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Data Sheet

VYTORIN^®

ezetimibe/simvastatin

10/10 mg, 10/20 mg, 10/40 mg & 10/80 mg tablets

Presentation

10/10 mg tablet: A white to off white, capsule shaped, biconvex compressed tablet marked 311 on one side. Dimensions are 8.48 mm x 4.24 mm.
10/20 mg tablet: A white to off white, capsule shaped, biconvex compressed tablet marked 312 on one side. Dimensions are 10.66 mm x 5.33 mm.
10/40 mg tablet: A white to off white, capsule shaped, biconvex compressed tablet marked 313 on one side. Dimensions are 13.86 mm x 5.98 mm.
10/80 mg tablet: A white to off white, capsule shaped, biconvex compressed tablet marked 315 on one side. Dimensions are 17.46 mm x 7.53 mm.

Therapeutic Class

VYTORIN (ezetimibe/simvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.

Indications

Primary Hypercholesterolaemia

VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in adult and adolescent (10 to 17 years of age) patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia in patients not adequately treated on a statin alone.

Homozygous Familial Hypercholesterolaemia (HoFH)

VYTORIN is indicated for the reduction of elevated total-C and LDL-C levels in adult and adolescent (10 to 17 years of age) patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).

Dosage and Administration

The patient should be placed on a standard cholesterol-lowering diet before receiving VYTORIN and should continue on this diet during treatment with VYTORIN. The dosage should be individualised according to the baseline LDL-C level, the recommended goal of therapy, and the patient's response. VYTORIN should be taken as a single daily dose in the evening, with or without food.

The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titration of VYTORIN, lipid levels may be analysed after 2 or more weeks and dosage adjusted, if needed.

Dosage in Patients with Homozygous Familial Hypercholesterolaemia

The recommended dosage for patients with homozygous familial hypercholesterolaemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the evening. VYTORIN should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Use in the Elderly

No dosage adjustment is required for elderly patients (see Pharmacokinetics).

Use in Paediatric (10 to 17 years of age) Patients

The recommended usual starting dose is 10/10 mg once a day in the evening. The recommended dosing range is 10/10 to a maximum of 10/40 mg/day. Doses should be individualised according to the recommended goal of therapy. Children <10 years: Treatment with VYTORIN is not recommended.

Use in Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with VYTORIN is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score >9) liver dysfunction. (See Warnings and Precautions, and Pharmacokinetics.)

Use in Renal Impairment

No dosage adjustment is required for patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance ≤30 mL/min) is deemed necessary, dosages above 10/10 mg/day should be implemented cautiously (see Pharmacokinetics).

Concomitant Therapy

Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

In patients taking cyclosporine or danazol concomitantly with VYTORIN, the dose of VYTORIN should not exceed 10/10 mg/day (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Interactions).

In patients taking amiodarone or verapamil concomitantly with VYTORIN, the dose of VYTORIN should not exceed 10/20 mg/day (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Interactions).

The safety and effectiveness of ezetimibe administered with fibrates have not been studied. Therefore, the combination of VYTORIN and fibrates should be avoided (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Interactions).

There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, although not recommended, if VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily (see Warnings and Precautions, Myopathy/Rhabdomyolysis and Interactions).

Contraindications

• Hypersensitivity to the active substances or to any of the excipients.
• Active liver disease or unexplained persistent elevations of serum transaminases.
• Pregnancy and nursing (see Pregnancy and Nursing Mothers).

Warnings and Precautions

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10 X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

• Because VYTORIN contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of VYTORIN with the following:

Potent inhibitors of CYP3A4: e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone, particularly with higher doses of VYTORIN (see Interactions).

Other Medicines:

Gemfibrozil or other fibrates, particularly with higher doses of VYTORIN (see Interactions).

Cyclosporine or danazol particularly with higher doses of VYTORIN (see Interactions).

Amiodarone or verapamil with higher doses of VYTORIN (see Interactions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.

Diltiazem: Patients on diltiazem treated concomitantly with VYTORIN 10/80 have a slightly increased risk of myopathy. In clinical studies, the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltiazem (see Interactions).

Fusidic acid: Patients on fusidic acid treated concomitantly with VYTORIN may have an increased risk of myopathy (see Interactions, Other Medicine Interactions).

