Pravastatin Drug Information
Generic name: PRAVASTATIN SODIUM
Uses of Pravastatin
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.
- 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.
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 of Pravastatin
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.
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.
Patients with Renal Impairment
In patients with severe renal impairment, a starting dose of 10 mg pravastatin daily is recommended.
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. 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.
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.
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.
Dosage in Patients Taking Clarithromycin
In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily.
Side Effects of Pravastatin
Postmarketing Experience
In addition to the events reported above, as with other drugs in this class, the following events have been reported during postmarketing experience with Pravastatin Sodium, regardless of causality assessment: Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis. There have been rare reports of 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.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
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.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).
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.
Laboratory Test Abnormalities Increases in ALT
AST values and CPK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy.
| Body System/Event | 5 mg N=100 | 10 mg N=153 | 20 mg N=478 | 40 mg N=171 | Any Dose N=902 | Placebo N=411 |
|---|---|---|---|---|---|---|
| Cardiovascular Angina Pectoris | 5.0 | 4.6 | 4.8 | 3.5 | 4.5 | 3.4 |
| Dermatologic Rash | 3.0 | 2.6 | 6.7 | 1.2 | 4.5 | 1.4 |
| Gastrointestinal Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension | 4.0 8.0 2.0 0.0 2.0 | 5.9 8.5 3.3 3.3 3.3 | 10.5 6.5 4.6 3.6 2.1 | 2.3 4.7 0.0 0.6 0.6 | 7.4 6.7 3.2 2.5 2.0 | 7.1 5.6 4.4 2.7 2.4 |
| General Fatigue Chest Pain Influenza | 4.0 4.0 4.0 | 1.3 1.3 2.6 | 5.2 3.3 1.9 | 0.0 1.2 0.6 | 3.4 2.7 2.0 | 3.9 1.9 0.7 |
| Musculoskeletal Musculoskeletal Pain Myalgia | 13.0 1.0 | 3.9 2.6 | 13.2 2.9 | 5.3 1.2 | 10.1 2.3 | 10.2 1.2 |
| Nervous System Headache Dizziness | 5.0 4.0 | 6.5 1.3 | 7.5 5.2 | 3.5 0.6 | 6.3 3.5 | 4.6 3.4 |
| Respiratory Pharyngitis Upper Respiratory Infection Rhinitis Cough | 2.0 6.0 7.0 4.0 | 4.6 9.8 5.2 1.3 | 1.5 5.2 3.8 3.1 | 1.2 4.1 1.2 1.2 | 2.0 5.9 3.9 2.5 | 2.7 5.8 4.9 1.7 |
| Investigation ALT Increased g-GT Increased CPK Increased | 2.0 3.0 5.0 | 2.0 2.6 1.3 | 4.0 2.1 5.2 | 1.2 0.6 2.9 | 2.9 2.0 4.1 | 1.2 1.2 3.6 |
| Body System/Event | Pravastatin (N=10,764) % of patients | Placebo (N=10,719) % of patients |
|---|---|---|
| Dermatologic Rash (including dermatitis) | 7.2 | 7.1 |
| General Edema Fatigue Chest Pain Fever Weight Gain Weight Loss | 3.0 8.4 10.0 2.1 3.8 3.3 | 2.7 7.8 9.8 1.9 3.3 2.8 |
| Musculoskeletal Musculoskeletal Pain Muscle Cramp Musculoskeletal Traumatism | 24.9 5.1 10.2 | 24.4 4.6 9.6 |
| Nervous System Dizziness Sleep Disturbance Anxiety/Nervousness Paresthesia | 7.3 3.0 4.8 3.2 | 6.6 2.4 4.7 3.0 |
| Renal/Genitourinary Urinary Tract Infection | 2.7 | 2.6 |
