Pravastatin Sodium: Package Insert and Label Information

PRAVASTATIN SODIUM- pravastatin sodium tablet
Glenmark Pharmaceuticals Inc., USA

1 INDICATIONS AND USAGE

Pravastatin sodium tablets are 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).

2.

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.

3.

As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia.

4.

As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH).

5.

As an adjunct to diet for the treatment of adults with:

•

Primary dysbetalipoproteinemia.

•

Hypertriglyceridemia.

2 DOSAGE AND ADMINISTRATION

Important Dosage and Administration Information

•

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.

2.2 Recommended Dosage in Adult Patients

The recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily.

Recommended Dosage in Pediatric Patients 8 Years of Age and Older with HeFH

•

In pediatric patients aged 8 to 13 years, the recommended dosage is pravastatin sodium tablets 20 mg once daily.

•

In pediatric patients aged 14 to 18 years, the recommended starting dosage is pravastatin sodium tablets 40 mg once daily.

2.4 Recommended Dosage in Patients with Renal Impairment

•

In patients with severe renal impairment, the recommended starting dosage is pravastatin sodium 10 mg once daily. 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.

2.5 Dosage and Administration Modifications Due to Drug Interactions

•

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)]:

•

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.

•

Clarithromycin and Erythromycin

The maximum recommended dosage is pravastatin sodium tablets 40 mg once daily.

3 DOSAGE FORMS AND STRENGTHS

Pravastatin Sodium Tablets, USP are supplied as:

•

10 mg of pravastatin sodium:Yellow colored, circular shaped, flat faced tablets with “G5” debossed on one side and “10” debossed on the other side.

•

20 mg of pravastatin sodium:Yellow, rounded-rectangular, biconvex tablets with “G5” debossed on one side and “20” debossed on the other side.

•

40 mg of pravastatin sodium:Green, rounded-rectangular, biconvex tablets with “G5” debossed on one side and “40” debossed on the other side.

•

80 mgof pravastatin sodium: Yellow, oval, biconvex tablets with “G5” debossed on one side and “80” debossed on the other side.

4 CONTRAINDICATIONS

​ Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 ​ ) ​ ].

​ Hypersensitivity to any pravastatin or any excipients in pravastatin sodium tablets.

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

Pravastatin sodium 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 sodium. 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 sodium-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 sodium dosage [see Drug Interactions (7.1)].

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

Pravastatin sodium is not recommended in patients taking gemfibrozil [see Drug Interactions (7)]. There are pravastatin sodium dosage restrictions for patients taking cyclosporin and select macrolide antibiotics [see Dosage and Administration (2.5)]. The following drugs when used concomitantly with pravastatin sodium may also increase the risk of myopathy and rhabdomyolysis: niacin, fibrates, and colchicine [see Drug Interactions (7)].

Discontinue pravastatin sodium if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if pravastatin sodium is discontinued. Temporarily discontinue pravastatin sodium 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 sodium dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

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 sodium if IMNM is suspected.

5.3 Hepatic Dysfunction

Increases in serum transaminases have been reported with use of pravastatin sodium [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 sodium or placebo in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with pravastatin sodium. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin sodium.

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 sodium initiation and when clinically indicated thereafter. pravastatin sodium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pravastatin sodium.

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 sodium. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

6 ADVERSE REACTIONS

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)]

6.1 Clinical Trials Experience

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 sodium placebo-controlled clinical trials, 1313 patients (age range 20 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 sodium 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 sodium-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

	% Placebo N=411	% Any Dose N=902
Nausea/Vomiting	7.1	7.4
Diarrhea	5.6	6.7
Headache	4.6	6.3
Upper Respiratory Infection	5.8	5.9
Angina Pectoris	3.4	4.5
Rash	1.4	4.5
CPK Increased	3.6	4.1
Dizziness	3.4	3.5
ALT Increased	1.2	2.9
Chest Pain	1.9	2.7
Cough	1.7	2.5
Myalgia	1.2	2.3
Influenza	0.7	2
g-GT Increased	1.2	2

Adverse Reactions (regardless of causality)

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.

In pravastatin sodium placebo-controlled clinical trials, 21,483 patients (age range 24 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 sodium 40 mg and 10,719 patients treated with placebo. Patients were exposed to pravastatin sodium for a mean of 4 to 5.1 years in WOS, CARE, and LIPID and 1.9 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 sodium 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

	Placebo (N=10,719) % of patients	Pravastatin sodium (N=10,764) % of patients
Musculoskeletal Pain	24.4	24.9
Upper Respiratory Tract Infection	20.2	21.2
Musculoskeletal Traumatism	9.6	10.2
Chest Pain	9.8	10
Influenza	9	9.2
Fatigue	7.8	8.4
Cough	7.4	8.2
Dizziness	6.6	7.3
Rash (including dermatitis)	7.1	7.2
Sinus Abnormality	6.7	7
Muscle Cramp	4.6	5.1

Adverse Reactions (regardless of causality)

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.