Tablet
COMPOSITION
NOVALES® 10 mg.
Each tablet contains 10 mg of Pravastatin Sodium.
NOVALES® 20 mg.
Each tablet contains 20 mg of Pravastatin Sodium.
PHARMACOLOGY
NOVALES® (Pravastatin) is one of a new class of lipid-lowering compounds, the HMG-CoA reductase inhibitors which reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMC-CoA to mevalonate. Pravastatin produces its lipid-lowering effect in 2 ways. First, as a consequence of its reversible inhibition of HMG-CoA reductase activity, it effects modest reductions in intracellular pools of cholesterol.
This result in an increase in the number of LDL-Receptors on the cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL. Second, it 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, e.g. the liver and ileum. Unlike other HMG-CoA reductase inhibitors, pravastatin has less effect on cholesterol synthesis in other tissues. In animal studies, it was not detected in the cerebrospinal fluid.
Clinical and pathologic studies have shown that elevated levels of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (a membrane transport complex for LDL) promote human atherosclerosis. Similarly, decreased levels of HDL-cholesterol (HDL-C) and its transport complex, apolipoprotein A, are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C and inversely with the level of HDL-C. In multi center clinical trials, those pharmacologic and/or non pharmacologic interventions that lowered Total-C and LDL-C and increased HDL-C, reduced the rate of cardiovascular events (both fatal and nonfatal myocardial infarctions) and improved survival. In both normal volunteers and patients with hypercholesterolemia, treatment with pravastatin reduced Total-C, LDL-C, apolipoprotein B, VLDL-C and TG while increasing HDL-C and apolipoprotein A.
Pharmacokinetics:
Pravastatin is administered orally in the active form. It is rapidly absorbed, with peak plasma levels attained 1-1.5 hours following ingestion. Based on urinary recovery of 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 without food. Pravastatin 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. In vitro studies demonstrated that pravastatin is transported into hepatocytes with substantially less uptake into other cells. In view of pravastatin extensive hepatic uptake and metabolism, plasma levels are limited value in predicting lipid-lowering efficacy. Pravastatin plasma concentrations including area under the concentration time curve (AUC), peak (C max) and the steady state minimum (C min) are directly proportional to administered dose. Pravastatin administered once daily at bedtime was more effective than after a morning dose despite a lower systemic bioavailability. Steady state AUCs, C max and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin. 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 hrs. Approximately 20% of a radiolabeled oral dose is excreted in urine and 70 % in the feces. After IV 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). Accumulation of drug and/or metabolites may occur in patients with renal or hepatic insufficiency although, as there are dual routes of elimination, the potential exists for compensatory excretion by the alternate route.
The major degradation product of pravastatin is the 3-α-hydroxy isomeric metabolite.
This metabolite has 1/10 -1/40 HMG-CoA reductase inhibitory activity of the parent compound.
Clinical studies : Pravastatin is highly effective in reducing Total-C and LDL-C in patients with heterozygous familial, presumed familial combined, and non familial (non-FH) forms of primary hypercholesterolemia. A therapeutic response is seen within 1 week, and the maximum response is usually achieved within 4 weeks. This response is maintained during extended periods of therapy. A single daily dose administered in the evening (recommended dosing) is as effective as the same total daily dose given twice a day. Once daily administration in the evening appears to be marginally more effective than once-daily administration in the morning, perhaps because of the hepatic cholesterol is synthesized mainly at night in multi center, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10-40 mg consistently and significantly decreased total-C, LDL-C and total-C/HDL-C and LDL-C/HDL-C ratios; modestly decreased VLDL-C and plasma TG levels and produced increase in HDL-C of variable magnitude.
Table 1. Primary Hypercholesterolemia Study Dose
Response of Pravastatin Once Daily
Administration at Bedtime
| ||||
| Dose (mg) | Total-C (%) | LDL-C (%) | HDL-C (%) | TG (%) |
10
20
40
|
-16
-24
-25
|
-22
-32
-34
|
+7
+2
+12
|
-15
-11
-24
|
| Mean percent change from baseline after 8 weeks | ||||
In another clinical trial, patients treated with pravastatin in combination with Cholestyramine (70 % of patients were taking Cholestyramine 20 - 24 g/day) had reductions ≥ 50 % in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).