Niacin (≥1 g/day): (see Interactions, Interactions with lipid-lowering medicines that can cause myopathy when given alone).

• As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,050 patients were treated with simvastatin, with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

Consequently:

1. Use of VYTORIN concomitantly with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin, or telithromycin is unavoidable, therapy with VYTORIN should be suspended during the course of treatment. Concomitant use with other medicines labelled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
2. The safety and effectiveness of ezetimibe administered with fibrates have not been studied. Therefore, the concomitant use of VYTORIN and fibrates should be avoided.
   
   There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this medicine combination. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. Therefore, although not recommended, if VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily.
3. The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant medication with cyclosporine or danazol. The benefits of the use of VYTORIN in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these medicine combinations and caution should be exercised when initiating VYTORIN in the setting of cyclosporine (see Interactions).
4. The dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
5. Patients on fusidic acid and VYTORIN should be closely monitored. Temporary suspension of VYTORIN treatment may be considered.
6. Caution should be used when prescribing VYTORIN and niacin (≥1 g/day), as niacin can cause myopathy when given alone.
7. All patients starting therapy with VYTORIN, or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. VYTORIN therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with VYTORIN or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
8. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking VYTORIN merit closer monitoring. Therapy with VYTORIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Liver Enzymes

In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥3 X ULN) have been observed. (See Adverse Effects.)

It is recommended that LFTs be performed before treatment with VYTORIN begins and thereafter when clinically indicated. Patients titrated to the 10/80 mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80 mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. 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 the transaminase levels show evidence of progression, particularly if they rise to 3 X ULN and are persistent, the medicine should be discontinued.

VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.

Hepatic Insufficiency

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients (see Pharmacokinetics).

Fibrates

The safety and efficacy of ezetimibe administered with fibrates have not been established; therefore, co-administration of VYTORIN and fibrates is not recommended (see Interactions).

Cyclosporine

Caution should be exercised when initiating VYTORIN in the setting of cyclosporine. Cyclosporine concentrations should be monitored in patients receiving VYTORIN and cyclosporine (see Interactions).

Anticoagulants

If VYTORIN is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Interactions).

Pregnancy

Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicines during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.

VYTORIN is contraindicated during pregnancy (see Animal Toxicology).

Simvastatin

The safety of simvastatin in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5 fold or greater increase in congenital anomalies over the background incidence.

Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, VYTORIN should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with VYTORIN should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see Contraindications).

Ezetimibe

No clinical data on exposed pregnancies are available for ezetimibe.

When ezetimibe was given with simvastatin, no teratogenic effects were observed in embryo-foetal development studies in pregnant rats. In pregnant rabbits, a low incidence of skeletal malformations was observed (see Animal Toxicology).

Nursing Mothers

Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active components of VYTORIN are excreted into human breast milk; therefore, women who are nursing should not take VYTORIN.

Paediatric Use

Safety and effectiveness of VYTORIN in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least one year post-menarche. Adolescent patients treated with VYTORIN had an adverse experience profile similar to that of adult patients treated with VYTORIN. However elevations of CPK (≥10 X ULN) occurred in two patients (2%) treated with VYTORIN and in zero patients treated with simvastatin alone. No cases of myopathy were reported. Doses greater than 10/40 mg/day have not been studied in this population. In this controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See Dosage and Administration, and Adverse Effects.) VYTORIN has not been studied in patients younger than 10 years of age or in pre-menarchal girls.

Animal Toxicology

Acute Toxicology

In animals, no toxicity was observed after single oral doses of 5000 mg/kg of ezetimibe in rats and mice and 3000 mg/kg in dogs.

The oral LD₅₀ of simvastatin in mice is approximately 3.8 g/kg and in rats is approximately 5 g/kg.

Chronic Toxicology

VYTORIN

The safety of concomitant administration of ezetimibe and simvastatin was assessed in rats and dogs. When ezetimibe was co-administered with simvastatin for three months, toxicologic findings were consistent with those seen with statins administered alone.

Ezetimibe

Ezetimibe was well tolerated by mice, rats and dogs. No target organs of toxicity were identified in chronic studies at daily doses up to 1500 (males) and 500 mg/kg (females) in rats, up to 500 mg/kg in mice, or up to 300 mg/kg in dogs.

