PRAVASTATIN SODIUM

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer without regard to meals.
-The package labeling states that pravastatin may be taken anytime of day, but guidelines suggest administration in the evening. Pravastatin has been shown to be similarly effective (slightly less effective, but not significantly different) in lowering cholesterol when administered in the morning versus evening.

Pravastatin has been well tolerated in controlled clinical trials. In a placebo-controlled trial in pediatric patients (n = 214, age 8-18.5 years), the safety and tolerability profile was similar in patients receiving pravastatin and placebo over a follow-up of 2 years. In this pediatric trial, there were no detectable differences seen in any endocrine parameters compared to placebo. In long-term trials in adult patients, the most common reasons for discontinuation of pravastatin were mild, non-specific gastrointestinal (GI) complaints.

Thyroid function abnormalities have been reported with post marketing experience of pravastatin.

Amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease) has been reported to the FDA in a higher than expected number of patients taking statins, such as pravastatin. ALS is a progressive motor neuron disorder with symptoms such as difficulty walking or standing, difficulty with fine motor skills, atrophy of tongue and hand muscles, dysphagia, dysarthria, and muscle paralysis. Due to the seriousness of ALS and the extensive use of statins, FDA further examined data from 41 long-term controlled clinical trials. The results of the review showed no increased incidence of ALS in patients treated with a statin compared with placebo. Specifically, 9 of approximately 64,000 patients treated with a statin (4.2 cases per 100,000 patient-years) and 10 of approximately 56,000 patients treated with placebo (5 case per 100,000 patient-years) were diagnosed with ALS. FDA is examining the feasibility of performing additional epidemiologic studies to further examine the incidence and clinical course of ALS in patients taking statins.

Gastrointestinal symptoms were the most common adverse effects to pravastatin therapy in a small trial of 30 pediatric patients (ages 4.1-18.5 years). Abdominal pain (6-13%), diarrhea (3-7%), and flatulence (3-17%) were all more common in the first few months of therapy and declined with continued use. Gastrointestinal adverse reactions were reported during pravastatin clinical trials in adults, but the incidence of these effects was generally similar to placebo. Nausea, vomiting, and diarrhea were the most common, occurring in 2-8% of subjects. Abdominal pain, constipation, flatulence, and dyspepsia or pyrosis (heartburn) was reported by 2-4%. Decreased appetite (anorexia) was reported in < 1% of patients treated with pravastatin in long-term trials. Dysgeusia has been reported in post marketing experience with pravastatin.

Sleep disorder was reported by 3-7% of pediatric patients in one small clinical trial of pravastatin (n = 30). Fatigue (1.9-9% of adults) and insomnia (< 2%) have also been associated with pravastatin use in adult patients. Moderate doses of pravastatin (40 mg/day PO) were associated with drowsiness and exertional fatigue in a study that randomized 1016 adult patients to simvastatin, pravastatin, or placebo for 6 months. Based on patient-reported energy and fatigue scales, statin use was associated with a statistically significant adverse effect on energy and exertional fatigue compared to placebo.

Fever and flushing were reported in <= 2.1% of adult patients during long-term pravastatin trials. If fever is accompanied by any muscle symptoms, carefully evaluate to rule out a more serious reaction.

Musculoskeletal pain is a relatively common adverse effect in adults (reported by up to nearly 25% in some long-term pravastatin trials), but serious muscle toxicity is much less common. Myalgia, myasthenia, muscle cramps, tendon disorder, and polymyositis have also been reported. The risk of serious toxicity appears to be extremely low in pediatric patients ; however, the true incidence is not known. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, has been rarely reported (< 0.1%) during pravastatin adult clinical trials. Statin-induced myopathy is generally dose-related and the risk is higher when statins are used in combination with certain interacting drugs. Rhabdomyolysis and acute renal failure (unspecified) (secondary to renal tubular obstruction, myoglobinuria) have been reported with statins. In general, rhabdomyolysis is a rare (< 1/100,000 prescriptions) complication of statin therapy. Rhabdomyolysis may occur anytime during drug treatment and the risk may be increased by a number of confounding factors including age, concomitant drug therapy, renal dysfunction, and concomitant disease states. Many cases result in hospitalization and a need for dialysis for treatment. Monitor patients for symptoms of myopathy or rhabdomyolysis (unexplained lethargy/drowsiness, myalgia, muscle cramps, muscle weakness, muscle tenderness, weakness/asthenia, myasthenia, fatigue, and/or fever) and elevated creatine phosphokinase (CPK) serum concentrations. Discontinue pravastatin immediately in any patient who develops myopathy or elevations in CPK.

