Pravastatin

Pravastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Pravastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and to reduce the risk of cardiovascular events, including myocardial infarction and stroke.

Pravastatin is administered orally in the active form. Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), Cmax, and steady-state minimum (C min), 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. Approximately 50% of the circulating drug is bound to plasma proteins. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). 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.

Pravastatin shows common side effects like Heartburn, headache, memory loss or forgetfulness, confusion.

Pravastatin is available in the form of an Oral Tablet.

Pravastatin is available in India, US, UK, Spain, Canada, Japan, Singapore, Russia, and China.

Pravastatin belongs to the Antilipemic Agent acts as a HMG-CoA Reductase Inhibitor.

Pravastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the rate-limiting enzyme involved in de novo cholesterol synthesis. In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects.

The Data of onset of action of Pravastatin is not clinically established.

The duration of action of Pravastatin is around 10 hours.

The Tmax of Pravastatin is approximately 1-1.5 hours.

Pravastatin is available in the form Oral Tablet.

Pravastatin Tablet is taken orally, usually once daily.

Pravastatin is a lipid-lowering medicine that contains pravastatin. It is used to reduce the levels of bad cholesterol and fats (triglycerides) in your blood to reduce the risk of strokes and heart attacks. Cholesterol is a fatty substance that forms in your blood vessels as plaques which reduces the free flow of blood and causes heart diseases. It reduces cholesterol by blocking an enzyme responsible for making cholesterol in your blood.

Pravastatin is an HMG-CoA reductase inhibitor belonging to Antilipemic Agent.

Pravastatin inhibits HMG-CoA reductase, the enzyme which catalyses the rate-limiting step in cholesterol biosynthesis. It reduces concentration of total cholesterol and LDL cholesterol and triglyceride. It produces an increase in HDL cholesterol and it increases hepatic cholesterol uptake from blood.

Pravastatin is approved for use in the following clinical indications

Adult indication

• Prevention of atherosclerotic cardiovascular disease
• Heterozygous familial hypercholesterolemia
• Homozygous familial hypercholesterolemia

Although not approved, there have been certain off-label indications. These include

• Transplantation

Pediatric indication

• Hyperlipidemia or heterozygous familial and nonfamilial hypercholesterolemia

Adult Dose

• Prevention of atherosclerotic cardiovascular disease

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

• Heterozygous familial hypercholesterolemia

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

• Homozygous familial hypercholesterolemia
• Primary prevention

Patients without diabetes, 40 to 75 years of age, and LDL-C 70 to 189 mg/dL:

ASCVD 10-year risk 5% to <7.5%

Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥7.5% to <20%:

Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49%; higher-risk patients with multiple risk-enhancing factors may benefit from high-intensity statin therapy (ie, with atorvastatin or rosuvastatin) to reduce LDL-C by ≥50%.

ASCVD 10-year risk ≥20% (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin)

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

Patients with diabetes:

Age 40 to 75 years without additional ASCVD risk factors:

Moderate-intensity therapy: Oral: 40 to 80 mg once daily to reduce LDL-C by 30% to 49%.

ASCVD 10-year risk ≥20% or multiple ASCVD risk factors (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

Patients with LDL-C ≥190 mg/dL and 20 to 75 years of age (regardless of ASCVD risk estimate or coexisting diabetes mellitus) (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

• Secondary prevention in patients with established atherosclerotic cardiovascular disease (eg, coronary heart disease, cerebrovascular disease [ischemic stroke or transient ischemic attack], peripheral arterial disease) (alternative agent):

Patients unable to tolerate high-intensity therapy (eg, appropriate dose of atorvastatin or rosuvastatin):

Moderate-intensity therapy: Oral: 40 to 80 mg once daily.

• Transplantation (off-label use)

Transplantation, post heart

Oral: Initial: 20 mg once daily starting 1 to 2 weeks after transplant, regardless of baseline cholesterol levels; increase dose based on response, tolerability, and concomitant drugs up to 40 mg once daily.

Transplantation, post kidney

Oral: Initial: 20 mg once daily; increase dose based on response, tolerability, and concomitant drugs up to 40 mg once daily.

Pediatric Dose

• Hyperlipidemia or heterozygous familial and nonfamilial hypercholesterolemia

Children and Adolescents 8 to 13 years

Oral: 20 mg once daily; lower doses (5 and 10 mg/day) have been evaluated and less efficacy observed compared to 20 mg doses; doses >20 mg has not been studied.

Adolescents 14 to 18 years

Oral: 40 mg once daily; lower doses have been evaluated and less efficacy observed; doses >40 mg has not been studied.

