Prescription Drug Information: PRAVASTATIN SODIUM (Page 2 of 7)

5.4 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 [girls] or testosterone [boys]) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo.

6 ADVERSE REACTIONS

Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant.

6.1 Adverse Clinical Events

Short-Term Controlled Trials

In the Pravastatin Sodium placebo-controlled clinical trials database of 1313 patients (age range 20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on Pravastatin Sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.

All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:

Table 1: Adverse Events in ≥2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients)
Body System/Event 5 mgN=100 10 mgN=153 20 mgN=478 40 mgN=171 Any DoseN=902 PlaceboN=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
GastrointestinalNausea/VomitingDiarrheaFlatulenceDyspepsia/HeartburnAbdominal Distension 4.08.02.00.02.0 5.98.53.33.33.3 10.56.54.63.62.1 2.34.70.00.60.6 7.46.73.22.52.0 7.15.64.42.72.4
GeneralFatigueChest PainInfluenza 4.04.04.0 1.31.32.6 5.23.31.9 0.01.20.6 3.42.72.0 3.91.90.7
Musculoskeletal Musculoskeletal Pain Myalgia 13.01.0 3.92.6 13.22.9 5.31.2 10.12.3 10.21.2
Nervous System Headache Dizziness 5.04.0 6.51.3 7.55.2 3.50.6 6.33.5 4.63.4
RespiratoryPharyngitisUpper Respiratory InfectionRhinitisCough 2.06.07.04.0 4.69.85.21.3 1.55.23.83.1 1.24.11.21.2 2.05.93.92.5 2.75.84.91.7
InvestigationALT Increasedg-GT IncreasedCPK Increased 2.03.05.0 2.02.61.3 4.02.15.2 1.20.62.9 2.92.04.1 1.21.23.6

The safety and tolerability of Pravastatin Sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Pravastatin Sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.

Long-Term Controlled Morbidity and Mortality Trials

In the Pravastatin Sodium placebo-controlled clinical trials database of 21,483 patients (age range 24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on Pravastatin Sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality.

Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.

Table 2: Adverse Events in ≥2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo- Controlled Trials
Body System/Event Pravastatin (N=10,764)% of patients Placebo (N=10,719)% of patients
DermatologicRash (including dermatitis) 7.2 7.1
GeneralEdemaFatigueChest PainFeverWeight GainWeight Loss 3.08.410.02.13.83.3 2.77.89.81.93.32.8
MusculoskeletalMusculoskeletal PainMuscle CrampMusculoskeletal Traumatism 24.95.110.2 24.44.69.6
Nervous SystemDizzinessSleep DisturbanceAnxiety/NervousnessParesthesia 7.33.04.83.2 6.62.44.73.0
Renal/Genitourinary Urinary Tract Infection 2.7 2.6
RespiratoryUpper Respiratory Tract InfectionCoughInfluenzaPulmonary InfectionSinus AbnormalityTracheobronchitis 21.28.29.23.87.03.4 20.27.49.03.56.73.1
Special SensesVision Disturbance (includes blurred vision, diplopia) 3.4 3.3
InfectionsViral Infection 3.2 2.9

In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in <2.0% of pravastatin-treated patients in the long-term trials included the following:

Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

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