Although rare, severe hepatotoxicity may occur during HMG-CoA reductase inhibitor (statin) therapy. Hepatitis, fatty changes of the liver, cholestasis with jaundice, pancreatitis, and rarely, cirrhosis, fulminant hepatic necrosis, hepatic failure, and hepatoma have been reported during statin therapy. Pravastatin therapy has been associated with elevated hepatic enzymes. Perform liver function tests (LFTs) prior to initiation of therapy with pravastatin and then repeat as clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart pravastatin. Marked elevations of ALT or AST have been reported in < 1.2% of adult patients receiving either placebo or pravastatin during long-term clinical trials. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as pravastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.

In a 2-year controlled study of children and adolescents aged 8 to 18 years with heterozygous familial hypercholesterolemia (n = 214), the safety and tolerability profile of pravastatin was generally similar to placebo, with headache being common in both treatment groups. In a small trial of 30 pediatric patients (4 to 18 years of age), 1 to 4 subjects reported headache at various time points during the study. During adult clinical trials for pravastatin, the following additional central nervous system adverse effects were reported: dizziness (1% to 8%), headache (1% to 7%), depression (1%), anxiety/nervousness (< 5%), and sleep disturbances (1%). Rare cases of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) have been associated with the use of statins in adults; the clinical implications of this in pediatric patients is not yet clear. An association between the event and a specific statin, statin dose, or concomitant medication was not found in an FDA review of available data. In general, post-marketing reports described patients over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon statin discontinuation. The time to symptom onset (1 day to years) and resolution (median 3 weeks) is variable. Vertigo, paresthesias, tremor, impairment of extraocular movement, facial paresis, and peripheral nerve palsy have been also been reported by adult patients; the incidence and relationship to the drug are not clear. Nightmares have been reported with post-marketing use.

Adult data has shown a risk for increased hemoglobin A1c and fasting serum glucose (hyperglycemia) with HMG-CoA reductase inhibitors (statins); the actual risk for pediatric patients is not clear. A meta-analysis of 13 statin trials with 91,140 adult participants showed a 9% increase in the likelihood of the development of diabetes mellitus (OR 1.09; 95% CI 1.02-1.17). The incidence of diabetes was higher in high-risk patients (i.e., age 70-82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure) compared to patients with low diabetes risk (i.e., low BMI). Additionally, an analysis of the data from the Women's Health Initiative (WHI) trial found that statin use in postmenopausal women is associated with an increased risk of new-onset diabetes mellitus (multivariate-adjusted HR 1.48; 95% CI 1.38-1.59). No difference in the risk for diabetes between statins was detected in either analysis. The increased risk of diabetes should be considered when initiating statin therapy in patients at low risk for cardiovascular events and in patient groups where the cardiovascular benefit of statin therapy has not been established.

Gynecomastia has been reported with statins. Statins interfere with cholesterol synthesis and lower circulating cholesterol concentrations and theoretically may blunt gonadal steroid hormone production. In a study of 21 adult males, the mean testosterone response to human chorionic gonadotropin (HCG) was significantly reduced after 16 weeks of treatment with pravastatin 40 mg; however, the percentage of patients showing a >= 50% rise in plasma testosterone after HCG stimulation did not change significantly after therapy in these patients. Although data are somewhat limited, clinical trials in children and adolescents have found no adverse effects on growth, sexual maturation, or hormone levels after 2 years of pravastatin therapy. Monitor patients carefully for any potential adverse effects on endocrine function and use caution if other drugs that affect endogenous steroid hormones are used concomitantly.

Anemia, thrombocytopenia, and leukopenia have been reported with HMG-CoA reductase inhibitors. Transient, asymptomatic eosinophilia has been reported with pravastatin; eosinophil counts generally return to normal with continued therapy.

During short- and long-term placebo-controlled clinical trials of pravastatin in adults, angina pectoris was reported in approximately 3-5% of patients (vs. 3% placebo) and chest pain (unspecified) was reported in 0.1-10% of patients (vs. 0-10% placebo). Edema was reported in approximately 3% of patients, which was similar to placebo.

