Pravastatin Sodium (Page 4 of 6)

8.2 Lactation

Risk Summary

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. Statins, including pravastatin sodium, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pravastatin sodium [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

8.4 Pediatric Use

The safety and effectiveness of pravastatin sodium as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of pravastatin sodium for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population.

The safety and effectiveness of pravastatin sodium have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).

8.5 Geriatric Use

In clinical studies, 4,797 (36.4%) pravastatin sodium-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients.

Mean pravastatin AUCs are 25% to 50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), and half-life (t½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology (12.3) ].

Advanced age (≥65 years) is a risk factor for pravastatin sodium-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving pravastatin sodium for the increased risk of myopathy [see Warnings and Precautions (5.1) ].

8.6 Renal Impairment

Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy.

In patients with severe renal impairment, the recommended starting dose is pravastatin sodium 10 mg once daily. The maximum recommended dosage in patients with severe renal impairment is pravastatin sodium 40 mg once daily. The recommended dosage for patients with mild or moderate renal impairment is the same as patients with normal renal function. [see Dosage and Administration (2.4), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Pravastatin sodium shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [Clinical Pharmacology (12.3)]. Pravastatin sodium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

10 OVERDOSAGE

No specific antidotes for pravastatin sodium are known. Contact Poison Control (1-800-222-1222) for latest recommendations.

11 DESCRIPTION

Pravastatin Sodium Tablets, USP is a statin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

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, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.

Structural formula:

structure
(click image for full-size original)

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 for oral use contain 10 mg, 20 mg, 40 mg, and 80 mg pravastatin sodium, which is equivalent to 9.48 mg, 18.97 mg, 37.94 mg and 75.88 mg of pravastatin, respectively. Inactive ingredients include: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol, meglumine, microcrystalline cellulose and starch. The 10 mg, 20 mg and 80 mg tablets also contain D&C yellow no. 10 aluminum lake and the 40 mg tablet also contains D&C yellow no. 10 aluminum lake and FD&C blue no. 1 aluminum lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

12.2 Pharmacodynamics

Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of pravastatin sodium is usually achieved by 4 weeks and is maintained after that.

12.3 Pharmacokinetics

Absorption

Pravastatin sodium is administered orally in the active form. 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 area under the concentration-time curve (AUC) and Cmax by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.

Pravastatin plasma concentrations, including AUC, Cmax , and steady-state minimum (Cmin ), 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 Cmax 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, Cmax , and Cmin 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.

Elimination

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 t½ for pravastatin is 1.8 hours in humans and the elimination half-life (t½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours.

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 Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations (8.6)].

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 Use in Specific Populations (8.6)].

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, Cmax , Tmax , and t½ 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 pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, 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 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin
Pravastatin
Coadministered Drug and Dosing Regimen Dose (mg) Change in AUC Change in Cmax
BID = twice daily; OD = once daily; QID = four times daily

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 Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine

20 mg single dose

↓40%↑12%↓12%

↓39%↑30%↓6.8%

Cholestyramine 24 g OD for 4 weeks

20 mg BID for 8 weeks5 mg BID for 8 weeks10 mg BID for 8 weeks

↓51%↓38%↓18%

↑4.9%↑23%↓33%

Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days

20 mg PO+10 mg IV20 mg PO+10 mg IV

↓34%↓16%

↓33%↓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%

↓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%

Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs
Pravastatin Dosing Regimen Name and Dose Change in AUC Change in Cmax
BID = twice daily; OD = once daily

20 mg BID for 6 days

Warfarin 5 mg OD for 6 daysChange in mean prothrombin time

↑17%↑0.4 sec

↑15%

20 mg OD for 9 days

Digoxin 0.2 mg OD for 9 days

↑4.6%

↑5.3%

20 mg BID for 4 weeks10 mg BID for 4 weeks5 mg BID for 4 weeks

Antipyrine 1.2 g single dose

↑3%↑1.6%↑ Less than 1%

Not Reported

20 mg OD for 4 days

Kaletra 400 mg/100 mg BID for 14 days

No change

No change

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