Pravastatin Sodium Dailymed

10 Overdosage

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

11 Description

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

Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic 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:



Pravastatin sodium 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. 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 for oral use contain 10 mg, 20 mg, 40 mg, and 80 mg pravastatin sodium, which is equivalent to 9.46, 18.97, 37.94 and 75.88 mg of pravastatin, respectively. Inactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, dehydrated alcohol, dibasic sodium phosphate anhydrous, ferric oxide brown, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

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 tablets is usually achieved by 4 weeks and is maintained after that.

12.3 Pharmacokinetics

Absorption

Pravastatin sodium tablets 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 C _max 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, 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 Cmax and AUC follwing 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 14C-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

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 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 weeks 5 mg BID for 8 weeks 10 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 IV 20 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	¯7.0%	¯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	20 mg single dose	¯1.8%	↑3.7%

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

Table 6: 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 Change 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 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks	Antipyrine 1.2 g single dose	↑3.0% ↑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

BID = twice daily; OD = once daily

13 Nonclinical Toxicology

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.

No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child.

14 Clinical Studies

Prevention of Coronary Heart Disease

In the Pravastatin Primary Prevention Study (WOS), the effect of Pravastatin sodium tablets on fatal and nonfatal CHD was assessed in 6595 male patients 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL. In this randomized, double-blind, placebo- controlled study, patients were treated with standard care, including dietary advice, and either Pravastatin sodium tablets 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25 ^th, 75 ^th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.

Pravastatin sodium tablets significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the Pravastatin sodium tablets group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with Pravastatin sodium tablets was similar across the age range studied and throughout the range of baseline LDL cholesterol levels.



Pravastatin sodium tablets also decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients).Cardiovascular deaths were decreased by 32% (73 vs 50) and there was no increase in death from non-cardiovascular causes.

Secondary Prevention of Cardiovascular Events

In the LIPID study, the effect of Pravastatin sodium tablets, 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 patients ≥65 years; 782 patients with diabetes) who had experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total- C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with Pravastatin sodium tablets significantly reduced the risk for total mortality by reducing coronary death (see Table 7). The risk reduction due to treatment with Pravastatin sodium tablets on CHD mortality was consistent regardless of age. Pravastatin sodium tablets significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris.

Table 7: LIPID - Primary and Secondary Endpoints

	Number (%) of Subjects
Event	Pravastatin sodium tablets 40 mg (N=4512)	Placebo (N=4502)	Risk Reduction	p -value
Primary Endpoint
CHD mortality	287 (6.4)	373 (8.3)	24%	0.0004
Secondary Endpoints
Total mortality	498 (11.0)	633 (14.1)	23%	<0.0001
CHD mortality or nonfatal MI	557 (12.3)	715 (15.9)	24%	<0.0001
Myocardial revascularization procedures (CABG or PTCA)	584 (12.9)	706 (15.7)	20%	<0.0001
Stroke
All-cause	169 (3.7)	204 (4.5)	19%	0.0477
Non-hemorrhagic	154 (3.4)	196 (4.4)	23%	0.0154
Cardiovascular mortality	331 (7.3)	433 (9.6)	25%	<0.0001

In the CARE study, the effect of Pravastatin sodium tablets, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with Pravastatin sodium tablets significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 8).

Table 8: CARE - Primary and Secondary Endpoints

	Number (%) of Subjects
Event	Pravastatin sodium tablets 40 mg (N=2081)	Placebo (N=2078)	Risk Reduction	p -value
Primary Endpoint
CHD mortality or nonfatal MI a	212 (10.2)	274 (13.2)	24%	0.003
Secondary Endpoints
Myocardial revascularization procedures (CABG or PTCA)	294 (14.1)	391 (18.8)	27%	<0.001
Stroke or TIA	93 (4.5)	124 (6.0)	26%	0.029

^a The risk reduction due to treatment with Pravastatin sodium tablets was consistent in both sexes.

Primary Hyperlipidemia

In multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with Pravastatin sodium tablets in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, and TG (see Table 9).

In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with Pravastatin sodium tablets at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25 ^th and 75 ^th percentile changes from baseline in LDL-C for Pravastatin sodium tablets 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 9).

Table 9: Primary Hyperlipidemia Trials: Dose Response of Pravastatin sodium tablets Once Daily Administration

Dose	Total- C	LDL- C	HDL- C	TG
Mean Percent Changes From Baseline After 8 Weeks a
Placebo (N=36)	−3%	−4%	+1%	−4%
10 mg (N=18)	−16%	−22%	+7%	−15%
20 mg (N=19)	−24%	−32%	+2%	−11%
40 mg (N=18)	−25%	−34%	+12%	−24%
Mean Percent Changes From Baseline After 6 Weeks b
Placebo (N=162)	0%	−1%	−1%	+1%
80 mg (N=277)	−27%	−37%	+3%	−19%

^a A multicenter, double-blind, placebo-controlled study.

^b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies.

