PRAVASTATIN SODIUM- pravastatin sodium_tablet

Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of pravastatin is usually achieved by 4 weeks and is maintained after that. Absorption Pravastatin is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 hours to 1. 5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max Pravastatin plasma concentrations, including AUC, C max min The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max Steady-state AUCs, C max min Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3alpha-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3alpha-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0. Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i. , biliary excretion and biotransformation). Following single dose oral administration of 14 ½ ½ Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3alpha-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max ½ [see Use in Specific Populations ( 8. 6 Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects. [see Use in Specific Populations ( 8. 6 Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 years to 75 years old) compared with younger men (19 years to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 years to 78 years old) compared with younger women (18 years to 38 years old). In both studies, C max max ½ [see Use in Specific Populations ( 8. 5 Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80. 7 (CV 44%) and 44. 8 (CV 89%) ng*hr/mL for pediatric patients 8 years to 11 years (N=14) and 12 years to 16 years (N=10), respectively. The corresponding values for C max [see Use in Specific Populations ( 8. 4 Drug-Drug Interactions Table 5 Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin BID = twice daily; OD = once daily; QID = four times daily Coadministered Drug and Pravastatin Dosing Regimen Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose up arrow 282% up arrow 327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days up arrow 110% up arrow 128% Boceprevir 800 mg TID for 6 days 40 mg single dose up arrow 63% up arrow 49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose up arrow 81% up arrow 63% Colestipol 10 g single dose 20 mg single dose down arrow 47% down arrow 53% Cholestyramine 4 g single dose 20 mg single dose down arrow 40% down arrow 39% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks down arrow 51% up arrow 4. 9% Fluconazole 20 mg PO+10 mg IV down arrow 34% down arrow 33% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days up arrow33% up arrow26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose up arrow 31% up arrow 42% Cimetidine 300 mg QID for 3 days 20 mg single dose up arrow 30% up arrow 9. 8% Antacids 15 mL QID for 3 days 20 mg single dose down arrow 28% down arrow 24% Digoxin 0. 2 mg OD for 9 days 20 mg OD for 9 days up arrow 23% up arrow 26% Probucol 500 mg single dose 20 mg single dose up arrow 14% up arrow 24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days down arrow 13% up arrow 6. 7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days up arrow 11% (compared to Day 1) up arrow 17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose down arrow 7% down arrow 20% Aspirin 324 mg single dose 20 mg single dose up arrow 4. 7% up arrow 8. 9% Niacin 1 g single dose 20 mg single dose down arrow 3. 6% down arrow 8. 2% Diltiazem 20 mg single dose up arrow 2. 7% up arrow 30% Grapefruit juice 40 mg single dose down arrow 1. 8% up arrow 3. 7% Table 6 Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs BID = twice daily; OD = once daily Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time up arrow 17% up arrow 15% 20 mg OD for 9 days Digoxin 0. 2 mg OD for 9 days up arrow 4. 6% up arrow 5. 3% 20 mg BID for 4 weeks Antipyrine 1. 2 g single dose up arrow 3% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change.

Pravastatin sodium tablet, USP is an HMG-CoA reductase inhibitor (statin) indicated ( 1 To reduce the risk of myocardial infarction, myocardial revascularization procedures and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Pravastatin sodium tablets are indicated: To reduce the risk of myocardial infarction, myocardial revascularization procedures and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack and slow the progression of coronary atherosclerosis in adults with clinically evident CHD.

Take orally once daily at any time of the day, with or without food ( 2. 1 For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment ( 2. 1 Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pravastatin sodium tablets, and adjust the dosage if necessary ( 2. 1 Adults: recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. 2 Pediatric Patients ( 2. 3 aged 8 to 13 years, the recommended dosage is 20 mg once daily. aged 14 to 18 years, the recommended starting dosage is 40 mg once daily. Severe renal impairment: recommended starting dosage is pravastatin sodium 10 mg once daily. Use another pravastatin sodium product to initiate dosing. Recommended maximum pravastatin sodium tablets dosage is 40mg once daily. 4 See full prescribing information for dosage modifications due to drug interactions ( 2. 5 7 Take pravastatin sodium tablets orally once daily as a single dose at any time of the day with or without food. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablets 80 mg daily prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate as early as 4 weeks after initiating pravastatin sodium tablets and adjust the dosage if necessary. The recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. In pediatric patients aged 8 years to 13 years the recommended dosage is pravastatin sodium tablets 20 mg once daily. In pediatric patients aged 14 years to 18 years the recommended starting dosage is pravastatin sodium tablets 40 mg once daily. In patients with severe renal impairment the recommended starting dosage is pravastatin sodium 10 mg once daily. Pravastatin sodium tablets are not available in a 10 mg strength. Use another pravastatin sodium product to initiate dosing in such patients. The maximum recommended dosage of pravastatin sodium tablets in patients with severe renal impairment is 40 mg once daily [see Clinical Pharmacology ( 12. 3 The recommended dosage of pravastatin sodium tablets for patients with mild or moderate renal impairment is the same as patients with normal renal function. In patients taking a bile acid sequestrant administer pravastatin sodium tablets at least 1 hour before or 4 hours after the bile acid sequestrant [see Drug Interactions ( 7. 2 Concomitant use of pravastatin sodium tablets with the following drugs requires dosage modifications of pravastatin sodium tablets [see Warnings and Precautions (5. 1) and Drug Interactions ( 7. 1 circle Cyclosporine In patients taking cyclosporine the recommended starting dosage is pravastatin sodium 10 mg once daily. The maximum recommended dosage of pravastatin sodium tablets in patients taking cyclosporine is 20 mg once daily. circle Clarithromycin and Erythromycin The maximum recommended dosage is pravastatin sodium tablets 40 mg once daily.

In short-term clinical trials, the most commonly reported adverse reactions (>= 2% and greater than placebo) were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea and headache. 1 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779, or FDA at 1-800-FDA-1088 or www. gov/medwatch. The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5. 1 Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5. 2 Hepatic Dysfunction [see Warnings and Precautions ( 5. 3 Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5. 4 Because clinical studies are conducted under widely varying conditions adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In pravastatin placebo-controlled clinical trials 1,313 patients (age range 20 years to 76 years, 32% women, 93. 5% White, 5% Black, 0. 9% Hispanic, 0. 4% Asian, 0. 2% Other) with a median treatment duration of 14 weeks, 3. 3% of patients on pravastatin and 1. 2% patients on placebo discontinued due to adverse reactions (regardless of causality). The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: hepatic transaminase elevations, nausea, anxiety/depression and dizziness. Adverse reactions (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 Reactions in >= 2% of Patients Treated with Pravastatin (Any Dose) and at an Incidence Greater Than Placebo in Short-Term Placebo- Controlled Trials Adverse Reactions (regardless of causality) % Placebo N=411 % Any Dose N=902 Nausea/Vomiting 7. 4 Diarrhea 5. 7 Headache 4. 3 Upper Respiratory Infection 5. 9 Angina Pectoris 3. 5 CPK Increased 3. 1 Dizziness 3. 5 ALT Increased 1. 9 Chest Pain 1. 5 Myalgia 1. 3 Influenza 0. 7 2 g-GT Increased 1. 2 2 The safety and tolerability of pravastatin at a dose of 80 mg in 2 controlled trials with a mean exposure of 8. 6 months was similar to that of pravastatin 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. In pravastatin placebo-controlled clinical trials 21,483 patients (age range 24 years to 75 years, 10. 3% women, 52. 3% White, 0. 8% Black, 0. 5% Hispanic, 0. 1% Asian, 0. 1% Other, 46. 1% not recorded) had a median treatment duration of 261 weeks. Adverse reactions (regardless of causality) 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. Patients were exposed to pravastatin for a mean of 4 years to 5. 1 years in WOS, CARE, and LIPID and 1. 9 years to 2. 9 years in PLAC I, PLAC II, KAPS and REGRESS. Adverse reactions (regardless of causality) occurring in >= 5% of patients treated with pravastatin in these studies are identified in Table 2: Table 2 Adverse Reactions in >= 5% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater than Placebo in Long-Term Placebo-Controlled Trials Adverse Reactions (regardless of causality) Placebo (N=10,719) % of patients Pravastatin (N=10,764) % of patients Musculoskeletal Pain 24. 9 Upper Respiratory Tract Infection 20. 2 Musculoskeletal Traumatism 9. 2 Chest Pain 9. 8 10 Influenza 9 9. 2 Fatigue 7. 2 Dizziness 6. 3 Rash (including dermatitis) 7. 2 Sinus Abnormality 6. 7 7 Muscle Cramp 4. 1 No new adverse reactions were identified in a study of pediatric patients with HeFH. Laboratory Abnormalities Increases in ALT, AST values and CK 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. The following adverse reactions have been identified during post approval use of pravastatin. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal myopathy, rhabdomyolysis, tendon disorder, polymyositis, 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. Rare postmarketing reports of cognitive impairment (e. , memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis including ocular myasthenia and reports of recurrence when the same or a different statin was administered. 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. , nodules, discoloration, dryness of mucous membranes, changes to hair/nails),lichen planus. 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.

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.

Pregnancy: May cause fetal harm ( 8. 1 Lactation: Breastfeeding not recommended during treatment with pravastatin sodium tablets ( 8. 2 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 (see Data). 2 (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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. 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 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 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). 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 (C max max ½ [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 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 sodium 10 mg once daily. Pravastatin is not available in a 10 mg strength. Use another pravastatin sodium product to initiate dosing in such patients. 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. 3 Pravastatin shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [Clinical Pharmacology ( 12. 3 [see Contraindications ( 4 5.

See full prescribing information for details regarding concomitant use of pravastatin sodium tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. 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 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. 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. Pravastatin is not available in a 10 mg strength. Use another pravastatin sodium product to initiate dosing. 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. , 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 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 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 Sodium Tablets 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.

OVERDOSAGE
No specific antidotes for pravastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations.
NONCLINICAL TOXICOLOGY
In a 2 year study in rats fed pravastatin at doses of 10 mg/kg, 30 mg/kg or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p < 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 In a 2 year study in mice fed pravastatin at doses of 250 mg/kg/day and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 mg/kg/day and 500 mg/kg/day (p < 0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg based on AUC. In another 2 year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro Salmonella typhimurium Escherichia coli Saccharomyces cerevisiae In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5 mg/kg/day, 15 mg/kg/day and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3 rd
CLINICAL STUDIES
Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), th th Pravastatin significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin group [CHD death=31, nonfatal MI=143], p=0. 0001 [see figure below]). The risk reduction with pravastatin was similar across the age range studied and throughout the range of baseline LDL cholesterol levels. Pravastatin also decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients). Cardiovascular deaths were decreased by 32% (73 vs 50) and there was no increase in death from non-cardiovascular causes. Secondary Prevention of Cardiovascular Events In the LIPID study, the effect of pravastatin, 40 mg daily, was assessed in 9,014 patients (7,498 men; 1,516 women; 3,514 patients >= 65 years; 782 patients with diabetes) who had experienced either an MI (5,754 patients) or had been hospitalized for unstable angina pectoris (3,260 patients) in the preceding 3 months to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5. 6 years (median of 5. 9 years) and at randomization had Total-C between 114 mg/dL and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 mg/dL and 274 mg/dL (mean 150 mg/dL), TG between 35 mg/dL and 2,710 mg/dL (mean 160 mg/dL), and HDL-C between 1 mg/dL and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin significantly reduced the risk for total mortality by reducing coronary death (see Table 7). The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age. Pravastatin significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 7 LIPID - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4,512) Placebo (N=4,502) Risk Reduction p Primary Endpoint CHD mortality 287 (6. 0004 Secondary Endpoints Total mortality 498 (11) 633 (14. 0001 CHD mortality or nonfatal MI 557 (12. 0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12. 0001 Stroke All-cause 169 (3. 0477 Non-hemorrhagic 154 (3. 0154 Cardiovascular mortality 331 (7. 0001 In the CARE study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4,159 patients (3,583 men and 576 women) who had experienced a MI in the preceding 3 months to 20 months and who had normal (below the 75 th th th Table 8 CARE - Primary and Secondary Endpoints a Number (%) of Subjects Event Pravastatin 40 mg (N=2,081) Placebo (N=2,078) Risk Reduction p Primary Endpoint CHD mortality or nonfatal MI a 212 (10. 003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14. 001 Stroke or TIA 93 (4. 029 Primary Hyperlipidemia In multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin in daily doses ranging from 10 mg to 40 mg consistently and significantly decreased Total-C, LDL-C and TG (see Table 9). In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C and TG. The 25 th th Table 9 Primary Hyperlipidemia Trials: Dose Response of Pravastatin Once Daily Administration a b Dose Total-C LDL-C HDL-C TG Mean Percent Changes From Baseline After 8 Weeks a Placebo (N=36) −3% −4% +1% −4% 10 mg (N=18) −16% −22% +7% −15% 20 mg (N=19) −24% −32% +2% −11% 40 mg (N=18) −25% −34% +12% −24% Mean Percent Changes From Baseline After 6 Weeks b Placebo (N=162) 0% −1% −1% +1% 80 mg (N=277) −27% −37% +3% −19% Hypertriglyceridemia The response to pravastatin in patients with hypertriglyceridemia (baseline TG > 200 mg/dL and LDL-C < 160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200. 5) mg/dL (see Table 10). Table 10 Patients with Hypertriglyceridemia Median (25 th th Pravastatin 40 mg (N=429) Placebo (N=430) TG −21. 3) Total-C −22. 8) LDL-C −31. 7 (−9, 10) HDL-C 7. 7) Non-HDL-C −27. 2 (−34, −18. 2, 7) Dysbetalipoproteinemia The response to pravastatin in two double-blind crossover studies of 46 patients with genotype E2/E2 and dysbetalipoproteinemia is shown in Table 11 Table 11 Patients with Dysbetalipoproteinemia Median (min, max) % Change from Baseline Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20) Study 1 Total-C 386. 5 (245, 672) −32. 6) TG 443 (275, 1299) −23. 7) VLDL-C a 206. 5 (110, 379) −43. 3) LDL-C a 117. 5 (80, 170) −40. 6) HDL-C 30 (18, 88) 6. 4 (−45, 105. 6) Non-HDL-C 344. 5 (215, 646) −36. 8) a Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26) Study 2 Total-C 340. 5, −13) TG 343. 8) VLDL-C 145 (71. 1) LDL-C 128. 5) HDL-C 38. 1, 58) 5 (−17. 7) Non-HDL-C 295. 5 (−81, −13. 5) HeFH in Pediatric Patients Aged 8 Years and Above A double-blind, placebo-controlled study in 214 pedatric patients (100 males and 114 females) with heterozygous familial hypercholesterolemia (HeFH), aged 8 years to 18 years was conducted for 2 years. The pediatric patients aged 8 years to 13 years were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the pediatric patients aged 14 years to 18 years were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95 th Pravastatin significantly decreased plasma levels of LDL-C, Total-C and ApoB in both pediatric age groups (see Table 12). The effect of pravastatin treatment in the 2 age groups was similar. Table 12 Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a a b Pravastatin 20 mg (Aged 8 years to 13 years) N=65 Pravastatin 40 mg (Aged 14 years to 18 years) N=41 Combined Pravastatin (Aged 8 years to 18 years) N=106 Combined Placebo (Aged 8 years to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo LDL-C −26. 83) HDL-C 1. 01) ApoB (N) −23. 18) The mean achieved LDL-C was 186 mg/dL (range: 67 mg/dL to 363 mg/dL) in the pravastatin group k to 236 mg/dL (range: 105 mg/dL to 438 mg/dL) in the placebo group. Pravastatin Sodium Tablets, USP.

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