Baycol (Cerivastatin Sodium)



Cerivastatin Sodium

Lipid Metabolism Regulator

Action And Clinical Pharmacology: Cerivastatin is an entirely synthetic, enantiomerically pure cholesterol-lowering agent and is structurally similar to the fungal derivatives of this therapeutic class.

Cerivastatin is a competitive inhibitor of 3-hydroxy-3methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. The inhibition of cholesterol biosynthesis by cerivastatin reduces the level of cholesterol in hepatic cells, which stimulates the synthesis of low density lipoprotein (LDL) receptors, thereby increasing the uptake of cellular LDL particles. The end result of these biochemical processes is a reduction of plasma total cholesterol (Total-C) and low density lipoprotein cholesterol (LDL-C).

Pharmacokinetics: Cerivastatin is rapidly absorbed following oral dosing. The absolute bioavailability of cerivastatin sodium tablets is 60% compared to oral solution. The pharmacokinetics of cerivastatin are linear over the dose range of 0.05 to 0.4 mg. Cerivastatin is >99% bound to plasma proteins. The elimination half-life is in the range of 2 to 4 hours; consequently no drug accumulation with once daily dosing is observed. The pharmacokinetics of cerivastatin are similar under fed and fasted conditions.

When 4-cerivastatin was given as an oral solution, the mean urinary excretion of total radioactivity was 24% of dose, while a mean of 70% was excreted in the feces. Thus, biliary secretion is a major pathway of drug (or metabolite) elimination. Only negligible quantities of 4 were associated with unchanged drug, indicating extensive metabolism. Cerivastatin is metabolized via a dual metabolic pathway utilizing at least 2 cytochrome P450 isoenzymes, CYP2C8 and CYP3A4. If one of the metabolic pathways (e.g., CYP3A4) is blocked, cerivastatin is metabolized, although not completely in some cases, by the alternate metabolic route. Three metabolites have been identified, and M1 and M23 are present in plasma, urine and feces, whereas M24 is present in urine and feces only. Plasma concentrations of all identified metabolites are substantially lower than those of parent drug, and the elimination half-lives are similar. Therefore, while some metabolites have pharmacologic (i.e., HMG-CoA reductase inhibitory) activity, they do not contribute significantly to the overall efficacy of cerivastatin.

Indications And Clinical Uses: As an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated Total-C and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb) when the response to dietary restriction of saturated fat and cholesterol and other nonpharmacological measures alone has been inadequate.

For the reduction of elevated cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridema, when the hypercholesterolemia is the abnormality of most concern.

Prior to initiating therapy with cerivastatin, secondary causes for hyperlipoproteinemia, such as obesity, poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy (e.g., some antihypertensive agents) or alcoholism, should be excluded. A lipid profile should be performed to measure Total-C, high density lipoprotein cholesterol (HDL-C) and triglycerides.

For patients with total triglycerides less than 4.52 mmol/L (400 mg/dL), LDL-C can be estimated using the following equation:

LDL-C (mmol/L)=Total-C -[(0.37´Trig)+HDL-C] LDL-C (mg/dL)=Total-C -[(0.16´Trig)+HDL-C] When total triglyceride levels exceed 4.52 mmol/L (400 mg/dL), this equation is less accurate and LDL-C concentrations should be directly measured by preparative ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases, cerivastatin is not indicated.

Lipid determinations should be performed at intervals of no less than 4 weeks and dosage adjusted according to the patient’s response to therapy.

Cerivastatin has not been studied in conditions where the major abnormality is elevation of chylomicrons, very low density lipoprotein (VLDL), or intermediate-density lipoprotein (IDL), i.e., hyperlipoproteinemia types I, III, IV, or V.

Contra-Indications: Hypersensitivity to any component of this medication.

Active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal (see Warnings).

Pregnancy and lactation (see Precautions).

Manufacturers’ Warnings In Clinical States: Pharmacokinetic Interactions : The use of HMG-CoA reductase inhibitors has been associated with severe myopathy, including rhabdomyolysis, which may be more frequent when they are co-administered with drugs that inhibit the cytochrome P450 enzyme system. Cerivastatin is metabolized via a dual metabolic pathway utilizing at least 2 cytochrome P450 isoenzymes, CYP2C8 and CYP3A4. If one of the metabolic pathways (e.g., CYP3A4) is blocked, cerivastatin is metabolized, although not completely in some cases, by the alternate metabolic route. (See Warnings, Muscle Effects and Precautions, Drug Interactions and Cytochrome P450 Inhibitors.)