Simvastatin

Administration of high dosage levels of simvastatin and related analogs to a variety of animal species has revealed a spectrum of changes in several tissues. These changes were not unexpected in view of the large doses used, the potency of these medicines in inhibiting mevalonate synthesis, and the essential role of the target enzyme in maintenance of cellular homeostasis. Extensive data generated on several of these changes indicate that they represent an exaggeration of the biochemical effect of these medicines at the high end of the dose-response curve. Thus, morphologic changes in the livers of rats, squamous epithelial hyperplasia of the forestomach of rats and mice and hepatotoxicity in rabbits have all been shown to be directly related to inhibition of HMG-CoA reductase.

Cataracts have been detected at high dosage levels in dog studies with simvastatin, although at a very low incidence. While there is no clear correlation between the magnitude of serum lipid-lowering and the development of cataracts, a consistent relationship has been observed between high serum levels of medicine and cataract development with simvastatin and related HMG-CoA reductase inhibitors.

Serum levels (expressed as total inhibitors) in dogs receiving the minimally cataractogenic dose of simvastatin of 50 mg/kg/day are 5 times higher than those in man receiving the maximally anticipated therapeutic dose of 1.6 mg/kg (based on 80 mg/day for a 50 kg man).

Elevated serum transaminases have been observed in dogs receiving simvastatin. These occur either as chronic low level elevations or as transient enzyme spikes in approximately 10-40% of the dogs receiving this medicine. None of the dogs experiencing these transaminase elevations demonstrated any symptoms of illness; and none of the transaminase elevations have progressed to levels associated with frank hepatic necrosis, despite continued medicine administration. No histopathological changes have been identified in the liver of any dogs receiving simvastatin.

Testicular degeneration has been seen in two dog safety studies with simvastatin. Special studies designed to further define the nature of these changes have not met with success since the effects are poorly reproducible and unrelated to dose, serum cholesterol levels, or duration of treatment. Simvastatin has been administered for up to 2 years to dogs at a dose of 50 mg/kg/day without any testicular effects.

Skeletal muscle necrosis was seen in one study in rats given 90 mg/kg twice daily, but this was a lethal dosage in rats.

Carcinogenicity

Ezetimibe

In two-year studies conducted in mice and rats, ezetimibe was not carcinogenic.

Simvastatin

Initial carcinogenicity studies conducted in rats and mice with simvastatin employed doses ranging from 1 mg/kg/day to 25 mg/kg/day. No evidence of a treatment-related incidence of tumour types was found in mice in any tissue. A statistically significant (p≤0.05) increase in the incidence of thyroid follicular cell adenomas was observed in female rats receiving 25 mg/kg of simvastatin per day (16 times the maximum recommended human dose). This benign tumour type was limited to female rats; no similar changes were seen in male rats or in female rats at lower dosages (up to 5 mg/kg/day). These tumours are a secondary effect reflective of a simvastatin-mediated enhancement of thyroid hormone clearance in the female rat. No other statistically significant increased incidence of tumour types was identified in any tissues in rats receiving simvastatin.

Data from both of these studies indicated that squamous epithelial hyperplasia of the forestomach occurred at all dosage levels. These gastric changes are confined to an anatomical structure which is not found in man. Moreover, identical cells found in other locations (e.g., oesophagus and anorectal junction of the rat, mouse and dog) are unaffected.

Results of an additional 73 week carcinogenicity study in mice receiving simvastatin doses up to 400 mg/kg/day (250 times the maximum recommended human dose, based on a 50 kg person) exhibited increased incidences of hepatocellular adenomas and carcinomas, pulmonary adenomas and harderian gland adenomas. A no-effect dose of 25 mg/kg/day (16 times the maximum recommended human dose) was established in this study and from the results of the initial 92 week carcinogenicity study in mice.

Results of an additional 106-week carcinogenicity study in rats receiving simvastatin doses ranging from 50 mg/kg/day to 100 mg/kg/day (31 to 63 times the maximum recommended human dose) exhibited a treatment-related increase in the incidence of hepatocellular neoplasms. The no-effect dose remains at 25 mg/kg/day (16 times the maximum recommended human dose) as established in the initial carcinogenicity study. An increase in the incidence of thyroid hyperplastic lesions was also observed; however, this is consistent with the previous finding that this is a species-specific response and has no implications for man.

Mutagenesis

VYTORIN

Combination of ezetimibe with simvastatin was not genotoxic in a series of in vitro and in vivo assays.