| Respiratory Upper Respiratory Tract Infection Cough Influenza Pulmonary Infection Sinus Abnormality Tracheobronchitis | 21.2 8.2 9.2 3.8 7.0 3.4 | 20.2 7.4 9.0 3.5 6.7 3.1 |
| Special Senses Vision Disturbance (includes blurred vision, diplopia) | 3.4 | 3.3 |
| Infections Viral Infection | 3.2 | 2.9 |
| Body System/Event | 5 mg N=100 | 10 mg N=153 | 20 mg N=478 | 40 mg N=171 | Any Dose N=902 | Placebo N=411 |
|---|---|---|---|---|---|---|
| Cardiovascular Angina Pectoris | 5.0 | 4.6 | 4.8 | 3.5 | 4.5 | 3.4 |
| Dermatologic Rash | 3.0 | 2.6 | 6.7 | 1.2 | 4.5 | 1.4 |
| Gastrointestinal Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension | 4.0 8.0 2.0 0.0 2.0 | 5.9 8.5 3.3 3.3 3.3 | 10.5 6.5 4.6 3.6 2.1 | 2.3 4.7 0.0 0.6 0.6 | 7.4 6.7 3.2 2.5 2.0 | 7.1 5.6 4.4 2.7 2.4 |
| General Fatigue Chest Pain Influenza | 4.0 4.0 4.0 | 1.3 1.3 2.6 | 5.2 3.3 1.9 | 0.0 1.2 0.6 | 3.4 2.7 2.0 | 3.9 1.9 0.7 |
| Musculoskeletal Musculoskeletal Pain Myalgia | 13.0 1.0 | 3.9 2.6 | 13.2 2.9 | 5.3 1.2 | 10.1 2.3 | 10.2 1.2 |
| Nervous System Headache Dizziness | 5.0 4.0 | 6.5 1.3 | 7.5 5.2 | 3.5 0.6 | 6.3 3.5 | 4.6 3.4 |
| Respiratory Pharyngitis Upper Respiratory Infection Rhinitis Cough | 2.0 6.0 7.0 4.0 | 4.6 9.8 5.2 1.3 | 1.5 5.2 3.8 3.1 | 1.2 4.1 1.2 1.2 | 2.0 5.9 3.9 2.5 | 2.7 5.8 4.9 1.7 |
| Investigation ALT Increased g-GT Increased CPK Increased | 2.0 3.0 5.0 | 2.0 2.6 1.3 | 4.0 2.1 5.2 | 1.2 0.6 2.9 | 2.9 2.0 4.1 | 1.2 1.2 3.6 |
| Body System/Event | Pravastatin (N=10,764) % of patients | Placebo (N=10,719) % of patients |
|---|---|---|
| Dermatologic Rash (including dermatitis) | 7.2 | 7.1 |
| General Edema Fatigue Chest Pain Fever Weight Gain Weight Loss | 3.0 8.4 10.0 2.1 3.8 3.3 | 2.7 7.8 9.8 1.9 3.3 2.8 |
| Musculoskeletal Musculoskeletal Pain Muscle Cramp Musculoskeletal Traumatism | 24.9 5.1 10.2 | 24.4 4.6 9.6 |
| Nervous System Dizziness Sleep Disturbance Anxiety/Nervousness Paresthesia | 7.3 3.0 4.8 3.2 | 6.6 2.4 4.7 3.0 |
| Renal/Genitourinary Urinary Tract Infection | 2.7 | 2.6 |
| Respiratory Upper Respiratory Tract Infection Cough Influenza Pulmonary Infection Sinus Abnormality Tracheobronchitis | 21.2 8.2 9.2 3.8 7.0 3.4 | 20.2 7.4 9.0 3.5 6.7 3.1 |
| Special Senses Vision Disturbance (includes blurred vision, diplopia) | 3.4 | 3.3 |
| Infections Viral Infection | 3.2 | 2.9 |
Warnings & Cautions for Pravastatin
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 Sodium. 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. The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. Some of these patients also received other concomitant immunosuppressive therapies.
Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. The use of fibrates alone may occasionally be associated with myopathy.
The benefit of further alterations in lipid levels by the combined use of Pravastatin Sodium with fibrates should be carefully weighed against the potential risks of this combination. Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine.
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.
Liver
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3 times the ULN for subjects with pretreatment values less than or equal to the ULN, or 4 times the pretreatment value for subjects with pretreatment values greater than the ULN but less than 1.5 times the ULN. Marked abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment groups.