Rash (unspecified) is the most common dermatological adverse effect reported with pravastatin therapy occurring in 1-8% of adults; the incidence in pediatric patients in not known. Less frequent reactions reported by < 2% of adults include alopecia, dry skin (xerosis), urticaria, and pruritus. Angioedema has been reported rarely during post-marketing use. A variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails) have also been reported during post-marketing experience of pravastatin. A hypersensitivity syndrome has been reported rarely with HMG-CoA reductase inhibitors that has included one or more of the following features or anaphylactoid reactions: anaphylaxis, angioedema, lupus-like symptoms, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome.

An association between HMG-CoA reductase inhibitors (statins), including pravastatin, and peripheral neuropathy has been reported in the literature (case series, case-control studies, cohort studies). Case reports and series indicate that the onset of neuropathy is typically > 1 year after drug initiation and is reversible with drug discontinuation. However, cases describing irreversible neuropathy are also reported. The adverse effect appears to be a class effect because in all cases, when a patient is either rechallenged or treated with a different statin, the symptoms of neuropathy return. While the data appear to support an association between HMG-CoA reductase inhibitors and peripheral neuropathy, the incidence is rare and estimated to be approximately 1 per 14,000 person-years. Furthermore, a causal relationship cannot be definitively established based on the observational nature of the available data. The benefits of statin therapy far outweigh any risk of peripheral neuropathy; however, until more information is available, health care providers should be aware of this adverse effect.

In a 2-year controlled study of children and adolescents aged 8 to 18 years with heterozygous familial hypercholesterolemia (n = 214), the safety and tolerability profile of pravastatin was generally similar to placebo, with influenza common in both treatment groups. Respiratory adverse reactions reported during short- and long-term placebo-controlled clinical trials of pravastatin in adults include dyspnea, cough, upper respiratory infection, and rhinitis. Interstitial lung disease has been reported with post-marketing use.

Urinary abnormalities, including dysuria, nocturia, and increased urinary frequency, were reported in <= 1% of adult patients in short- and long-term clinical trials of pravastatin and during post-marketing evaluation. The incidence in pediatric patients is unknown.

Vision disturbances, including blurred vision and diplopia, was reported in approximately 1-4% of adult patients during long-term clinical trials of pravastatin. Lens opacity was reported in < 1% of adults during long-term clinical trials; the clinical implications for the long-term use in pediatric patients is unclear.

HMG-CoA reductase inhibitors (statins), such as pravastatin, inhibit the synthesis of mevalonate and decrease Co-Enzyme Q-10 concentrations, which may lead to Co-Enzyme Q-10 deficiency. Supplementation with vitamin Co-Enzyme Q-10 may limit potential adverse reactions.

Exacerbation and induction of myasthenia gravis has been reported during treatment with statins, including pravastatin. In a review of adult patients enrolled at a neuromuscular disease clinic over a 4-year time period, 6 of 54 myasthenia gravis patients (11%) receiving statin therapy experienced worsening myasthenia gravis. In a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database, 169 of 3,967 (4.2%) of adverse reactions with the term 'myasthenia gravis and related conditions' were related to statin therapy. The reporting odds ratio (ROR) of myasthenia gravis relative to all other adverse reactions was 2.66 [95% CI: 2.28, 3.1] for statin therapy. In addition, the ROR was greater than 1 and statistically significant for all individual statins except lovastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

Pravastatin is contraindicated in patients with certain types of hepatic disease, specifically acute liver failure and decompensated cirrhosis (hepatic decompensation). Use pravastatin with caution in patients who consume substantial quantities of alcohol (alcoholism) and/or have a history of liver disease, including cholestasis, hepatic encephalopathy, hepatitis, or jaundice. Assess liver enzymes prior to initiating pravastatin therapy and repeat as clinically indicated. Although rare, there have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins. Previous recommendations included a specific schedule for monitoring liver enzymes; however, after extensive data review, the FDA concluded that the risk of serious liver injury is very low and routine periodic monitoring of liver enzymes has not been effective in detection or prevention of serious hepatic injury. Instruct patients and caregivers to promptly report any symptoms of hepatic injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice). If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin, promptly discontinue therapy.

