20 mg N=478 40 mg N=171 Any Dose N=902 Placebo N=411 Cardiovascular Angina Pectoris 5.0 4.6 4.8 3.5 4.5

3.4 Dermatologic

Rash 3.0 2.6 6.7 1.2 4.5

1.4 Gastrointestinal

Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension 4.0 8.0 2.0 0.0 2.0 5.9 8.5 3.3 3.3 3.3 10.5 6.5 4.6 3.6 2.1 2.3 4.7 0.0 0.6 0.6 7.4 6.7 3.2 2.5 2.0 7.1 5.6 4.4 2.7

2.4 General

Fatigue Chest Pain Influenza 4.0 4.0 4.0 1.3 1.3 2.6 5.2 3.3 1.9 0.0 1.2 0.6 3.4 2.7 2.0 3.9 1.9

0.7 Musculoskeletal

Musculoskeletal Pain Myalgia 13.0 1.0 3.9 2.6 13.2 2.9 5.3 1.2 10.1 2.3 10.2

1.2 Nervous

System Headache Dizziness 5.0 4.0 6.5 1.3 7.5 5.2 3.5 0.6 6.3 3.5 4.6

3.4 Respiratory

Pharyngitis Upper Respiratory Infection Rhinitis Cough 2.0 6.0 7.0 4.0 4.6 9.8 5.2 1.3 1.5 5.2 3.8 3.1 1.2 4.1 1.2 1.2 2.0 5.9 3.9 2.5 2.7 5.8 4.9

1.7 Investigation ALT

Increased g-GT Increased CPK Increased 2.0 3.0 5.0 2.0 2.6 1.3 4.0 2.1 5.2 1.2 0.6 2.9 2.9 2.0 4.1 1.2 1.2

3.6 The safety and tolerability of

Pravastatin Sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Pravastatin Sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials In the Pravastatin Sodium placebo-controlled clinical trials database of 21,483 patients (age range 24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on Pravastatin Sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality. Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo- Controlled Trials Body System/Event Pravastatin (N=10,764) % of patients Placebo (N=10,719) % of patients Dermatologic Rash (including dermatitis) 7.2

7.1 General

Edema Fatigue Chest Pain Fever Weight Gain Weight Loss 3.0 8.4 10.0 2.1 3.8 3.3 2.7 7.8 9.8 1.9 3.3

2.8 Musculoskeletal

Musculoskeletal Pain Muscle Cramp Musculoskeletal Traumatism 24.9 5.1 10.2 24.4 4.6

9.6 Nervous

System Dizziness Sleep Disturbance Anxiety/Nervousness Paresthesia 7.3 3.0 4.8 3.2 6.6 2.4 4.7

3.0 Renal/Genitourinary

Urinary Tract Infection 2.7

2.6 Respiratory

Upper Respiratory Tract Infection Cough Influenza Pulmonary Infection Sinus Abnormality Tracheobronchitis 21.2 8.2 9.2 3.8 7.0 3.4 20.2 7.4 9.0 3.5 6.7

3.1 Special

Senses Vision Disturbance (includes blurred vision, diplopia) 3.4

3.3 Infections

Viral Infection 3.2 2.9 In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the long-term trials included the following: Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

6.2 Postmarketing

Experience In addition to the events reported above, as with other drugs in this class, the following events have been reported during postmarketing experience with Pravastatin Sodium, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).

Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

Renal: urinary abnormality (including dysuria, frequency, nocturia).

Respiratory: dyspnea, interstitial lung disease.

Psychiatric: nightmare.

Reproductive: gynecomastia.

Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

6.3 Laboratory

Test Abnormalities Increases in ALT, AST values and CPK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins

6.4 Pediatric

Patients In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.

6.1 Adverse

Clinical Events Short-Term Controlled Trials In the Pravastatin Sodium placebo-controlled clinical trials database of 1313 patients (age range 20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on Pravastatin Sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness. All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1: Adverse Events in ≥2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients) Body System/Event 5 mg N=100 10 mg N=153 20 mg N=478 40 mg N=171 Any Dose N=902 Placebo N=411 Cardiovascular Angina Pectoris 5.0 4.6 4.8 3.5 4.5

3.4 Dermatologic

Rash 3.0 2.6 6.7 1.2 4.5

1.4 Gastrointestinal

Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension 4.0 8.0 2.0 0.0 2.0 5.9 8.5 3.3 3.3 3.3 10.5 6.5 4.6 3.6 2.1 2.3 4.7 0.0 0.6 0.6 7.4 6.7 3.2 2.5 2.0 7.1 5.6 4.4 2.7

2.4 General

Fatigue Chest Pain Influenza 4.0 4.0 4.0 1.3 1.3 2.6 5.2 3.3 1.9 0.0 1.2 0.6 3.4 2.7 2.0 3.9 1.9

0.7 Musculoskeletal

Musculoskeletal Pain Myalgia 13.0 1.0 3.9 2.6 13.2 2.9 5.3 1.2 10.1 2.3 10.2

1.2 Nervous

System Headache Dizziness 5.0 4.0 6.5 1.3 7.5 5.2 3.5 0.6 6.3 3.5 4.6

3.4 Respiratory

Pharyngitis Upper Respiratory Infection Rhinitis Cough 2.0 6.0 7.0 4.0 4.6 9.8 5.2 1.3 1.5 5.2 3.8 3.1 1.2 4.1 1.2 1.2 2.0 5.9 3.9 2.5 2.7 5.8 4.9

1.7 Investigation ALT

Increased g-GT Increased CPK Increased 2.0 3.0 5.0 2.0 2.6 1.3 4.0 2.1 5.2 1.2 0.6 2.9 2.9 2.0 4.1 1.2 1.2

3.6 The safety and tolerability of

Pravastatin Sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Pravastatin Sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials In the Pravastatin Sodium placebo-controlled clinical trials database of 21,483 patients (age range 24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on Pravastatin Sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality. Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo- Controlled Trials Body System/Event Pravastatin (N=10,764) % of patients Placebo (N=10,719) % of patients Dermatologic Rash (including dermatitis) 7.2

7.1 General

Edema Fatigue Chest Pain Fever Weight Gain Weight Loss 3.0 8.4 10.0 2.1 3.8 3.3 2.7 7.8 9.8 1.9 3.3

2.8 Musculoskeletal

Musculoskeletal Pain Muscle Cramp Musculoskeletal Traumatism 24.9 5.1 10.2 24.4 4.6

9.6 Nervous

System Dizziness Sleep Disturbance Anxiety/Nervousness Paresthesia 7.3 3.0 4.8 3.2 6.6 2.4 4.7

3.0 Renal/Genitourinary

Urinary Tract Infection 2.7

2.6 Respiratory

Upper Respiratory Tract Infection Cough Influenza Pulmonary Infection Sinus Abnormality Tracheobronchitis 21.2 8.2 9.2 3.8 7.0 3.4 20.2 7.4 9.0 3.5 6.7

3.1 Special

Senses Vision Disturbance (includes blurred vision, diplopia) 3.4

3.3 Infections

Viral Infection 3.2 2.9 In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the long-term trials included the following: Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

6.2 Postmarketing

Experience In addition to the events reported above, as with other drugs in this class, the following events have been reported during postmarketing experience with Pravastatin Sodium, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).

Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

Renal: urinary abnormality (including dysuria, frequency, nocturia).

Respiratory: dyspnea, interstitial lung disease.

Psychiatric: nightmare.

Reproductive: gynecomastia.

Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

6.3 Laboratory

Test Abnormalities Increases in ALT, AST values and CPK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins

6.4 Pediatric

Patients In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.