Pravastatin is available in various strengths as 10 mg; 20 mg; 40 mg; 80 mg.

Pravastatin is available in the form of Oral Tablet.

• Dosage Adjustment in Kidney Patient

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl ≤30 mL/minute: Initial: 10 mg once daily. May increase based on efficacy and tolerability up to the indication-specific usual recommended dose.

• Dosage Adjustment in Hepatic impairment Patient

Active hepatic disease or unexplained persistent elevations of serum transaminases: Use is contraindicated.

Chronic liver disease: Some experts suggest starting at a low dose (eg, 10 mg once daily) and adjusting gradually based on monitoring of aminotransferase level.

Pravastatin is contraindicated in patients with

• Hypersensitivity

Hypersensitivity to any component of this medication.

• Liver disease

Active liver disease or unexplained, persistent elevations of serum transaminases.

• Pregnancy

Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. Pravastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately, and the patient apprised of the potential hazard to the fetus.

• Lactation

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

• Immune-Mediated Necrotizing Myopathy

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which 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. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

• Diabetes mellitus

Increases in HbA_1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.

• Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Uncomplicated myalgia has also been reported in pravastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the ULN, was rare (<0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Pravastatin. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur, or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking Pravastatin should not nurse. Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Common Adverse effects

• Nausea, vomiting, heartburn, diarrhoea, headache, cough, insomnia, chest pain, rash, fatigue, dizziness, influenza, blurred vision, myalgia, elevated serum transaminase, alopoecia, paraesthesia, impotence, gynaecomastia.

Rare Adverse effects

• Severe rhabdomyolysis w/ acute renal failure. Hepatitis, pancreatitis. Rare: Stevens-Johnson syndrome, anaphylaxis, toxic epidermal necrolysis.

• Cyclosporine

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

• Clarithromycin And Other Macrolide Antibiotics

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin.

Other macrolides (e.g., erythromycin and azithromycin) have the potential to increase statin exposures while used in combination. Pravastatin should be used cautiously with macrolide antibiotics due to a potential increased risk of myopathies.

• Colchicine

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

• Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Pravastatin with gemfibrozil should be avoided.

• Other Fibrates

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

• Niacin

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

The common side effects of Pravastatin include the following

Common

● Heartburn, headache, memory loss or forgetfulness, confusion.

Rare

● Muscle pain, tenderness, or weakness, lack of energy, fever, yellowing of the skin or eyes, pain in the upper right part of the stomach, nausea, extreme tiredness, weakness, unusual bleeding or bruising, dark colored urine, loss of appetite, flu-like symptoms, rash, hives, itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness.

• Pregnancy

Pregnancy Category X

Safety in pregnant women has not been established. Available data in women inadvertently taking Pravastatin while pregnant do not suggest any adverse clinical events. However, there are no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether pravastatin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus and patients have been informed of the potential hazards.

• Nursing Mothers

A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking Pravastatin should not nurse. Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.

• Pediatric Use

The safety and effectiveness of Pravastatin in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy. Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

• Geriatric Use

Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was like that seen in younger subjects. The adverse event profile in the elderly was like that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25%-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. Since advanced age (≥65 years) is a predisposing factor for myopathy, Pravastatin should be prescribed with caution in the elderly.

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

Pharmacodynamic

The action of pravastatin on the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase produces an increase in the expression of hepatic LDL receptors which in order decreases the plasma levels of LDL cholesterol. The effect of pravastatin has been shown to significantly reduce the circulating total cholesterol, LDL cholesterol, and apolipoprotein B. As well, it modestly reduces very low-density-lipoproteins (VLDL) cholesterol and triglycerides while increasing the level of high-density lipoprotein (HDL) cholesterol and apolipoprotein A. In clinical trials with patients with a history of myocardial infarction or angina with high total cholesterol, pravastatin decreased the level of total cholesterol by 18%, decreased of LDL by 27%, decreased of triglycerides by 6% and increased of high-density lipoprotein (HDL) by 4%. As well, there was reported a decrease in risk of death due to coronary disease of 24%. When co-administered with cholestyramine, pravastatin can reduce by 50% the levels of LDL and slow the progression of atherosclerosis and the risk of myocardial infarction and death.

Pharmacokinetics

• Absorption

Pravastatin 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 a morning 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 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.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019898s062lbl.pdf
• https://www.rxlist.com/pravachol-drug.htm#indications
• https://reference.medscape.com/drug/pravachol-pravastatin-342460
• https://medlineplus.gov/druginfo/meds/a692025.html#side-effects
• https://www.uptodate.com/contents/pravastatin-drug-information#F212484