Pravastatin Drug Information

General Dosing Information

The patient should be placed on a standard cholesterol-lowering diet before receiving Pravastatin Sodium and should continue on this diet during treatment with Pravastatin Sodium.

Adult Patients

The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. Pravastatin Sodium can be administered orally as a single dose at any time of the day, with or without food.

Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

Patients with Renal Impairment

In patients with severe renal impairment, a starting dose of 10 mg pravastatin daily is recommended.

Pediatric Patients Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population. Adolescents (Ages 14 to 18 Years) The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age.

Doses greater than 40 mg have not been studied in this patient population. Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.

Concomitant Lipid-Altering Therapy Pravastatin Sodium may be used with bile acid resins.

When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, Pravastatin Sodium should be given either 1 hour or more before or at least 4 hours following the resin.

Dosage in Patients Taking Cyclosporine

In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily.

Dosage in Patients Taking Clarithromycin

In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily.

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

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

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

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

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

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

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

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 ; Cholesterol and Recurrent Events study ; Long-term Intervention with Pravastatin in Ischemic Disease study ; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study ; Pravastatin, Lipids and Atherosclerosis in the Carotids study ; Regression Growth Evaluation Statin Study ; and Kuopio Atherosclerosis Prevention Study ) 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

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

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

2.4 4.7

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

Special Senses Vision Disturbance (includes blurred vision, diplopia) 3.4 3.3 Infections Viral

Infection 3.2

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.

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.

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

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.

Cyclosporine

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine.

Clarithromycin and Other Macrolide Antibiotics

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin. Other macrolides (e.g., erythromycin and azithromycin) have the potential to increase statin exposures while used in combination.

Pravastatin should be used cautiously with macrolide antibiotics due to a potential increased risk of myopathies.

Colchicine

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine.

Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when

HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Pravastatin Sodium with gemfibrozil should be avoided.

Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Pravastatin Sodium should be administered with caution when used concomitantly with other fibrates.

Niacin

The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in Pravastatin Sodium dosage should be considered in this setting.

Pregnancy Risk Summary Pravastatin Sodium is contraindicated for use in pregnant woman because of the potential for fetal harm. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Pravastatin Sodium during pregnancy, Pravastatin Sodium should be immediately discontinued as soon as pregnancy is recognized. Limited published data on the use of Pravastatin Sodium in pregnant women are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.

In animal reproduction studies, no evidence of fetal malformations was seen in rabbits or rats exposed to 10 times to 120 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day. Fetal skeletal abnormalities, offspring mortality, and developmental delays occurred when pregnant rats were administered 10 times to 12 times the MRHD during organogenesis to parturition. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Limited published data on pravastatin have not shown an increased risk of major congenital malformations or miscarriage.

Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence.

In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1000 mg/kg/day.

Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 ). In lactating rats, up to 7 times higher levels of pravastatin are present in the breast milk than in the maternal plasma, which corresponds to exposure 2 times the MRHD of 80 mg/day based on body surface area (mg/m 2 ).

Pediatric Use The safety and effectiveness of Pravastatin Sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. Doses greater than 40 mg have not been studied in this population.

Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy. For dosing information. Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

Hypersensitivity Hypersensitivity to any component of this medication. 4.2 Liver Active liver

disease or unexplained, persistent elevations of serum transaminases.

Pregnancy Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during

pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.

Lactation Pravastatin is present in human milk.

Because statins have the potential for serious adverse reactions in nursing infants, women who require Pravastatin Sodium treatment should not breastfeed their infants.

To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required.