Pravastatin Sodium

• Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] .
• Hypersensitivity to any pravastatin or any excipients in pravastatin sodium tablets.
• Hypersensitivity to pravastatin or any excipient in pravastatin sodium tablets.
• (4) Acute liver failure or decompensated cirrhosis (4 , 5.3)

• Myopathy and Rhabdomyolysis:
• Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher pravastatin dosage.
• Discontinue pravastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
• Temporarily discontinue pravastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.
• Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing pravastatin dosage.
• Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
• (5.1 , 7.1 , 8.5 , 8.6) Immune-Mediated Necrotizing Myopathy (IMNM):
• Rare reports of IMNM, an autoimmune myopathy, have been reported.
• Discontinue pravastatin if IMNM is suspected (5.2) .
• Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent.
• Rare reports of fatal and non-fatal hepatic failure have occurred.
• Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter.
• If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue (5.3) .
• 5.1 Myopathy and Rhabdomyolysis Pravastatin may cause myopathy and rhabdomyolysis.
• Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including pravastatin.
• Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) to greater than 10 times the upper limit of normal (ULN), occurred < 0.1%; in pravastatin-treated patients in clinical trials.
• Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher pravastatin dosage [see Drug Interactions (7.1) ].
• Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Pravastatin is not recommended in patients taking gemfibrozil [see Drug Interactions (7) ].
• There are pravastatin dosage restrictions for patients taking cyclosporin and select macrolide antibiotics [see Dosage and Administration (2.5) ].
• The following drugs when used concomitantly with pravastatin may also increase the risk of myopathy and rhabdomyolysis:
• niacin, fibrates, and colchicine [see Drug Interactions (7) ].
• Discontinue pravastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
• Muscle symptoms and CK increases may resolve if pravastatin is discontinued.
• Temporarily discontinue pravastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
• Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pravastatin dosage.
• 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered.
• IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents.
• Additional neuromuscular and serologic testing may be necessary.
• Treatment with immunosuppressive agents may be required.
• Discontinue pravastatin if IMNM is suspected.
• 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of pravastatin [see Adverse Reactions (6.1) ] .
• In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.
• Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1% of patients receiving either pravastatin or placebo in clinical studies.
• Marked persistent increases of hepatic transaminases have also occurred with pravastatin.
• There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin.
• Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
• Consider liver enzyme testing before pravastatin initiation and when clinically indicated thereafter.
• If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pravastatin.
• 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pravastatin.

• Risk Summary Discontinue pravastatin when pregnancy is recognized.
• Alternatively, consider the ongoing therapeutic needs of the individual patient.
• Pravastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pravastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] .
• In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.
• Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.
• Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations.
• Published data from prospective and retrospective observational cohort studies with pravastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) .
• In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m 2 ).
• An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data) .
• 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% to 4% and 15% to 20%, respectively.
• Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders -including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods.
• The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus.
• There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders.
• In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
• Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.
• 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 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, 500 mg/kg/day, and 1,000 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 1,000 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 mg/kg/day, 100 mg/kg/day, and 1,000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), 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 SPECIFIC POPULATIONS Pregnancy:
• May cause fetal harm (8.1) Lactation:
• Breastfeeding not recommended during treatment with pravastatin sodium tablets (8.2)
• 8.1 Pregnancy Risk Summary Discontinue pravastatin when pregnancy is recognized.
• Alternatively, consider the ongoing therapeutic needs of the individual patient.
• Pravastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pravastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] .
• In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.
• Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.
• Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations.
• Published data from prospective and retrospective observational cohort studies with pravastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) .
• In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m 2 ).
• An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data) .
• 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% to 4% and 15% to 20%, respectively.
• Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders -including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods.
• The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus.
• There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders.
• In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
• Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.
• 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 mg/kg/day, 20 mg/kg/day, 100 mg/kg/day, 500 mg/kg/day, and 1,000 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 1,000 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 mg/kg/day, 100 mg/kg/day, and 1,000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), 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 ).
• 8.2 Lactation Risk Summary Based on one lactation study in published literature, pravastatin is present in human milk.
• There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production.
• Statins, including pravastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.
• Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pravastatin. [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) ] .
• 8.4 Pediatric use The safety and effectiveness of pravastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH.
• Use of pravastatin for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH.
• Doses greater than 40 mg daily have not been studied in this population.
• The safety and effectiveness of pravastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).
• 8.5 Geriatric Use In clinical studies, 4,797 (36.4%) pravastatin-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older.
• No significant differences in efficacy or safety were observed between geriatric patients and younger patients.
• Mean pravastatin AUCs are 25% to 50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology (12.3) ].
• Advanced age (≥65 years) is a risk factor for pravastatin-associated myopathy and rhabdomyolysis.
• Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy.
• Monitor geriatric patients receiving pravastatin for the increased risk of myopathy [see Warnings and Precautions (5.1) ].
• 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis.
• Monitor all patients with renal impairment for development of myopathy.
• In patients with severe renal impairment, the recommended starting dose is pravastatin 10 mg once daily.
• The maximum recommended dosage in patients with severe renal impairment is pravastatin 40 mg once daily.
• The recommended dosage for patients with mild or moderate renal impairment is the same as patients with normal renal function [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ].
• 8.7 Hepatic Impairment Pravastatin shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [ Clinical Pharmacology (12.3) ].
• Pravastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) , Warnings and Precautions (5.3) ].