Pravastatin may cause myopathy and rhabdomyolysis. Acute renal failure secondary to myoglobinuria and rare fatalities due to rhabdomyolysis have been reported with statin therapy. Discontinue pravastatin immediately in any patient who develops myopathy, marked elevations in creatinine phosphokinase (CK), or rhabdomyolysis. Consider myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CK values greater than 10 times upper limit of normal (ULN), in any patient with diffuse myalgias, muscle tenderness, or weakness, and/or marked elevation of CK. Advise patients to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Predisposing risk factors for myopathy and/or rhabdomyolysis include uncontrolled hypothyroidism, females, renal disease or renal insufficiency, liver disease, diabetes, uncontrolled seizure disorder, pre-existing muscle disease, Chinese ancestry, major surgery, or trauma. The true risk in pediatric patients is not known. Temporary withdrawal of pravastatin is recommended in patients with acute or serious conditions that places them at high risk of developing renal failure due to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic disorder, endocrine disease, or electrolyte imbalance; or uncontrolled epilepsy). The risk of developing myopathy is increased when pravastatin is used concomitantly with selected other drugs, such as gemfibrozil, erythromycin, cyclosporine, niacin, fibrates, colchicine, and OATP1B1 inhibitors. Although renal impairment does not appear to alter the pharmacokinetics of pravastatin, a lower initial dose and careful dosage titration is recommended in patients with severe renal impairment since renal insufficiency is a risk factor for myopathy.

Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, has occurred rarely (1 to 3 of every 100,000 patients) with HMG-CoA reductase inhibitors, such as pravastatin. Recurrence of IMNM has been reported following administration of the same or a different statin. IMNM is characterized by myalgia with symmetrical and proximal muscle weakness and elevated serum creatine phosphokinase, which persist despite discontinuation of HMG-CoA reductase inhibitor treatment. Some cases have occurred months to years after starting HMG-CoA reductase therapy and the myopathy progressed following therapy discontinuation. Other characteristics include positive anti-HMG-CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Dysphagia and respiratory failure have also been reported in patients with IMNM. Reported serum creatine phosphokinase levels have ranged from 576 to 35,000 International Units/L. Patients who develop IMNM may require additional neuromuscular and serologic testing. If IMNM develops, HMG-CoA reductase inhibitor therapy should be discontinued and treatment with immunosuppressants, such as high dose corticosteroids, intravenous immune globulin (IVIG), or other immunosuppressive agents, may be needed.

Increased hemoglobin A1c, hyperglycemia, and worsening glycemic control have been reported during therapy with HMG-CoA reductase inhibitors. Although statin therapy has been associated with a risk of hyperglycemia and new-onset diabetes mellitus, this is not deemed to be of clinical importance as the beneficial effects of statins on cardiovascular event reduction outweigh potential risk. Inform patients of the potential risk and the importance of optimizing lifestyle measures, including regular exercise, maintaining a healthy bodyweight, and making healthy food choices.

Safety and efficacy of pravastatin have not been established in infants and children younger than 8 years of age. Because cholesterol plays a crucial role in growth and development, the clinical implications of using pharmacologic therapy to alter the normal production of cholesterol in young children is not clear. Because of these potential safety concerns and lack of safety data, most experts generally recommend delaying cholesterol-lowering medications until the child is at least 8 to 10 years old. In some cases of severe familial hypercholesterolemia, however, HMG-CoA reductase inhibitors have been used in younger children with careful monitoring of growth and development.

Exacerbation and induction of myasthenia gravis have been reported during treatment with statins, including pravastatin. The onset of symptoms following initiation of statin therapy has ranged from 1 week to 4 months for exacerbation and 6 months to 6 years for induction of myasthenia gravis. Partial or complete recovery has been reported following discontinuation of statin therapy; however, some patients have required treatment with pyridostigmine or immunosuppressive agents. Though this appears to be a rare adverse reaction, clinicians should closely monitor patients with myasthenia gravis for disease exacerbation and encourage them to report any muscle-related symptoms.