For more information on the metabolism of cerivastatin in humans, see Pharmacology.

It is recommended that liver function tests be performed before the initiation of treatment, and within 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter, e.g., semiannually. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) show evidence of progression, particularly if they rise to >3 times the ULN and are persistent, the dosage should be reduced or the drug discontinued.

The drug should be used with caution in patients with a history of liver disease or heavy alcohol ingestion (>14 drinks/week).

Active liver disease or unexplained transaminase elevations are contraindications to the use of cerivastatin; if such conditions develop during therapy, the drug should be discontinued (see Contraindications).

Muscle Effects: Myopathy, defined as muscle aching or muscle weakness, associated with increases in plasma creatine phosphokinase (CPK) values to greater than 10 times the ULN was rare (
The risk of myopathy and rhabdomylosis during treatment with HMG-CoA reductase inhibitors is increased if therapy with cyclosporine, fibric acid derivatives, erythromycin, niacin (nicotinic acid) in lipid-lowering doses, nefazodone or azole antifungals is administered concurrently. The benefits and risks of combined therapy should be carefully considered (see Precautions, Drug Interactions).

Rhabdomyolysis with renal dysfunction secondary to myoglobinuria have been reported with other HMG-CoA reductase inhibitors. This has not been reported with cerivastatin sodium to date. Cerivastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Cerivastatin should be temporarily withheld in any patient experiencing an acute or serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine or electrolyte disorders; or uncontrolled epilepsy.

Precautions: General: The effects of cerivastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol on cardiovascular morbidity or mortality or total mortality have not been established.

Before instituting therapy with cerivastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in obese patients, and treatment of underlying medical problems (see Indications). The patient should be advised to inform subsequent physicians of the prior use of cerivastatin or any other lipid lowering agent.

Effect on Lens: Current data from clinical trials do not indicate an adverse effect of cerivastatin on the human lens.

Homozygous Familial Hypercholesterolemia: Cerivastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. Most HMG-CoA reductase inhibitors are less or not effective in this subgroup of hypercholesterolemic patients.

Effect on Lipoprotein (a): In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein (a) [Lp(a)] levels. Therefore, until further experience is obtained from controlled clinical trials, it is suggested that measurements of serum Lp(a) be followed-up in patients placed on cerivastatin therapy.

Effect on CoQ10 Levels (Ubiquinone): Significant decreases in circulating ubiquinone levels in patients treated with other statins has been observed. The clinical significance of a potential long-term statin-induced deficiency of ubiquinone has not yet been established. It has been reported that a decrease in myocardial ubiquinone levels could lead to impaired cardiac function in patients with borderline congestive heart failure.

Hypersensitivity: An apparent hypersensitivity syndrome has been reported rarely with other HMG-CoA reductase inhibitors. This has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive antinuclear antibody (ANA), erythrocyte sedimentation rate (ESR) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme including Stevens-Johnson syndrome. Although to date hypersensitivity syndrome has not been described as such, cerivastatin should be discontinued if hypersensitivity is suspected.

Pregnancy : Cerivastatin is contraindicated during pregnancy (see Contraindications).

Safety in pregnant women has not been established. Atherosclerosis is a chronic process and discontinuation of lipid metabolism regulators 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. Cerivastatin should be administered to women of child-bearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, cerivastatin should be discontinued and the patient should be apprised of the potential hazard to the fetus.

Lactation: Based on preclinical data, cerivastatin is present in breast milk in a 1.3:1 ratio (milk:plasma). It is not known whether cerivastatin is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, women taking cerivastatin should not nurse (see Contraindications).

Children: Limited experience with the use of other HMG-CoA reductase inhibitors is available in children. Safety and effectiveness of cerivastatin in children have not been established.

Geriatrics and Gender: The effect of age on the pharmacokinetics of cerivastatin was evaluated. Results indicate that for the general patient population, plasma concentrations of cerivastatin do not vary as a function of age. A slight increase in plasma cerivastatin levels was observed in females (approximately 12% higher for Cmax and 16% higher for AUC).

Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and lower cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Cerivastatin demonstrated no effect upon nonstimulated cortisol levels and no effect on thyroid metabolism as assessed by TSH. Clinical studies with other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce plasma testosterone concentration. In rare cases, however, impotence may occur following their administration. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with cerivastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs, e.g., ketoconazole, spironolactone, or cimetidine, that may decrease the levels of endogenous steroid hormones (see Drug Interactions, Cytochrome Inhibitors).

Drug Interactions: Concomitant Therapy with Other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.

Bile Acid Sequestrants: Coadministration of cerivastatin and cholestyramine resulted in a 22% decrease in cerivastatin plasma concentration (AUC). Administration of cholestyramine 1 hour before the evening meal and cerivastatin 4 hours after the same evening meal resulted in a decrease in the cerivastatin plasma concentration of less than 8%. Therefore, it would be expected that a dosing schedule of cerivastatin given at bedtime and cholestyramine administered before the evening meal would not result in a significant decrease in the clinical effect of cerivastatin.

Gemfibrozil, Fenofibrate and Niacin: Myopathy, including rhabdomylosis, has occurred in patients receiving HMG-CoA reductase inhibitors with fibric acid derivatives and niacin (in lipid-lowering doses), particularly in subjects with pre-existing renal insufficiency (see Warnings, Muscle Effects).

Erythromycin: Coadministration of erythromycin 500 mg b.i.d., a known inhibitor of cytochrome P450 3A4, with cerivastatin 0.3 mg every day during 10 days in hypercholesterolemic patients resulted in a 50% increase in cerivastatin AUC and in a 24% increase in Cmax (see Warnings, Pharmacokinetic Interactions and Muscle Effects, and Precautions, Inhibitors).

Azole Antifungals: Coadministration with the antifungal agent itraconazole 200 mg every evening, another potent CYP3A4 inhibitor, and cerivastatin 0.3 mg every evening during 10 days in hypercholesterolemic patients resulted in a 40% increase in cerivastatin steady-state plasma concentrations (see Warnings, Pharmacokinetic Interactions and Muscle Effects, and Precautions, Inhibitors).

Calcium Channel Blockers: Coadministration of a single dose of 60 mg nifedipine extended release and cerivastatin 0.3 mg to hypercholesterolemic patients did not show any effect on either nifedipine or cerivastatin plasma concentrations.

Coumarin Anticoagulants: Coadministration of warfarin and cerivastatin had no effect on the plasma concentration of either agent.

Antacid (Magnesium-Aluminum Hydroxide): Coadministration of antacid with cerivastatin resulted in an approximate 10% decrease in the cerivastatin plasma concentration.

Cimetidine: Coadministration of cerivastatin (0.2 mg) with cimetidine (400 mg) resulted in an 11% decrease in the cerivastatin plasma concentration.

Other Concomitant Therapy: Although specific interaction studies were not performed, in clinical studies cerivastatin sodium was used concomitantly with angiotensin converting enzyme (ACE) inhibitors, b-blockers, calcium-channel blockers, diuretics, estrogen replacement therapy, and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence to date of clinically significant adverse interactions.

Cytochrome P450 Inhibitors: Cerivastatin is metabolized via a dual metabolic pathway utilizing at least two cytochrome P-450 isoenzymes, CYP2C8 and CYP3A4. Although not complete in some cases, a compensatory effect is observed when one pathway is inhibited. When coadministered with erythromycin, a known inhibitor of cytochrome P450 isoform 3A4, cerivastatin plasma concentrations increased by 50%. Drugs or common agents such as grapefruit juice that inhibit this enzyme may represent a potential for drug interactions when combined with cerivastatin. Caution should thus be exercised with concomitant use of drugs such as immunosuppressants, antifungal agents (e.g., itraconazole, ketoconazole), macrolide antibiotics including erythromycin, antidepressants (e.g., nefazodone) or grapefruit juice (see Warnings, Muscle Effects and Precautions, Endocrine Function).

Patients with Severe Hypercholesterolemia: Higher drug dosages (0.3 mg/day) required for some patients with severe hypercholesterolemia are associated with increased plasma level of cerivastatin. Caution should be exercised in such patients who are also significantly renally impaired, elderly, or are concomitantly being administered digoxin, erythromycin or other cytochrome P450 inhibitors (see Warnings, Muscle Effects and Precautions, Drug Interactions).

