Prescription Drug Information: Pravastatin Sodium (Page 2 of 8)

5.2 Liver

Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In 3 long-term (4.8 to 5.9 years), placebo-controlled clinical trials (WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or placebo [see Clinical Studies (14)]. 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 320 patient 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. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. 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 [see Contraindications (4.2)]. 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.

5.3 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 to 13 years and 40 mg in the adolescents aged 14 to 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 to 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)

5 mg

10 mg

20 mg

40 mg

Any Dose

Placebo

Body System/Event

N = 100

N = 153

N = 478

N = 171

N = 902

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

4.0

5.9

10.5

2.3

7.4

7.1

Diarrhea

8.0

8.5

6.5

4.7

6.7

5.6

Flatulence

2.0

3.3

4.6

0.0

3.2

4.4

Dyspepsia/Heartburn

0.0

3.3

3.6

0.6

2.5

2.7

Abdominal Distension

2.0

3.3

2.1

0.6

2.0

2.4

General

Fatigue

4.0

1.3

5.2

0.0

3.4

3.9

Chest Pain

4.0

1.3

3.3

1.2

2.7

1.9

Influenza

4.0

2.6

1.9

0.6

2.0

0.7

Musculoskeletal

Musculoskeletal Pain

13.0

3.9

13.2

5.3

10.1

10.2

Myalgia

1.0

2.6

2.9

1.2

2.3

1.2

Nervous System

Headache

5.0

6.5

7.5

3.5

6.3

4.6

Dizziness

4.0

1.3

5.2

0.6

3.5

3.4

Respiratory

Pharyngitis

2.0

4.6

1.5

1.2

2.0

2.7

Upper Respiratory

Infection

6.0

9.8

5.2

4.1

5.9

5.8

Rhinitis

7.0

5.2

3.8

1.2

3.9

4.9

Cough

4.0

1.3

3.1

1.2

2.5

1.7

Investigation

ALT Increased

2.0

2.0

4.0

1.2

2.9

1.2

g-GT Increased

3.0

2.6

2.1

0.6

2.0

1.2

CPK Increased

5.0

1.3

5.2

2.9

4.1

3.6


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 to 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

Pravastatin

Placebo

(N = 10,764)

(N = 10,719)

Body System/Event

% of patients

% of patients

Dermatologic

Rash (including dermatitis)

7.2

7.1

General

Edema

3.0

2.7

Fatigue

8.4

7.8

Chest Pain

10.0

9.8

Fever

2.1

1.9

Weight Gain

3.8

3.3

Weight Loss

3.3

2.8

Musculoskeletal

Musculoskeletal Pain

24.9

24.4

Muscle Cramp

5.1

4.6

Musculoskeletal Traumatism

10.2

9.6

Nervous System

Dizziness

7.3

6.6

Sleep Disturbance

3.0

2.4

Anxiety/Nervousness

4.8

4.7

Paresthesia

3.2

3.0

Renal/Genitourinary

Urinary Tract Infection

2.7

2.6

Respiratory

Upper Respiratory Tract Infection

21.2

20.2

Cough

8.2

7.4

Influenza

9.2

9.0

Pulmonary Infection

3.8

3.5

Sinus Abnormality

7.0

6.7

Tracheobronchitis

3.4

3.1

Special Senses

Vision Disturbance (includes blurred vision, diplopia)

3.4

3.3

Infections

Viral 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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