Atherosclerosis : In the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I) study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range 130-190 mg/dl). In this double blind, multi center, controlled clinical trial, in which 408 patients were randomized, angiograms were evaluated at baseline and at 3 years in 264 patients. No statistical difference between pravastatin and placebo was seen for the primary endpoint (per patient change in mean coronary artery diameter), or for 1 of 2 secondary endpoint (change in percent lumen diameter stenosis). For the secondary endpoints (change in minimum lumen diameter), statistically significant slowing of the disease was seen in the pravastatin treatment group (p = 0.02). Although trial was not designed to assess clinical coronary events, for myocardial infarction (fatal and non fatal), the event rate was reduced in the pravastatin group by a statistically significant margin (10.5 % for placebo versus 4.2 % for pravastatin p = 0.0498). For another 3 years, double blind, placebo-controlled, randomized trial in patients with mild to moderate hyperlipidemia, the pravastatin lipids and atherosclerosis in the carotids (PLAC II) study, the effect of pravastatin therapy on carotid atherosclerosis was assessed by B-mode ultrasound. No statistically significant differences were seen in the carotid bifurcation, internal carotid artery, or all segments combined (the primary endpoint): Pravastatin did reduce the increase in wall thickness in the common carotid artery (p == 0.02). Although the study was not designed to assess cardiovascular events or mortality, the event rates were reduced in the pravastatin treatment group by statistically significant margins for 2 endpoints: Non fatal or fatal myocardial infarction (13.3 % placebo versus 2.7 % for pravastatin, p = 0.18); and non fatal myocardial infarction or all deaths (17.1 % for placebo versus 6.7 % for pravastatin, p = 0.49).
Analysis of pooled events from the PLAC and PLAC II trials showed that treatment with pravastatin was associated with a 67 % reduction in the event rate of fatal and non fatal myocardial infarction (11.4 % for placebo versus 3.8 % for pravastatin, p = 0.003) and 55 % for the combined endpoint of non fatal myocardial infarction or death from any cause (13.8 % placebo versus 6.2 % pravastatin, p = 0.009).
Divergence in the cumulative event rate curves began at 1 year and was statistically significant at 2 years.
INDICATIONS
Reduction of elevated total and LDL cholesterol level in patients with primary hypercholesterolemia. Prior to initiating therapy with NOVALES®, secondary causes for hypercholesterolemia (e.g. obesity, poorly-controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure Total-C, HDL-C and TG. For patients with triglycerides (TG) levels ‹
400 mg/dl, LDL-C can be estimated using the following equation: LDL-C = Total-C - HDL-C -1/5 TG.
For TG levels › 400 mg/dl, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. Periodic lipid determinations should be performed at interval of not less than 4 weeks and dosage adjusted according to the patients response to therapy. In the report of the National (United States) Cholesterol Education Program's expert panel (NCEP, 1993), total and LDL-cholesterol levels are classified as follow:
Blood Cholesterol
|
Total-C
| |
mg/dL
|
mmol/L
| |
| Desirable | ‹ 200 | ‹ 5.2 |
| Bordeline | 200 - 239 | 5.2 - 6.2 |
| High | ≥ 240 | ≥ 6.2 |
The National (United States) Cholesterol Education Program's drug treatment guidelines are summarized :
Definite
Atherosclerotic
Disease*
|
2 or more
other risk
factors **
|
LDL-Cholesterol mg/dL
(mmol/L) Initiation
| |||||
| Level | Goal | ||||||
| No | No | ≥ 190 (4.9) | ‹ 160 (4.1) | ||||
| No | Yes | ≥ 160 (4.1) | ‹ 130 (3.4) | ||||
| Yes | Yes or No | ≥ 130 (3.4) | ≤ 100 (2.6) | ||||
| |||||||
The efficacys has not been evaluated in patients with combined elevated Total-C and hypertriglyceridemia (› 500 mg/dL) who may also have elevated intermediate-density lipoproteins.
Atherosclerotic Cardiovascular Disease :
NOVALES® is indicated as an adjunct to diet to slow the progressive course of coronary atherosclerosis and reduce the incidence of clinical cardiac events in patients with hypercholesterolemia and documented atherosclerotic coronary artery disease.
CONTRAINDICATIONS
Hypersensitivity to any component of NOVALES®, active liver disease or unexplained persistent elevations in liver function tests.
Use in pregnancy and lactation:
Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women. Therefore, HMG-CoA reductase inhibitors are contraindicated during pregnancy and in nursing mothers.
Woman of childbearing potential: Safety in pregnant women has not been established.
Although pravastatin was not teratogenic in rats at doses as high as 1000 mg/Kg daily nor in rabbits at doses up to 50 mg/Kg daily, it should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patients become pregnant while taking this class of drug, therapy should be discontinued and the patient again appraised of the potential hazard to the fetus. A negligible amount of pravastatin is excreted in human milk. Because of the potential for adverse reactions in nursing infants, if the mother is being treated with pravastatin, nursing should be discontinued.