Ezetimibe

Ezetimibe was not genotoxic in a series of in vivo and in vitro tests.

Simvastatin

An extensive battery of in vitro and in vivo genetic toxicity tests have been conducted on both simvastatin and the corresponding open acid β-hydroxy-acid. These include assays for microbial mutagenesis, mammalian cell mutagenesis, single stranded DNA breakage and tests for chromosome aberrations. The results of these studies provided no evidence of an interaction between simvastatin or β-hydroxy-acid with genetic material at the highest soluble noncytotoxic concentrations tested in in vitro assay systems or at maximally tolerated doses tested in vivo.

Reproduction

Ezetimibe

Ezetimibe did not affect the fertility of male or female rats.

Simvastatin

At maximally tolerated doses in both the rat and the rabbit, simvastatin had no effects on fertility or reproductive function.

Development

VYTORIN

Concomitant administration of ezetimibe and simvastatin was not teratogenic in rats. In pregnant rabbits, a low incidence of skeletal malformations (fused caudal vertebrae, reduced number of caudal vertebrae) was observed when ezetimibe (1000 mg/kg; ≥146 times the human exposure at 10 mg daily based on AUC_0-24hr for total ezetimibe) was administered with simvastatin (5 and 10 mg/kg). Exposure to the pharmacologically active form of simvastatin was ≥246 times the human exposure at 10 mg daily) based on AUC_0-24hr.

Ezetimibe

Ezetimibe was not teratogenic in rats or rabbits and had no effect on prenatal or postnatal development.

Simvastatin

At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no foetal malformations and had no effects on neonatal development. However, in rats, an oral dose of 60 mg/kg/day of the hydroxy acid, pharmacologically active metabolite of simvastatin, resulted in decreased maternal body weight and an increased incidence of foetal resorptions and skeletal malformations compared with controls. Subsequent studies conducted at dosages of up to 60 mg/kg/day with this metabolite showed that these resorptions and skeletal malformations were consequences of maternal toxicity (forestomach lesions associated with maternal weight loss) specific to rodents and are highly unlikely to be due to a direct effect on the developing foetus. Although no studies have been conducted with simvastatin, maternal treatment of pregnant rats with a closely related HMG-CoA reductase inhibitor at dosages of 80 and 400 mg/kg/day (10 and 52-fold the maximum recommended therapeutic dose based on mg/m² body surface area) has been shown to reduce the foetal plasma levels of mevalonate.

Effects on the Ability to Drive and Use Machinery

No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects that have been reported with VYTORIN may affect some patients' ability to drive or operate machinery. Individual responses to VYTORIN may vary. (See Adverse Effects.)

Adverse Effects

VYTORIN (or co-administration of ezetimibe and simvastatin equivalent to VYTORIN) has been evaluated for safety in more than 3800 patients in clinical trials. VYTORIN was generally well tolerated.

The following common (≥1/100, <1/10) medicine-related adverse experiences were reported in patients taking VYTORIN (n=1236) during three, similarly designed, placebo-controlled trials:

Gastrointestinal disorders: flatulence

Musculoskeletal and connective tissue disorders: myalgia

Nervous system disorders: headache

Paediatric (10 to 17 Years of Age) Patients

In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), the safety and tolerability profile of the group treated with VYTORIN was similar to that of adult patients treated with VYTORIN (see Warnings and Precautions, Paediatric Use).

Post-marketing Experience

The adverse reactions reported for VYTORIN are consistent with those previously reported with ezetimibe and/or simvastatin.

Additional adverse events reported commonly with ezetimibe during clinical trials: Gastrointestinal disorders: abdominal pain, diarrhoea; General disorders and administration site conditions: fatigue. During post-marketing use the following adverse events were reported, regardless of causality assessment: Blood and lymphatic system disorders: thrombocytopenia; Hepato-biliary disorders: cholelithiasis, cholecystitis, hepatitis; Musculoskeletal, connective tissue and bone disorders: arthralgia, and, very rarely, myopathy/rhabdomyolysis (see Warnings and Precautions); Psychiatric disorders: depression; Nervous system disorders: dizziness; paresthesia; Laboratory values: increased CPK, elevations of liver transaminases; Skin and subcutaneous tissue disorders: Hypersensitivity reactions, including rash and urticaria (rare (≥1/10,000, <1/1000)) and anaphylaxis and angioedema (very rare (<1/10,000));erythema multiforme; Gastrointestinal disorders: nausea (rare), pancreatitis (very rare).