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. In a 320patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the ULN for those with normal ALT (≤ ULN) at baseline or a doubling of the baseline ALT for those with elevated ALT (> ULN) at baseline.
Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation. It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin.
Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Pravastatin Sodium, promptly interrupt therapy.
If an alternate etiology is not found do not restart Pravastatin Sodium.
Endocrine Function
Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin.
However, the percentage of patients showing a ≥50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary- gonadal axis in pre-menopausal females are unknown.
Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones. In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8-13 years and 40 mg in the adolescents aged 14-18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol or testosterone ) relative to placebo.
There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo.
Drug Interactions with Pravastatin
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
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.
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.
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.
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.
Pregnancy Safety for Pravastatin
Pregnancy Risk Summary Pravastatin Sodium is contraindicated for use in pregnant woman because of the potential for fetal harm. As safety in pregnant women has not been established and there is no apparent benefit to therapy with Pravastatin Sodium during pregnancy, Pravastatin Sodium should be immediately discontinued as soon as pregnancy is recognized. Limited published data on the use of Pravastatin Sodium in pregnant women are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage.
In animal reproduction studies, no evidence of fetal malformations was seen in rabbits or rats exposed to 10 times to 120 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day. Fetal skeletal abnormalities, offspring mortality, and developmental delays occurred when pregnant rats were administered 10 times to 12 times the MRHD during organogenesis to parturition. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Limited published data on pravastatin have not shown an increased risk of major congenital malformations or miscarriage.
Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence.
In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. 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, 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 ).
In lactating rats, up to 7 times higher levels of pravastatin are present in the breast milk than in the maternal plasma, which corresponds to exposure 2 times the MRHD of 80 mg/day based on body surface area (mg/m 2 ).
Pediatric Use of Pravastatin
Pediatric Use The safety and effectiveness of Pravastatin Sodium 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. For dosing information. Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.
Contraindications for Pravastatin
Hypersensitivity Hypersensitivity to any component of this medication.
Liver
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 Sodium treatment should not breastfeed their infants.
Overdosage Information for Pravastatin
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.
Clinical Studies of Pravastatin
Primary Hypercholesterolemia ( Fredrickson Types IIa and IIb) Pravastatin Sodium is highly effective in reducing Total-C, LDL-C, and TG in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy.
In addition, Pravastatin Sodium is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous MI. A single daily dose is as effective as the same total daily dose given twice a day. In multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7).
In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The efficacy results of the individual studies were consistent with the pooled data (see Table 7). Treatment with Pravastatin Sodium modestly decreased VLDL-C and Pravastatin Sodium across all doses produced variable increases in HDL-C (see Table 7).
Table 7: Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Sodium Once Daily Administration In another clinical trial, patients treated with pravastatin in combination with cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).
Hypertriglyceridemia ( Fredrickson Type IV)
The response to pravastatin in patients with Type IV hyperlipidemia (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 246.0 mg/dL (see Table 8). The children (aged 8-13 years) were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the adolescents (aged 14-18 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 percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was similar.
Table 10: 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) The above least-squares mean values were calculated based on log-transformed lipid values. −23.16 Significant at p≤0.0001 when compared with placebo. The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the pravastatin group compared to 236 mg/dL (range: 105-438 mg/dL) in the placebo group. The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children.
The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
| Number (%) of Subjects | ||||
|---|---|---|---|---|
| Event | Pravastatin 40 mg (N=2081) | Placebo (N=2078) | Risk Reduction | p -value |
| Primary Endpoint | ||||
| CHD mortality or nonfatal MI The risk reduction due to treatment with Pravastatin Sodium was consistent in both sexes. | 212 (10.2) | 274 (13.2) | 24% | 0.003 |
| Secondary Endpoints | ||||
| Myocardial revascularization procedures (CABG or PTCA) | 294 (14.1) | 391 (18.8) | 27% | <0.001 |
| Stroke or TIA | 93 (4.5) | 124 (6.0) | 26% | 0.029 |
| Dose | Total-C | LDL-C | HDL-C | TG |
|---|---|---|---|---|
| Mean Percent Changes From Baseline After 8 Weeks A multicenter, double-blind, placebo-controlled study. | ||||
| Placebo (N=36) | −3% | −4% | +1% | −4% |
| 10mg (N=18) | −16% | −22% | +7% | −15% |
| 20mg (N=19) | −24% | −32% | +2% | −11% |
| 40mg (N=18) | −25% | −34% | +12% | −24% |
| Mean Percent Changes From Baseline After 6 Weeks Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies. | ||||
| Placebo (N=162) | 0% | −1% | -1% | +1% |
| 80mg (N=277) | −27% | −37% | +3% | −19% |
| Pravastatin 40 mg (N=429) | Placebo (N=430) | |
|---|---|---|
| TG | −21.1 (−34.8, 1.3) | −6.3 (−23.1, 18.3) |
| Total-C | −22.1 (−27.1, −14.8) | 0.2 (−6.9, 6.8) |
| LDL-C | −31.7 (−39.6, −21.5) | 0.7 (−9.0, 10.0) |
| HDL-C | 7.4 (−1.2, 17.7) | 2.8 (−5.7, 11.7) |
| Non-HDL-C | −27.2 (−34.0, −18.5) | −0.8 (−8.2, 7.0) |
| Median (min, max) at Baseline (mg/dL) | Median % Change(min, max) Pravastatin 40 mg (N=20) | |
| Study 1 | ||
| Total-C | 386.5 (245.0, 672.0) | −32.7 (−58.5, 4.6) |
| TG | 443.0 (275.0, 1299.0) | −23.7 (−68.5, 44.7) |
| VLDL-C a | 206.5 (110.0, 379.0) | −43.8 (−73.1, −14.3) |
| LDL-C a | 117.5 (80.0,170.0) | −40.8 (−63.7, 4.6) |
| HDL-C | 30.0 (18.0,88.0) | 6.4 (−45.0,105.6) |
| Non-HDL-C | 344.5 (215.0, 646.0) | −36.7 (−66.3, 5.8) |
| a N=14 | ||
| Median (min, max) at Baseline (mg/dL) | Median % Change(min, max) Pravastatin 40 mg (N=26) | |
| Study 2 | ||
| Total-C | 340.3 (230.1, 448.6) | −31.4 (−54.5, −13.0) |
| TG | 343.2 (212.6, 845.9) | −11.9 (−56.5, 44.8) |
| VLDL-C | 145.0 (71.5,309.4) | −35.7 (−74.7, 19.1) |
| LDL-C | 128.6 (63.8,177.9) | −30.3 (−52.2, 13.5) |
| HDL-C | 38.7 (27.1,58.0) | 5.0 (−17.7, 66.7) |
| Non-HDL-C | 295.8 (195.3, 421.5) | −35.5 (−81.0, −13.5) |
| Pravastatin 20 mg (Aged 8-13 years) N=65 | Pravastatin 40 mg (Aged 14-18 years) | Combined Pravastatin (Aged 8-18 years) N=106 | Combined Placebo (Aged 8-18 years) N=108 | 95% CI of the Difference Between Combined Pravastatin and Placebo | |
|---|---|---|---|---|---|
| LDL-C | −26.04 | −21.07 | −24.07 | −1.52 | (−26.74, −18.86) |
| TC | −20.75 | −13.08 | −17.72 | −0.65 | (−20.40, −13.83) |
| HDL-C | 1.04 | 13.71 | 5.97 | 3.13 | (−1.71, −7.43) |
| TG | −9.58 | −0.30 | −5.88 | −3.27 | (−13.95, 10.01) |
| ApoB (N) | −23.16 (61) Significant at p≤0.0001 when compared with placebo. | −18.08 (39) | −21.11 (100) | −0.97 (106) | (−24.29, −16.18) |
| Number (%) of Subjects | ||||