Use in children: Safety and effectiveness in individuals ‹ 18 years have not been established. Hence, treatment in patients ‹ 18 years is not recommended at this time.
SIDE EFFECTS
Pravastatin is generally well tolerated. Adverse events, both clinical and laboratory, are usually mild and transients. In all clinical studies (controlled and uncontrolled), approximately 2 % of patients were discontinued from treatment due to adverse experiences attributable to pravastatin.
Adverse clinical reactions : all adverse clinical events (regardless of attribution) reported in › 2 % of patients in the placebo-controlled studies of up to 4 months duration are presented in the table :
| Adverse Clinical Events Reported In Pravastatin-Treated Patients | ||
| % of Total Population Treated | ||
| Pravastatin (N=900)% | Placebo (N=411)% | |
| Gastrointestinal Nausea/Vomiting Diarrhea Constipation Abdominal Pain Flatulence Musculoskeletal Musculoskeletal Pain (Localized) Myalgia Respiratory Common Cold Rhinitis Nervous System Headache Dizziness General Fatigue Chest Pain (noncardiac) Dermatologic Rash Cardiovascular Chest Pain |
7.3
6.2
4.0
5.4
3.3
10.0
2.7
7.0
4.0
6.2
3.3
3.8
3.7
4.0*
4.0
|
7.1
5.6
7.1
6.9
3.6
9.0
1.0
6.3
4.1
3.9
3.2
3.4
1.9
1.1
3.4
|
| * Statistically and significantly different from placebo. | ||
WARNINGS AND PRECAUTIONS
General : HMG-CoA reductase inhibitors have been associated with biochemical abnormalities of liver function. As with other lipid lowering agents, including non-absorbable bile acid-binding resins, increasing in liver enzyme to ‹ 3 times the normal upper limit have occurred during therapy with pravastatin. 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 pravastatin in clinical trials, these increased values declined to pretreatment levels despite continuation of therapy at the same dose.
Marked persistent increases (› 3 times the normal upper limit) in serum transaminases were seen in 6 out of 1139 (0.5 %) patients treated by pravastatin in clinical trials.
These elevations were not associated with clinical signs and symptom of liver disease and usually declined to pretreatment levels upon discontinuation of therapy. Only 2 patients had persistent abnormalities possibly attributable to therapy.
As with other lipid-lowering agents, liver function tests 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) ≥ 3 times the normal upper limit and persist, therapy should be discontinued.
Caution should be exercised when pravastatin 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 HMG-CoA reductase inhibitors. Uncomplicated myalgia has rarely been reported in pravastatin treated patients with an incidence similar to placebo.
Myopathy defined as muscle aching or muscle weakness in conjunction with increases in creatinine phosphokinase (CPK) values to › 10 times the normal upper limit, was reported to be possibly due to pravastatin in ‹ 0.1 % of patients in clinical trials.
Rhabdomyolysis with renal dysfunction secondary to myoglobinuria has also been very rarely reported with pravastatin. However myopathy should be considered in any patient with diffused myalgia, muscle tenderness or weakness and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness. Pravastatin 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 inhibitors is increased with concurrent therapy with either fibrates, cyclosporin, erythromycin or niacin.
The use of fibrate alone is occasionally associated with myopathy. in a limited size clinical trial of combined therapy with pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), myopathy was not reported although a trend towards CPK elevations and musculoskeletal symptoms was seen. The combined use of pravastatin and fibrates should generally be avoided. Myopathy has not been observed in clinical trials involving a total of 100 post-transplant patients (76 cardiac and 24 renal) treated concurrently for up to 2 years with pravastatin (10-40 mg) and cyclosporin, some of who also received other immunosuppressants. Further, in clinical trials involving small numbers of patients treated by pravastatin together with niacin, there were no reports of myopathy.
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 HMG-CoA reductase inhibitors are less effective because the patients lack functional LDL receptors.
Carcinogenicity, Mutagenicity and Impairment of Fertility:
A 22 months oral study in mice, with doses of 10 - 100 mg/Kg daily of pravastatin did not demonstrate any carcinogenic potential. In 12 years oral study in rats, a statistically significant increase in the incidence of hepatocellular carcinomas was observed in male rates given 100 mg/Kg daily (125 times the maximum human dose) of pravastatin. This change was not seen in male rats given 40 mg/Kg daily (50 times the recommended human dose) or less, or in female rats at any dose level. In 6 in vitro toxicology studies performed with pravastatin, there was no evidence of mutagenic potential at the chromosomal or gene level. In a study in rats, with daily doses as high as 500 mg/Kg (625 times the maximum human dose), pravastatin did not produce any adverse effects on fertility or general reproductive performance.
