INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
PRAVA 10 mg Tablets
PRAVA 20 mg Tablets
PRAVA 40 mg Tablets

SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form)

PRAVA 10 mg Tablets
PRAVA 20 mg Tablets
PRAVA 40 mg Tablets

COMPOSITION
Tablets each containing 10 mg, 20 mg or 40 mg of Pravastatin sodium, designated chemically as [1S-{1 alpha(betaS*, deltaS*)2alpha, 6alpha, 8beta(R*), 8a alpha}]-1, 2, 6, 7, 8, 8a-hexahydro-beta, delta, 6-trihydroxy- 2-methyl-8- (2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid, monosodium salt.

PHARMACOLOGICAL CLASSIFICATION
Category A 7.5 Serum-cholesterol reducers.

PHARMACOLOGICAL ACTION
Pravastatin Sodium is one of a class of lipid-lowering compounds, the HMG-CoA reductase inhibitors, that reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalysing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.
Pravastatin sodium produces its lipid-lowering effect in two ways. First as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol. This results in an increase in the number of LDL- receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, pravastatin inhibits LDL production by inhibiting hepatic synthesis of VLDL, the LDL precursor. In vitro and animal studies have shown that pravastatin, a hydrophilic HMG-CoA reductase inhibitor, is tissue selective such that inhibitory activity is highest in those tissues with the highest rates of cholesterol synthesis, such as the liver and ileum. PRAVA has less effect on cholesterol synthesis in other tissues.
In both normal volunteers and patients with hypercholesterolemia, treatment with pravastatin sodium reduced Total-C, LDL-C, apolipoprotein B, VLDL-C and TG while increasing HDL-C and apolipoprotein A.
Pravastatin sodium administered orally is rapidly absorbed, with peak plasma levels attained 1 to 1,5 hours following ingestion. Based on urinary recovery of radiolabelled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%.
While the presence of food in the gastro-intestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or one hour prior to meals.
Pravastatin sodium undergoes extensive first-pass extraction in the liver (extraction ratio 0,66) which is its primary site of action, and the primary site of cholesterol synthesis and of LDL-C clearance. Since it is excreted in the bile, plasma levels are of limited value in predicting therapeutic effectiveness.
Pravastatin sodium plasma concentrations [including: area under the concentration-time curve (AUC), peak (Cmax) and steady-state minimum (Cmin)] are directly proportional to administered dose.
Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets. Approximately 50% of the circulating drug is bound to plasma proteins.
The plasma elimination half-life (t½) of pravastatin (oral) is between 1,5 and 2 hours. Approximately 20% of a radio-labelled oral dose is excreted in urine and 70% in the faeces. After intravenous administration of radio-labelled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (ie. biliary excretion and biotransformation). Since there are dual routes of elimination, the potential exists for compensatory excretion by the alternate route in patients with renal or hepatic insufficiency. The major degradation product of pravastatin is the 3 alpha-hydroxy isometric metabolite. This metabolite has one-tenth to one-fortieth the HMG-CoA reductase inhibitory activity of the parent compound.
Reduction of Cardiovascular Event Risk
In a large placebo-controlled study in men only (West of Scotland Coronary Prevention Study - WOS), 6595 persons with no previous Myocardial Infarction (MI) and LDL-cholesterol of (4 -6,7 mmol/L) of whom 8% had symptomatic Ischaemic Heart Disease (IHD), used 40 mg of pravastatin sodium or placebo for 4,8 years. The rate of first coronary events (either Coronary Heart Disease (CHD) death or non-fatal MI) was 7,65% placebo and 5,27% on pravastatin sodium , revascularisation procedures were needed in 3,9% versus 2,7% and Cardiovascular System (CVS) death was 2,2% versus 1,5%. The difference between placebo and pravastatin sodium was statistically significant

INDICATIONS
Primary Prevention of Coronary Events
In hypercholesterolemic patients without clinically evident coronary heart disease, PRAVA (pravastatin sodium) is indicated to:

-	Reduce the risk of myocardial infarction
-	Reduce the risk of undergoing myocardial revascularisation procedures.
-	Reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.

Secondary Prevention of Cardiovascular Events
Atherosclerosis
In hypercholesterolemic patients withclinically evident coronary heart disease, including prior myocardial infarction, PRAVA (pravastatin sodium) is indicated to:

-	slow the progression of coronary atherosclerosis
-	reduce the risk of acute coronary events

Myocardial Infarction
In patients with previous myocardial infarction, and normal (below the 75th percentile of the general population) cholesterol levels, PRAVA is indicated to:

-	reduce the risk of recurrent myocardial infarction
-	reduce the risk of undergoing myocardial revascularization procedures
-	reduce the risk of stroke or transient ischemic attack (TIA)

Hypercholesterolemia
PRAVA is indicated for the reduction of elevated total cholesterol and LDL-cholesterol levels in patients with primary hypercholesterolemia.
It is recommended that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, the Total-C could be used to monitor therapy.
PRAVA is not indicated when hypercholesterolemia is due to hyperalphalipoproteinemia (elevated HDL-C). The efficacy of pravastatin has not been evaluated in patients with combined elevated Total-C and hypertriglyceridemia (>13,0 mmol/L) who may also have elevated intermediate density lipoproteins.

CONTRA-INDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations in liver function disease.
Pregnancy and Lactation: Safety in pregnant women has not been established. Since Prava decreases cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, it may cause foetal harm when administered to a pregnant woman. Therefore, Prava is contra-indicated during pregnancy.
Pravastatin is excreted in human breast milk. Because of the potential for adverse reactions in nursing infants, if the mother is being treated with pravastatin, nursing should be discontinued.

DOSAGE AND DIRECTIONS FOR USE
Prior to initiating PRAVA, the patient should be placed on a standard cholesterol-lowering diet which should be continued during treatment.
The recommended dose is 10 to 20 mg once daily at bedtime. If serum cholesterol is markedly elevated the dosage may be initiated at 40 mg per day. PRAVA may be taken without regard to meals.
Since the maximal effect of a given dose is seen within four weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient's response to therapy and established treatment guidelines.
The dose range is 10 to 40 mg administered once a day at bedtime.
In patients taking cyclosporine, with or without other immunosuppressive drugs, concomitantly with Prava, therapy should be initiated at the normal recommended dose of 10 mg per day, and titration to higher doses should be performed with caution. Most patients treated with the combination received a maximum Prava dose of 20 mg/day.
Concomitant Therapy
The lipid-lowering effects of PRAVA on total and LDL cholesterol are enhanced when combined with a bile acid-binding resin. When administering a bile acid-binding resin (e.g. cholestyramine, colestipol) and Prava, PRAVA should be given either one hour or more before or at least four hours following the resin.
Some patients may require combination therapy with one or more lipid-lowering agents. Pharmacokinetic interaction studies with Prava administered concurrently with nicotinic acid, probucol, and gemfibrozil did not demonstrate any alterations in the bioavailability of pravastatin.
Paediatric Use
Safety and effectiveness in individuals less than 18 years old have not been established. Hence treatment in patients less than 18 years old is not recommended at this time.
Dosage in patients with Renal Impairment
Safety of Prava has not been established in this group of patients.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
SIDE EFFECTS
The following adverse reactions have been reported:

Gastrointestinal:	Nausea, vomiting, diarrhoea, constipation, abdominal pain, flatulence and heartburn.
Musculoskeletal:	Musculoskeletal pain, myalgia.
Respiratory:	Upper respiratory infection, rhinitis.
General:	Fatigue and chest pain (noncardiac).
Dermatologic:	Rash.
Cardiovascular:	Cardiac chest pain.

SPECIAL PRECAUTIONS
Laboratory Test Abnormalities
Liver: PRAVA may be associated with biochemical abnormalities of liver function. Increases in liver enzymes to less than three times the upper limit of normal have occurred during therapy with PRAVA. The significance of these changes, which usually appear during the first few months of treatment initiation, is not known. In the majority of patients treated with PRAVA in clinical trials, these increased values declined to pre-treatment levels despite continuation of therapy at the same dose.
Liver function tests should be performed periodically. Special attention should be given to patients who develop increased transaminase levels. Liver function tests should be repeated to confirm an elevation and subsequently monitored at more frequent intervals. If increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal or exceed three times the upper limit of normal and persist, therapy should be discontinued.
Caution should be exercised when PRAVA is administered to patients with a history of liver disease or heavy alcohol ingestion.
Skeletal Muscle: Myalgia, myopathy, and rhabdomyolysis have been reported with the use of Prava. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatinine phosphokinase (CPK) values to greater than 10 times the upper limit of normal, was reported to be possibly due to Prava. Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also very rarely been reported with Prava. However, myopathy should be considered in any patients with diffuse myalgia, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness. Prava therapy should be discontinued if markedly elevated CPK levels occur or myopathy is suspected or diagnosed. The risk of myopathy during treatment with another HMG-CoA reductase inhibitor is increased with concurrent therapy with either fibrates, cyclosporine, erythromycin or niacin
The combined use of Prava and fibrates should generally be avoided.
Homozygous Familial Hypercholesterolemia: PRAVA has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that HMG-CoA reductase inhibitors are less effective because of the patient's lack of functional LDL receptors.

INTERACTIONS:
Cholestyramine/Colestipol: When PRAVA was administered one hour before or four hours after cholestyramine or one hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect. Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of PRAVA. (See Concomitant Therapy DOSAGE AND DIRECTIONS FOR USE).
Cyclosporine: Concomitant use of Prava can cause elevations in cyclosporine plasma levels.
Warfarin: Bioavailability parameters at steady state for PRAVA were not altered following concomitant administration with warfarin. PRAVA did not alter the plasma protein-binding of warfarin. Chronic dosing of the two drugs did not produce any changes in the anticoagulant action of warfarin (i.e. no increase was seen in mean prothrombin time after six days of concomitant therapy).
Other Medicines:
Prava is not significantly metabolized by cytochrome P450 3A4. Therefore, plasma levels of pravastatin in vivo are not elevated when cytochrome P450 3A4 is inhibited by agents such as itraconazole or diltiazem.
In interaction studies with aspirin, antacids (one hour prior to PRAVA), cimetidine, gemfibrozil, nicotinic acid or probucol, no statistically significant differences in bioavailability were seen when PRAVA was administered.
During clinical trials, no noticeable drug interactions were reported when PRAVA was added to: diuretics, antihypertensives, digitalis, converting-enzyme inhibitors, calcium channel blockers, beta-blockers, or nitroglycerines.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Should an accidental overdose occur, treat symptomatically and institute supportive measures as required.

IDENTIFICATION

PRAVA 10 mg:	Yellow capsule-shaped biconvex tablet with "10" engraved on one side.
PRAVA 20 mg:	Yellow capsule-shaped biconvex tablet with "20" engraved on one side.
PRAVA 40 mg:	Yellow capsule-shaped biconvex tablet with "40" engraved on one side.

PRESENTATION
PRAVA 10 mg, 20 and 40 mg tablets are available in Alu-Alu blister packs of 30 tablets.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C. Protect from moisture and light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
PRAVA 10 mg: X/7.5/121
PRAVA 20 mg: X/7.5/122
PRAVA 40 mg: 31/7.5/423

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road,
Bedfordview. 2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
March 2000

* Authorised User of the TM PRAVA

Updated on this site: August 2005
Source: Pharmaceutical Industry
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