Drug/Lab Interactions : HMG-CoA reductase inhibitors may elevate CPK and transaminase levels (see Adverse Effects, Laboratory Tests). In the differential diagnosis of chest pain in a patient on therapy with cerivastatin, cardiac and non-cardiac fractions of these enzymes should be determined.

Adverse Reactions: Cerivastatin is generally well-tolerated. Adverse events have usually been mild and transient. In 1 394 patients treated in placebo-controlled clinical studies investigating doses of 0.2 mg and 0.3 mg, less than 2% of patients were discontinued due to adverse reactions attributable to cerivastatin, compared to 2.5% for placebo. Of these 1 394 patients, 855 were treated for ³1 year.

Adverse experiences occurring at an incidence ³1% in patients participating in placebo-controlled clinical studies of cerivastatin 0.2 or 0.3 mg/day and reported to be possibly, probably, or definitely drug related are shown in Table I.

Ophthalmological Observations: See Precautions, Effect on Lens.

Laboratory Tests: Increases of serum transaminases and CPK have been noted in clinical trials (see Warnings).

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with cerivastatin therapy: myopathy, muscle cramps, rhabdomyolysis, arthralgias, dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, memory loss, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, insomnia, depression, pancreatitis, hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis (rare), fulminant hepatic necrosis (rare), hepatoma (rare), anorexia, vomiting, alopecia, pruritus, gynecomastia, loss of libido, erectile dysfunction, progression of cataracts (lens opacities), ophthalmoplegia.

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme including Stevens-Johnson syndrome.

Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, g-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Symptoms And Treatment Of Overdose: Symptoms: The maximum single oral dose of cerivastatin received by healthy volunteers and patients is 0.8 mg.

Treatment: No specific recommendations concerning the treatment of an overdosage can be made. Should an overdose occur, it should be treated symptomatically and supportive measures should be undertaken as required.

The ability of cerivastatin and its metabolites to be dialyzed in humans is not known.

Dosage And Administration: The patient should be placed on a standard cholesterol-lowering diet [at least equivalent to the American Heart Association (AHA) Step 1 diet] before receiving cerivastatin and should continue on this diet during treatment with cerivastatin. If appropriate, a program of weight control and physical exercise should be implemented.

The recommended starting dose is 0.2 mg once daily in the evening. The recommended dosing range is 0.2 to 0.3 mg as a single dose in the evening. Cerivastatin may be taken with or without food since there are no apparent differences in the lipid lowering effects of cerivastatin administered with the evening meal or at bedtime. Dosages should be individualized according to the recommended goal of therapy and the patient’s response.

Since the maximal effect of a given dose of cerivastatin is seen within 4 weeks, periodic lipid determinations should be performed at this time and the dosage adjusted to the patient’s response to therapy and established treatment guidelines.

Consideration should be given to reducing the dosage of cerivastatin if cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP) and/or the Canadian Consensus Conference Guidelines.

Severe Hypercholesterolemia: In patients with severe hypercholesterolemia, higher dosages (0.3 mg/day) may be required (see Warnings, Muscle Effects and Precautions, Drug Interactions).

Concomitant Therapy: See Precautions, Drug Interactions.

Patients with Renal Insufficiency: See Precautions.

Availability And Storage: 0.2 mg: Each light yellow-brown tablet, with 283 on one side and 200 MCG on the other, contains: cerivastatin sodium 0.2 mg. Nonmedicinal ingredients: crospovidone, ferric oxide, hydroxypropyl methylcellulose, magnesium stearate, mannitol, polyethylene glycol 4000, povidone 25, sodium hydroxide and titanium dioxide. Bottles of 100.

0.3 mg: Each yellow-brown tablet, with 284 on one side and 300 MCG on the other, contains: cerivastatin sodium 0.3 mg. Nonmedicinal ingredients: crospovidone, ferric oxide, hydroxypropyl methylcellulose, magnesium stearate, mannitol, polyethylene glycol 4000, povidone 25, sodium hydroxide and titanium dioxide. Bottles of 100.

Store at room temperature (15 to 25°C). Dispense in tight containers.

BAYCOL® Bayer Cerivastatin Sodium Lipid Metabolism Regulator

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