|---|---|---|---|---|
| Event | Pravastatin 40 mg (N=2081) | Placebo (N=2078) | Risk Reduction | p -value |
| Primary Endpoint | ||||
| CHD mortality or nonfatal MI The risk reduction due to treatment with Pravastatin Sodium was consistent in both sexes. | 212 (10.2) | 274 (13.2) | 24% | 0.003 |
| Secondary Endpoints | ||||
| Myocardial revascularization procedures (CABG or PTCA) | 294 (14.1) | 391 (18.8) | 27% | <0.001 |
| Stroke or TIA | 93 (4.5) | 124 (6.0) | 26% | 0.029 |
| Dose | Total-C | LDL-C | HDL-C | TG |
|---|---|---|---|---|
| Mean Percent Changes From Baseline After 8 Weeks A multicenter, double-blind, placebo-controlled study. | ||||
| Placebo (N=36) | −3% | −4% | +1% | −4% |
| 10mg (N=18) | −16% | −22% | +7% | −15% |
| 20mg (N=19) | −24% | −32% | +2% | −11% |
| 40mg (N=18) | −25% | −34% | +12% | −24% |
| Mean Percent Changes From Baseline After 6 Weeks Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies. | ||||
| Placebo (N=162) | 0% | −1% | -1% | +1% |
| 80mg (N=277) | −27% | −37% | +3% | −19% |
| Pravastatin 40 mg (N=429) | Placebo (N=430) | |
|---|---|---|
| TG | −21.1 (−34.8, 1.3) | −6.3 (−23.1, 18.3) |
| Total-C | −22.1 (−27.1, −14.8) | 0.2 (−6.9, 6.8) |
| LDL-C | −31.7 (−39.6, −21.5) | 0.7 (−9.0, 10.0) |
| HDL-C | 7.4 (−1.2, 17.7) | 2.8 (−5.7, 11.7) |
| Non-HDL-C | −27.2 (−34.0, −18.5) | −0.8 (−8.2, 7.0) |
| Median (min, max) at Baseline (mg/dL) | Median % Change(min, max) Pravastatin 40 mg (N=20) | |
| Study 1 | ||
| Total-C | 386.5 (245.0, 672.0) | −32.7 (−58.5, 4.6) |
| TG | 443.0 (275.0, 1299.0) | −23.7 (−68.5, 44.7) |
| VLDL-C a | 206.5 (110.0, 379.0) | −43.8 (−73.1, −14.3) |
| LDL-C a | 117.5 (80.0,170.0) | −40.8 (−63.7, 4.6) |
| HDL-C | 30.0 (18.0,88.0) | 6.4 (−45.0,105.6) |
| Non-HDL-C | 344.5 (215.0, 646.0) | −36.7 (−66.3, 5.8) |
| a N=14 | ||
| Median (min, max) at Baseline (mg/dL) | Median % Change(min, max) Pravastatin 40 mg (N=26) | |
| Study 2 | ||
| Total-C | 340.3 (230.1, 448.6) | −31.4 (−54.5, −13.0) |
| TG | 343.2 (212.6, 845.9) | −11.9 (−56.5, 44.8) |
| VLDL-C | 145.0 (71.5,309.4) | −35.7 (−74.7, 19.1) |
| LDL-C | 128.6 (63.8,177.9) | −30.3 (−52.2, 13.5) |
| HDL-C | 38.7 (27.1,58.0) | 5.0 (−17.7, 66.7) |
| Non-HDL-C | 295.8 (195.3, 421.5) | −35.5 (−81.0, −13.5) |
| Pravastatin 20 mg (Aged 8-13 years) N=65 | Pravastatin 40 mg (Aged 14-18 years) | Combined Pravastatin (Aged 8-18 years) N=106 | Combined Placebo (Aged 8-18 years) N=108 | 95% CI of the Difference Between Combined Pravastatin and Placebo | |
|---|---|---|---|---|---|
| LDL-C | −26.04 | −21.07 | −24.07 | −1.52 | (−26.74, −18.86) |
| TC | −20.75 | −13.08 | −17.72 | −0.65 | (−20.40, −13.83) |
| HDL-C | 1.04 | 13.71 | 5.97 | 3.13 | (−1.71, −7.43) |
| TG | −9.58 | −0.30 | −5.88 | −3.27 | (−13.95, 10.01) |
| ApoB (N) | −23.16 (61) Significant at p≤0.0001 when compared with placebo. | −18.08 (39) | −21.11 (100) | −0.97 (106) | (−24.29, −16.18) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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