Additional adverse events reported rarely with simvastatin during clinical studies and/or post-marketing use: Blood and lymphatic system disorders: anaemia; Gastrointestinal disorders: abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, pancreatitis; General disorders and administration site conditions: asthenia; Hepatic disorders: hepatitis/jaundice and very rarely, hepatic failure; Musculoskeletal, connective tissue and bone disorders: muscle cramps, myopathy, rhabdomyolysis (see Warnings and Precautions); Nervous system disorders: dizziness, paresthesia, peripheral neuropathy, memory impairment; Skin and subcutaneous tissue disorders: alopecia, pruritus, rash; Psychiatric disorders: insomnia. An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

Laboratory Test Findings

In controlled clinical co-administration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was 1.7% for patients treated with VYTORIN. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. (See Warnings and Precautions.)

Clinically important elevations of CK (≥10 X ULN) were seen in 0.2% of the patients treated with VYTORIN.

In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of CPK (≥10 X ULN) occurred in two patients (2%) treated with VYTORIN and in zero patients treated with simvastatin alone. No cases of myopathy were reported.

Interactions

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with simvastatin.

VYTORIN is bioequivalent to co-administered ezetimibe and simvastatin.

CYP3A4 Interactions

In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 medicine metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other medicines metabolised by CYP3A4. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of the simvastatin component of VYTORIN:

See Warnings and Precautions, Myopathy/Rhabdomyolysis.

Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone

Interactions with lipid-lowering medicines that can cause myopathy when given alone

The risk of myopathy is also increased by the following lipid-lowering medicines that are not potent inhibitors of CYP3A4, but which can cause myopathy when given alone.

See Warnings and Precautions, Myopathy/Rhabdomyolysis

Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1g/day)

Other Medicine Interactions

Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol, particularly with higher doses of VYTORIN (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of VYTORIN (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be lessened by this interaction.

Diltiazem: Patients on diltiazem treated concomitantly with VYTORIN 10/80 have a slightly increased risk of myopathy (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Fusidic Acid: Patients on fusidic acid treated concomitantly with VYTORIN may have an increased risk of myopathy (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5 and 1.7 fold, respectively; however, these increases are not considered clinically significant. The safety and effectiveness of VYTORIN administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see Animal Toxicology). Although the relevance of this preclinical finding to humans is unknown, co-administration of VYTORIN with fibrates is not recommended until use in patients is studied.

Niacin: In a study of 15 healthy adults, concomitant VYTORIN (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%). These increases are not considered clinically significant.

Other Interactions

Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of medicines metabolised by CYP3A4. The effect of typical consumption (one 250 mL glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, very large quantities (over 1 litre daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided while taking VYTORIN (see Warnings and Precautions, Myopathy/Rhabdomyolysis).

Anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting VYTORIN and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased International Normalised Ratio in patients who had ezetimibe added to warfarin, or fluindione. Most of these patients were also on other medications (see Warnings and Precautions).

The effect of VYTORIN on the prothrombin time has not been studied.

Antacids

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.

Cyclosporine

In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of cyclosporine, a single 10 mg dose of ezetimibe resulted in a 3.4 fold (range 2.3 to 7.9 fold) increase in the mean AUC for total ezetimibe compared to a healthy control population from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12 fold greater exposure to total ezetimibe compared to concurrent controls. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100 mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100 mg dose of cyclosporine alone (see Warnings and Precautions).

Overdosage

VYTORIN

No specific treatment of overdosage with VYTORIN can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Co-administration of ezetimibe (1000 mg/kg) and simvastatin (1000 mg/kg) was well tolerated in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The estimated oral LD₅₀ for both species was ezetimibe ≥1000 mg/kg / simvastatin ≥1000 mg/kg.

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated.

A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin

A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.

Actions

VYTORIN

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.

Ezetimibe

Ezetimibe inhibits the intestinal absorption of cholesterol. Ezetimibe is orally active and has a mechanism of action that differs from other classes of cholesterol reducing compounds (e.g., statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.

Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction.

In a 2 week clinical study in 18 hypercholesterolaemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo.