• See full prescribing information for details regarding concomitant use of pravastatin sodium tablets with other drugs that increase the risk of myopathy and rhabdomyolysis.
• (2.5, 7.1) Bile Acid Sequestrants:
• in patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant (7.2)
• 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Pravastatin is a substrate of the transport protein OATP1B1.
• Pravastatin plasma levels can be significantly increased with concomitant administration of inhibitors of OATP1B1.
• Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with pravastatin and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].
• Table 3:Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Gemfibrozil Clinical Impact:
• There is an increased risk of myopathy/rhabdomyolysis when pravastatin is administered with gemfibrozil Intervention:
• Avoid concomitant use of gemfibrozil with pravastatin.
• Cyclosporine Clinical Impact:
• The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with pravastatin.
• Intervention: Initiate with a dosage of pravastatin sodium 10 mg once daily.
• Do not exceed pravastatin 20 mg once daily [see Dosage and Administration (2.5) ].
• Select Macrolide Antibiotics Clinical Impact:
• The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with pravastatin.
• Other macrolides (e.g., azithromycin) have the potential to increase pravastatin exposures and increase the risk of myopathy and rhabdomyolysis when used concomitantly.
• Intervention:
• For patients taking erythromycin or clarithromycin,
• do not exceed 40 mg pravastatin once daily [see Dosage and Administration (2.5) ].
• Niacin Clinical Impact:
• Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with pravastatin.
• Intervention:
• Consider if the benefit of using niacin concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis.
• If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
• Fibrates (other than Gemfibrozil) Clinical Impact:
• Fibrates may cause myopathy when given alone.
• The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with pravastatin.
• Intervention:
• Consider if the benefit of using fibrates concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis.
• If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
• Colchicine Clinical Impact:
• Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with pravastatin.
• Intervention:
• Consider if the benefit of using colchicine concomitantly with pravastatin outweighs the increased risk of myopathy and rhabdomyolysis.
• If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
• 7.2 Drug Interactions that Decrease the Efficacy of Pravastatin Table 4 presents drug interactions that may decrease the efficacy of pravastatin and instructions for preventing or managing them.
• Table 4:
• Drug Interactions that Decrease the Efficacy of Pravastatin Bile Acid Sequestrants Clinical Impact:
• Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [see Clinical Pharmacology (12.3) ].
• Intervention:
• In patients taking a bile acid sequestrant, administer pravastatin at least 1 hour before or at least 4 hours after the bile acid sequestrant [see Dosage and Administration (2.5) ].
• Drug-Drug Interactions Table 5:
• Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Pravastatin Coadministered Drug and Dosing Regimen Dose (mg) Change in AUC Change in C max BID = twice daily;
• OD = once daily;
• QID = four times daily Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ↓47% ↓53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓51% ↓38% ↓18% ↑4.9% ↑23% ↓33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑33% ↑26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓28% ↓24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓7.0% ↓20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ↓3.6% ↓8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 40 mg single dose ↓1.8% ↑3.7% Table 6:
• Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max BID = twice daily;
• OD = once daily 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17% ↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0% ↑1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change

No specific antidotes for pravastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations.