CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.

12.3 Pharmacokinetics

General

Absorption: Pravastatin Sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 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 systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.

Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), Cmax, and steady-state minimum (Cmin), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose.

The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin Cmax and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of Pravastatin Sodium tablets.

Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.

Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-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 0.66).

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.e., biliary excretion and biotransformation).

Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for pravastatin is 1.8 hours in humans.

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 3α-hydroxyl 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 Cmax values, respectively, and a 0.61 hour shorter t1/2 for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).

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 Warnings and Precautions (5.3).]

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 (65-75 years old) compared with younger men (19-31 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 (65-78 years old) compared with younger women (18-38 years old). In both studies, Cmax, Tmax, and t1/2 values were similar in older and younger subjects. [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 children (8-11 years, N=14) and adolescents (12-16 years, N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability. [See Use in Specific Populations (8.4).]

Drug-Drug Interactions

Table 3: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin

BID = twice daily; OD = once daily; QID = four times daily

Table 4: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs

BID = twice daily; OD = once daily

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INDICATIONS & USAGE SECTION

Highlight: Pravastatin Sodium is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to:

• Reduce the risk of MI, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident CHD.(1.1)
• Reduce the risk of total mortality by reducing coronary death, MI, revascularization, stroke/TIA, and the progression of coronary atherosclerosis in patients with clinically evident CHD.(1.1)
• Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL­ C in patients with primary hypercholesterolemia and mixed dyslipidemia.(1.2)
• Reduce elevated serum TG levels in patients with hypertriglyceridemia.(1.2)
• Treat patients with primary dysbetalipoproteinemia who are not responding to diet.(1.2)
• Treat children and adolescent patients ages 8 years and older with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy.(1.2)

Limitations of use:

• Pravastatin sodium has not been studied in Fredrickson Types I and V dyslipidemias.(1.3)

1 INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

1.1 Prevention of Cardiovascular Disease

In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), Pravastatin Sodium is indicated to:

• reduce the risk of myocardial infarction (MI).
• reduce the risk of undergoing myocardial revascularization procedures.
• reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.

In patients with clinically evident CHD, Pravastatin Sodium is indicated to:

• reduce the risk of total mortality by reducing coronary death.
• reduce the risk of MI
• reduce the risk of undergoing myocardial revascularization procedures.
• reduce the risk of stroke and stroke/transient ischemic attack (TIA).
• slow the progression of coronary atherosclerosis.

1.2 Hyperlipidemia

Pravastatin Sodium is indicated:

• as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb).1
• as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV).
• for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet.
• as an adjunct to diet and lifestyle modification for treatment of heterozygous familial hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present:

a. LDL-C remains ≥190 mg/dL or

b. LDL-C remains ≥160 mg/dL and:

• there is a positive family history of premature cardiovascular disease (CVD) or
• two or more other CVD risk factors are present in the patient.

1.3 Limitations of Use

Pravastatin Sodium has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

DOSAGE & ADMINISTRATION SECTION

Highlight: * Adults: the recommended starting dose is 40 mg once daily. Use 80 mg dose only for patients not reaching LDL-C goal with 40 mg. (2.2)

• Significant renal impairment: the recommended starting dose is pravastatin 10 mg once daily. (2.3)
• Children (ages 8 to 13 years, inclusive): the recommended starting dose is 20 mg once daily. (2.4)
• Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg once daily. (2.4)

2 DOSAGE AND ADMINISTRATION

2.1 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 [see NCEP Treatment Guidelines for details on dietary therapy].

2.2 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.

2.3 Patients with Renal Impairment

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

2.4 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 [see Indications and Usage (1.2)].

2.5 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. [See Clinical Pharmacology (12.3)]

2.6 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 [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].

2.7 Dosage in Patients Taking Clarithromycin

In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions (7.2)].

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DRUG INTERACTIONS SECTION

Highlight: * Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with Pravastatin Sodium.(7)

• Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg once daily. (2.6, 7.1)
• Clarithromycin: combination increases exposure. Limit pravastatin to 40 mg once daily.(2.7, 7.2)

7 DRUG INTERACTIONS

For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or erythromycin, the risk of myopathy increases [see Warnings and Precautions(5.1)** andClinical Pharmacology (12.3)****].**

7.1 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 [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

7.2 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 [see Dosage and Administration (2.7), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

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.

7.3 Colchicine

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine [see Warnings and Precautions (5.1)].

7.4 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 [see Warnings and Precautions (5.1)].

7.5 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 [see Warnings and Precautions (5.1)].

7.6 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 [see Warnings and Precautions (5.1)].

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, 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/m2) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 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, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

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.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.

A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5-45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body- weight gain was observed during the dosing and 52-day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period.

Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water- maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Muscle Pain

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Pravastatin Sodium [see Warnings and Precautions (5.1)].

Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of Pravastatin Sodium, and thereafter when clinically indicated. All patients treated with Pravastatin Sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.3)].

Embryofetal Toxicity

Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4.3), Use in Specific Populations (8.1,8.3)].

Lactation

Advise women not to breastfeed during treatment with Pravastatin Sodium [see Contraindications (4.4), Use in Specific Populations (8.2)].

Manufactured by:

Appco Pharma LLC
Piscataway, NJ 08854

Manufactured for:

Biocon Pharma Inc.,
485 US Highway 1 S
Suite B305, Iselin
NJ 08830-3009

USA

Revised: 10/2020

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied
Pravastatin Sodium Tablets, USP are supplied as:

40 mg tablets: White to off-white, rounded, rectangular-shaped, biconvex tablets debossed with “B 40” on one side and plain on other side. They are supplied in bottles of 30’s Count (NDC: 63629-9164-1), 60’s Count (NDC: 63629-9164-2).

16.2 Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.

Repackaged/Relabeled by:
Bryant Ranch Prepack, Inc.
Burbank, CA 91504

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