A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [¹⁴C] cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Simvastatin

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolysed in the liver to the corresponding active β-hydroxy-acid form which has a potent activity in inhibiting HMG CoA reductase (3 hydroxy - 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG CoA to mevalonate, an early and rate limiting step in the biosynthesis of cholesterol.

Simvastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with simvastatin. In addition, simvastatin moderately increases HDL-C and reduces plasma TG. As a result of these changes, the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

Pharmacokinetics

Absorption

Ezetimibe

After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (C_max) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.

Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as ezetimibe 10 mg tablets.

Simvastatin

The availability of the β-hydroxy-acid to the systemic circulation following an oral dose of simvastatin was found to be less than 5% of the dose, consistent with extensive hepatic first-pass extraction. The major metabolites of simvastatin present in human plasma are the β-hydroxy-acid and four additional active metabolites.

Relative to the fasting state, the plasma profiles of both active and total inhibitors were not affected when simvastatin was administered immediately before a test meal.

Distribution

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.

Simvastatin

Both simvastatin and the β-hydroxy-acid are bound to human plasma proteins (95%).

The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicine occurred after multiple dosing. In all of the above pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post-dose.

Metabolism

Ezetimibe

Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major medicine-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total medicine in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Simvastatin

Simvastatin is an inactive lactone which is readily hydrolysed in vivo to the corresponding β-hydroxy-acid, a potent inhibitor of HMG CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is its primary site of action, with subsequent excretion of medicine equivalents in the bile. Consequently, availability of active medicine to the systemic circulation is low.

Following an intravenous injection of the β-hydroxy-acid metabolite, its half-life averaged 1.9 hours.

Elimination

Ezetimibe

Following oral administration of ¹⁴C-ezetimibe (20 mg) to human subjects, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the faeces and urine, respectively, over a 10 day collection period. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Simvastatin

Following an oral dose of radioactive simvastatin to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicine equivalents excreted in bile as well as unabsorbed medicine. Following an intravenous injection of the β-hydroxy-acid metabolite an average of only 0.3% of the IV dose was excreted in urine as inhibitors.

Characteristics in Patients

Paediatric Patients

The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the paediatric population <10 years of age are not available.

Geriatric Patients

Plasma concentrations for total ezetimibe are about 2 fold higher in the elderly (≥65 years) than in the young (18 to 45 years). LDL-C reduction and safety profile are comparable between elderly and young subjects treated with ezetimibe.

Gender

Plasma concentrations for total ezetimibe are slightly higher (<20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.

Race

Based on a meta-analysis of pharmacokinetic studies with ezetimibe, there were no pharmacokinetic differences between Blacks and Caucasians.

Hepatic Insufficiency

After a single 10 mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7 fold in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14 day, multiple dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4 fold on Day 1 and Day 14 compared to healthy subjects. No dosage adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score >9) hepatic insufficiency, ezetimibe is not recommended in these patients (see Warnings and Precautions).

Renal Insufficiency

Ezetimibe

After a single 10 mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m²), the mean AUC for total ezetimibe was increased approximately 1.5 fold, compared to healthy subjects (n=9).

An additional patient in this study (post-renal transplant and receiving multiple medications, including cyclosporine) had a 12 fold greater exposure to total ezetimibe.

Simvastatin

In a study of patients with severe renal insufficiency (creatinine clearance <30 mL/min), the plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase inhibitor were approximately two-fold higher than those in healthy volunteers.

Pharmaceutical Precautions

Store up to 25°C, usual climatic temperature excursions permitted. Keep container tightly closed.

Medicine Classification

Prescription Medicine

Package Quantities

VYTORIN tablets are available in packs of 30 tablets.

Further Information

Chemistry

VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.

Ezetimibe

The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C₂₄H₂₁F₂NO₃ and its molecular weight is 409.4.

Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is:

Simvastatin

Simvastatin, an inactive lactone, is hydrolysed to the corresponding β-hydroxy-acid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β (2S*,4S*),-8aβ]]. The empirical formula of simvastatin is C₂₅H₃₈O₅ and its molecular weight is 418.57.

Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Its structural formula is:

Inactive Ingredients

Each tablet contains the following inactive ingredients: butylated hydroxyanisole, citric acid monohydrate, croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and propyl gallate.

Name and Address

Merck Sharp & Dohme (NZ) Ltd
P O Box 99851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673

Date of Preparation

14 May 2009

DP-VYT-0509(140509)

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