Description: Pravastatin is an oral antilipemic agent that inhibits HMG-CoA reductase. In contrast to many other statins, pravastatin is relatively hydrophilic and does not require hydrolysis for activation. Pravastatin is effective in reducing total and LDL-cholesterol as well as plasma triglycerides and apolipoprotein B. At doses of 10 to 60 mg once daily, pravastatin reduces mean LDL concentrations in pediatric patients by 24% to 32%. Pravastatin is indicated in adult patients to prevent fatal and nonfatal cardiovascular events based on the favorable findings of several studies, which demonstrated reduced all-cause mortality, coronary deaths, and rates of myocardial infarction, stroke, and revascularization. Although evidence of beneficial long term effects on cardiovascular outcomes and mortality in pediatric patients is not available, statins are recommended as first-line for pharmacologic therapy of hyperlipidemia in pediatric patients based on evidence of short-term safety and efficacy. Although statins are typically approved for use in pediatric patients 10 years and older, pravastatin is FDA-approved in patients as young as 8 years of age with heterozygous familial hypercholesterolemia.

General Dosing Information
-Pravastatin is FDA-approved for the treatment of heterozygous familial high cholesterol and is recommended after an adequate trial of diet, if the LDL-C remains 190 mg/dL or more; or if the LDL-C remains 160 mg/dL or more in a high-risk patient (positive family history of premature cardiovascular disease or the presence of 2 or more other cardiovascular disease risk factors).

For the treatment of hypercholesterolemia (including heterozygous familial hypercholesterolemia), hyperlipoproteinemia, and/or hypertriglyceridemia, as an adjunct to dietary control, for the purpose of reducing the risk of cardiovascular events (e.g., myocardial infarction prophylaxis, stroke prophylaxis):
Oral dosage:
Children 4 to 7 years*: Pharmacologic therapy is not generally recommended for young children; however, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Mean serum total cholesterol, LDL, and triglyceride concentrations were decreased by 26%, 32%, and 34%, respectively, after 2 years of treatment. Although pharmacologic therapy is not routinely recommended for patients younger than 10 years of age, it may be considered in patients with severe primary hyperlipidemia or high level risk factors (e.g. diabetes, organ transplant, obesity, hypertension, chronic renal disease, strong family history of premature cardiovascular disease). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 8 to 13 years: 20 mg PO once daily is the FDA-approved dosage. Alternatively, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Decreases in mean serum total cholesterol, LDL, and triglyceride concentrations reported in observational and placebo-controlled studies were 18% to 26%, 24% to 32%, and 6% to 34%, respectively, after 2 years of treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents 14 to 18 years: 40 mg PO once daily is the FDA-approved dosage. Alternatively, 10 mg PO once daily initially, then titrated up in 10 mg increments every 2 months (Max: 60 mg/day) was studied in a small observational study of 30 patients with familial hypercholesterolemia (ages 4.1 to 18.5 years). Pravastatin was started at 10 mg in all patients regardless of age or size; the dosage was increased gradually if the target total cholesterol concentration of 194 mg/dL or less was not achieved. At 2 years, doses of pravastatin in patients available for follow-up were as follows: 10 mg, n = 1; 20 mg, n = 4; 40 mg, n = 2; 50 mg, n = 4; 60 mg, n = 3. Decreases in mean serum total cholesterol, LDL, and triglyceride concentrations reported in observational and placebo-controlled studies were 18% to 26%, 24% to 32%, and 6% to 34%, respectively, after 2 years of treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 3 years: Safety and efficacy have not been established.
4 to 7 years: Safety and efficacy have not been established; however, doses of 10 mg/day PO or more were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).
8 to 12 years: 20 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).
-Adolescents
13 years: 20 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age was not defined, overall maximum for the study was 60 mg/day).
14 to 18 years: 40 mg/day PO is the FDA-approved maximum dose; however, higher doses were reported in a small study (exact maximum dosage for this age group was not defined, overall maximum for the study was 60 mg/day).

Patients with Hepatic Impairment Dosing
Contraindicated in patients with active liver disease or with unexplained or persistent hepatic transaminase elevations.

Patients with Renal Impairment Dosing
Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available. Modify dosage depending on clinical response and degree of renal impairment. An initial dose of 10 mg PO once daily is recommended in adult patients with severe renal impairment and the maximum recommended dose is 40 mg once daily.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Pravastatin is a reversible inhibitor of hydroxymethylglutaryl-Coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol concentrations in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol (LDL-C) from the blood. Sustained inhibition of cholesterol synthesis in the liver also decreases concentrations of very-low-density lipoproteins (VLDL), the precursor for LDL. The result is a reduction of circulating total cholesterol and LDL-C. Minor effects are also seen on HDL cholesterol (increase) and triglycerides (decrease).