DRUG INTERACTIONS
Antipyrine : Clearance by the cytochrome P 450 system was unaltered by concomitant administration of pravastatin. Since pravastatin does not appear to induce hepatic drug metabolizing enzymes, it is not expected that any significant interactions of pravastatin with other drugs (e.g., phenytoin, quinidine) metabolized by the cytochrome P 450 system will occur. Cholestyramine/colestipol: when pravastatin was administered 1 hr before or 4 hrs after Cholestyramine, or 1 hr before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effects. Concomitant administration have resulted in an approximately 40-50 % decrease in the mean AUC of pravastatin.
Cyclosporin: Some investigators have measured cyclosporin plasma levels in patients on pravastatin, and to date, these results indicate no clinically meaningful elevations in cyclosporin level. In 1 single dose study pravastatin plasma level were found to be increased in cardiac transplant patients receiving cyclosporin.
Warfarin : Bioavailability parameters at steady state for pravastatin were not altered following concomitant administration with warfarin. Pravastatin did not alter the plasma protein-binding of warfarin. Chronic dosing of the 2 drugs did not produce any changes in the anticoagulant action of warfarin (i.e., no increase was seen in mean prothrombin time after 6 days of concomitant therapy). In interaction studies with aspirin, antacids (1 hr prior to pravastatin), cimetidine, gemfibrozil, nicotinic acid or probucol, no statistically significant differences in bioavailability were seen when pravastatin was administered.
Other drugs : During clinical trials, no noticeable drug interactions were reported when pravastatin was added to : Diuretics, antihypertensives, digitalis, converting-enzyme inhibitors, calcium-channel blockers, B-blockers or nitroglycerin.
Laboratory test abnormalities : Increases in serum transaminases and in creatinine kinase (CK, CPK) in patients treated with pravastatin.
Concomitant therapy: Pravastatin has been administered concurrently with Cholestyramine, colestipol, nicotinic acid and probucol. No adverse reactions unique to the combination or in addition to those previosly reported for each drug alone have been reported. Myositis has been reported with the combination of gemfibrozil and lovastatin.
DOSAGE AND ADMINISTRATION
Prior to initiating NOVALES®, the patients should be placed on a standard cholesterol-lowering diet which should be continued during treatment. The recommended dose is 10 - 20 mg once daily at bedtime. NOVALES® may be taken without regard to meals. In primary hypercholesterolemic patients with history of significant renal or hepatic dysfunction and in the elderly, a starting dose of 10 mg daily at bedtime is recommended. Since the maximal effect of given dose is seen within 4 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 recommended dosage range is 10 - 20 mg administered once a day at bedtime.
In patients taking cyclosporin with or without other immunosuppressive drugs, concomitantly with pravastatin, therapy should be initiated with 10 mg/day and titration to higher doses should be performed with caution. Most patients treated with this combination received a maximum dose of 20 mg/day.
Concomitant therapy : Some patients may require combination therapy with 1 or more lipid-lowering agents. Pharmacokinetic interaction studies with Pravastatin administered concurrently with nicotinic acid, probucol and gemfibrozil, did not demonstrate any alterations in the bioavailability of pravastatin. The lipid lowering effects of pravastatin 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 pravastatin, pravastatin should be given either 1 hr or more before or at least 4 hrs following the resin.
Overdosage :
There has been limited experience with overdosage of pravastatin. To date, there were 2 reported cases, both of which were asymptomatic and not associated with clinical laboratory test abnormalities. Of these 2 cases, 1 occurred in a clinical trial patient who ingested 3 g pravastatin; the other ingested 280 mg pravastatin as marketed tablets. Both cases also involved overdose of concomitant medications.
Should an accidental overdose occurs, treat symptomatically and institute supportive measures as required.
STORAGE
Store at room temperature (below 30°C).
Avoid moisture, protect from light.
PRESENTATION
NOVALES 10 mg
Box, 3 strips @ 10 tablets
Reg. No. : DKL0033501610A1
NOVALES 20 mg
Box, 3 strips @ 10 tablets
Reg. No. : DKL0033501610B1
ON MEDICAL PRESCRIPTION ONLY
HARUS DENGAN RESEP DOKTER
Manufactured by :
NOVELL
PHARMACEUTICAL
LABORATORIES
BOGOR-INDONESIA
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