Pravastatin Sodium (Page 5 of 9)

8.2 Lactation

Risk Summary

Pravastatin use is contraindicated during breastfeeding [see Contraindications (4.4)]. Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with pravastatin sodium.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Pravastatin sodium may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with pravastatin sodium.

8.4 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 [see Adverse Reactions (6.4)]. 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 [see Contraindications (4.3) and Use in Specific Populations (8.1)]. For dosing information [see Dosage and Administration (2.4)].

Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

8.5 Geriatric Use

Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.

Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology (12.3)].

Since advanced age (≥ 65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.6 Homozygous Familial Hypercholesterolemia

Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that statins are less effective because the patients lack functional LDL receptors.

10 OVERDOSAGE

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.

11 DESCRIPTION

Pravastatin sodium, USP is one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.

Pravastatin sodium, USP is designated chemically as 1-naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1 S -[1α (β S *,δ S *),2α,6α,8β( R *),8aα]]-. It has the following structural formula:

pravastatin sodium structural formula

C 23 H 35 NaO 7 M.W. 446.52

Pravastatin sodium, USP is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (> 300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether.

Pravastatin sodium tablets USP are available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg tablets. Inactive ingredients include: calcium phosphate dibasic, crospovidone, lactose anhydrous, microcrystalline cellulose, and povidone. Additionally, the 10 mg, 20 mg, and 40 mg tablet contains croscarmellose sodium and sodium stearyl fumarate. Additionally, the 10 mg tablet contains ferric oxide red; the 20 mg tablet contains ferric oxide yellow; the 40 mg tablet contains FD&C Blue No. 1 Aluminum Lake and Yellow D&C No. 10; and the 80 mg tablet contains magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.

12.3 Pharmacokinetics

General

Absorption: Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.

Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose.

The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.

Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets.

Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.

Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).

Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation).

Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans.

Specific Populations

Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).

Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N = 7) and normal subjects (N = 7), the mean AUC varied 18 fold in cirrhotic patients and 5 fold in healthy subjects. Similarly, the peak pravastatin values varied 47 fold for cirrhotic patients compared to 6 fold for healthy subjects [see Warnings and Precautions (5.2)].

Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C max , T max , and t ½ values were similar in older and younger subjects [see Use in Specific Populations (8.5)].

Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8 to 11 years, N = 14) and adolescents (12 to 16 years, N = 10), respectively. The corresponding values for C max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [ see Use in Specific Populations ( 8.4) ].

Drug-Drug Interactions

Table 3: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin

Coadministered Drug and Dosing Regimen

Pravastatin

Dose (mg)

Change in AUC

Change in C max

Cyclosporine 5 mg/kg single dose

40 mg single dose

↑282%

↑327%

Clarithromycin 500 mg BID for 9 days

40 mg OD for 8 days

↑110%

↑128%

Boceprevir 800 mg TID for 6 days

40 mg single dose

↑63%

↑49%

Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days

40 mg single dose

↑81%

↑63%

Colestipol 10 g single dose

20 mg single dose

↓47%

↓53%

Cholestyramine 4 g single dose

20 mg single dose

Administered simultaneously

↓40%

↓39%

Administered 1 hour prior to
cholestyramine

↑12%

↑30%

Administered 4 hours after
cholestyramine

↓12%

↓6.8%

Cholestyramine 24 g OD for 4 weeks

20 mg BID for 8 weeks

↓51%

↑4.9%

5 mg BID for 8 weeks

↓38%

↑23%

10 mg BID for 8 weeks

↓18%

↓33%

Fluconazole

200 mg IV for 6 days

20 mg PO + 10 mg IV

↓34%

↓33%

200 mg PO for 6 days

20 mg PO + 10 mg IV

↓16%

↓16%

Kaletra 400 mg/100 mg BID for 14

days

20 mg OD for 4 days

↑33%

↑26%

Verapamil IR 120 mg for 1 day and

Verapamil ER 480 mg for 3 days

40 mg single dose

↑31%

↑42%

Cimetidine 300 mg QID for 3 days

20 mg single dose

↑30%

↑9.8%

Antacids 15 mL QID for 3 days

20 mg single dose

↓28%

↓24%

Digoxin 0.2 mg OD for 9 days

20 mg OD for 9 days

↑23%

↑26%

Probucol 500 mg single dose

20 mg single dose

↑14%

↑24%

Warfarin 5 mg OD for 6 days

20 mg BID for 6 days

↓13%

↑6.7%

Itraconazole 200 mg OD for 30 days

40 mg OD for 30 days

↑11% (compared to Day 1)

↑17% (compared to Day 1)

Gemfibrozil 600 mg single dose

20 mg single dose

↓7.0%

↓20%

Aspirin 324 mg single dose

20 mg single dose

↑4.7%

↑8.9%

Niacin 1 g single dose

20 mg single dose

↓3.6%

↓8.2%

Diltiazem

20 mg single dose

↑2.7%

↑30%

Grapefruit juice

40 mg single dose

↓1.8%

↑3.7%

BID = twice daily; OD = once daily; QID = four times daily

Table 4: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs

Pravastatin Dosing Regimen

Name and Dose

Change in AUC

Change in C max

20 mg BID for 6 days

Warfarin 5 mg OD for 6 days

↑17%

↑15%

Change in mean prothrombin time

↑0.4 sec

20 mg OD for 9 days

Digoxin 0.2 mg OD for 9 days

↑4.6%

↑5.3%

20 mg BID for 4 weeks

Antipyrine 1.2 g single dose

↑3.0%

Not Reported

10 mg BID for 4 weeks

↑1.6%

5 mg BID for 4 weeks

↑ Less than 1%

20 mg OD for 4 days

Kaletra 400 mg/100 mg BID for 14 days

No change

No change

BID = twice daily; OD = once daily

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