HMG-CoA reductase inhibitors have also been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

Pharmacokinetics: Pravastatin is administered orally. It is approximately 50% protein bound and undergoes extensive first-pass extraction and metabolism by the liver. The major metabolic pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3-alpha-hydroxyisomer of pravastatin and (b) enzymatic ring hydroxylation to SQ 31.945. Metabolites do not possess significant clinical activity. After oral administration, roughly 20% of a dose is eliminated in the urine and 70% in the feces. The elimination half-life of pravastatin is approximately 1.6 to 1.8 hours.

Affected cytochrome P450 isoenzymes and drug transporters: OATP1B1, OATP1B3, OAT3, and MRP2
Pravastatin is a substrate for the drug transporters OATP1B1, OATP1B3, OAT3, and MRP2. Unlike many other statins, in vitro and in vivo data with known CYP3A4 inhibitors suggest that pravastatin is not a clinically significant CYP3A4 substrate. For example, diltiazem (CYP3A4 inhibitor and substrate) has no effect on the pharmacokinetics of pravastatin.


-Route-Specific Pharmacokinetics
Oral Route
Pravastatin is rapidly absorbed from the GI tract. Unlike lovastatin or simvastatin, pravastatin does not require hydrolysis for activation. In adults, peak plasma concentrations (Cmax) are reached approximately 1 to 1.5 hours after administration. In a small pharmacokinetic trial in 20 pediatric patients, the mean time to Cmax was 1.4 hours (range, 0.5 to 4 hours) after a 10 mg dose. The average absorption is 34%, but due to significant first-pass elimination (extraction ratio 0.66), absolute bioavailability is only 17%. While the presence of food reduces the AUC by 31% and Cmax by 49%, the lipid-lowering effect was similar whether pravastatin was taken with or 1 hour prior to meals. Systemic bioavailability of pravastatin after a bedtime dose was 60% lower than the bioavailability after morning administration. Despite the difference in bioavailability, the efficacy of pravastatin is slightly higher (but not statistically significantly different) with evening dosing relative to morning dosing. This may be explained by more extensive uptake of the drug by hepatocytes, the site of action, and/or the diurnal variation in cholesterol synthesis.


-Special Populations
Pediatrics
Children and Adolescents
The pharmacokinetics of pravastatin in patients with heterozygous familial hypercholesterolemia (n = 20, age 4.9 to 15.6 years) after a single oral dose of 10 mg were similar to those of adults. The mean Cmax, AUC, and elimination half-life were 15.7 ng/mL (SD, 14.4), 26.6 ng x hour/mL (SD, 17), and 1.6 hours (SD, 0.7), respectively, compared to 11.6 ng/mL, 31.3 ng x hour/mL, and 1.8 hours in adults. There was a significant negative correlation between Cmax and age and weight, indicating that plasma concentrations of pravastatin are higher in younger and smaller patients. In another study of pravastatin 20 mg PO once daily for 2 weeks, Cmax and AUC were 42.4 ng/mL and 80.7 ng x hour/mL, respectively, in children 8 to 11 years and 18.6 ng/mL and 44.8 ng x hour/mL, respectively, in adolescents 12 to 16 years.

Hepatic Impairment
Pravastatin undergoes extensive first-pass extraction and metabolism by the liver. Although data are limited, it appears that patients with cirrhosis display significantly altered pharmacokinetics; the effect of less severe hepatic disease is not clear. In a study comparing the pharmacokinetics of pravastatin in adult patients with cirrhosis (n = 7) to individuals with normal hepatic function (n = 7), pravastatin demonstrated large inter-subject pharmacokinetic variability in patients with liver cirrhosis. The mean AUC varied by 18-fold and the Cmax by 47-fold in patients with cirrhosis compared to 5-fold and 6-fold, respectively, in healthy patients.

Renal Impairment
Renal impairment does not appear to affect the pharmacokinetics of pravastatin or its 3-alpha-hydroxy isomeric metabolite. However, compared to healthy individuals with normal renal function, an increase in the mean AUC and Cmax of 69% and 37%, respectively, and decrease in the half-life of the inactive enzymatic ring hydroxylation metabolite has been documented in patients with severe renal impairment.