Hypertriglyceridemia

The response to Pravastatin sodium tablets in patients with hypertriglyceridemia (baseline TG >200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246.0 (200.5, 349.5) mg/dL (see Table 10).

Table 10: Patients with Hypertriglyceridemia Median (25 ^th, 75 ^th percentile) % Change from Baseline

	Pravastatin 40 mg (N=429)	Placebo (N=430)
TG	−21.1 (−34.8, 1.3)	−6.3 (−23.1, 18.3)
Total-C	−22.1 (−27.1, −14.8)	0.2 (−6.9, 6.8)
LDL-C	−31.7 (−39.6, −21.5)	0.7 (−9.0, 10.0)
HDL-C	7.4 (−1.2, 17.7)	2.8 (−5.7, 11.7)
Non-HDL-C	−27.2 (−34.0, −18.5)	−0.8 (−8.2, 7.0)

Dysbetalipoproteinemia

The response to Pravastatin sodium tablets in two double-blind crossover studies of 46 patients with genotype E2/E2 and dysbetalipoproteinemia is shown in Table 11.

Table 11: Patients with Dysbetalipoproteinemia Median (min, max) % Change from Baseline

	Median (min, max) at Baseline (mg/dL)	Median % Change (min, max) Pravastatin 40 mg (N=20)
Study 1
Total-C	386.5 (245.0, 672.0)	−32.7 (−58.5, 4.6)
TG	443.0 (275.0, 1299.0)	−23.7 (−68.5, 44.7)
VLDL-C a	206.5 (110.0, 379.0)	−43.8 (−73.1, −14.3)
LDL-C a	117.5 (80.0, 170.0)	−40.8 (−63.7, 4.6)
HDL-C	30.0 (18.0, 88.0)	6.4 (−45.0, 105.6)
Non-HDL-C	344.5 (215.0, 646.0)	−36.7 (−66.3, 5.8)

^a N=14

	Median (min, max) at Baseline (mg/dL)	Median % Change (min, max) Pravastatin 40 mg (N=26)
Study 2
Total-C	340.3 (230.1, 448.6)	−31.4 (−54.5, −13.0)
TG	343.2 (212.6, 845.9)	−11.9 (−56.5, 44.8)
VLDL-C	145.0 (71.5, 309.4)	−35.7 (−74.7, 19.1)
LDL-C	128.6 (63.8, 177.9)	−30.3 (−52.2, 13.5)
HDL-C	38.7 (27.1, 58.0)	5.0 (−17.7, 66.7)
Non-HDL-C	295.8 (195.3, 421.5)	−35.5 (−81.0, −13.5)

HeFH in Pediatric Patients Aged 8 Years and Above

A double-blind, placebo-controlled study in 214 pedatric patients (100 males and 114 females) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The pediatric patients aged 8 to 13 years were randomized to placebo (N=63) or 20 mg of Pravastatin sodium tablets daily (N=65) and the pediatric patients aged 14 to 18 years were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL) groups, respectively.

Pravastatin sodium tablets significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both pediatric age groups (see Table 12). The effect of Pravastatin sodium tablets treatment in the 2 age groups was similar.

Table 12: Lipid-Lowering Effects of Pravastatin sodium tablets in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean

% Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) ^a

	Pravastatin 20 mg (Aged 8-13 years) N=65	Pravastatin 40 mg (Aged 14-18 years) N=41	Combined Pravastatin (Aged 8-18 years) N=106	Combined Placebo (Aged 8-18 years) N=108	95% CI of the Difference Between Combined Pravastatin and Placebo
LDL-C	−26.04 b	−21.07 b	−24.07 b	−1.52	(−26.74, −18.86)
TC	−20.75 b	−13.08 b	−17.72 b	−0.65	(−20.40, −13.83)
HDL-C	1.04	13.71	5.97	3.13	(−1.71, 7.43)
TG	−9.58	−0.30	−5.88	−3.27	(−13.95, 10.01)
ApoB	−23.16 b	−18.08 b	−21.11 b	−0.97	(−24.29, −16.18)
(N)	(61)	(39)	(100)	(106)

^a The above least-squares mean values were calculated based on log-transformed lipid values.

^b Significant at p≤0.0001 when compared with placebo.

The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the Pravastatin sodium tablets group k to 236 mg/dL (range: 105-438 mg/dL) in the placebo group.

Myopathy and Rhabdomyolysis

Advise patients that Pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [ see Warnings and Precautions (5.1), Drug Interactions (7.1) ].

Hepatic Dysfunction

Inform patients that Pravastatin sodium tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [ see Warnings and Precautions (5.3) ].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with Pravastatin sodium tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [ see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who may become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if Pravastatin sodium tablets should be discontinued [ see Use in Specific Populations (8.1) ] .

Lactation

Advise patients that breastfeeding is not recommended during treatment with Pravastatin sodium tablets [ see Use in Specific Populations (8.2) ] .

Manufactured for:

Apnar Pharma LP

CHINO, CA, USA 91710

Rev. 06/2022