Pravastatin Sodium (Page 4 of 9)

6.2 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 [see Warnings and Precautions ( 5.1)].

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.

6.3 Laboratory Test Abnormalities

Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions (5.1, 5.2)].

Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.

6.4 Pediatric Patients

In a 2 year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n = 214; age range 8 to 18.5 years, 53% female, 95% Caucasians, < 1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo [see Warnings and Precautions (5.3), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)].

7 DRUG INTERACTIONS

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

7.1 Cyclosporine

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

7.2 Clarithromycin and Other Macrolide Antibiotics

The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin [see Dosage and Administration (2.7), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

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

7.3 Colchicine

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

7.4 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].

7.5 Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)].

7.6 Niacin

The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 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 [see Contraindications (4.3)]. 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 [see Data ]. 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 to 4% and 15 to 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 given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥ 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2).

In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2).

In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at ≥ 100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2).

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).

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