1. Name of the medicinal product

Ezetimibe Tablets USP 10mg Taj Pharma

  1. Qualitative and quantitative composition

Ezetimibe Tablets USP 10mg Taj Pharma
Each tablet contains:
Ezetimib USP 10mg
Excipients: Q.S.

Excipient(s) with known effect: Lactose monohydrate.

Each tablet contains 62mg lactose monohydrate.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Tablet.

White to off white capsule-shaped,

  1. Clinical particulars
  • Therapeutic indications

Primary hypercholesterolaemia

Ezetimibe Taj Pharma, co-administered with an HMG-CoA reductase inhibitor (statin) is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia who are not appropriately controlled with a statin alone.

Ezetimibe Taj Pharma monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.

Prevention of cardiovascular events

Ezetimibe Taj Pharma is indicated to reduce the risk of cardiovascular events (see section 5.1) in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH)

Ezetimibe Taj Pharma co-administered with a statin, is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).

  • Posology and method of administration

Posology

The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetimibe Taj Pharma.

The recommended dose is one Ezetimibe Taj Pharma 10mg tablet daily.

When Ezetimibe Taj Pharma is added to a statin, either the indicated usual initial dose of that particular statin or the already established higher statin dose should be continued. In this setting, the dosage instructions for that particular statin should be consulted.

Use in patients with coronary heart disease and ACS event history

For incremental cardiovascular event reduction in patients with coronary heart disease and ACS event history, Ezetimibe Taj Pharma 10mg may be administered with a statin with proven cardiovascular benefit.

Co-administration with bile acid sequestrants

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

Elderly patients

No dosage adjustment is required for elderly patients (see section 5.2).

Use in hepatic impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with Ezetimibe Taj Pharma is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score>9) liver dysfunction (see sections 4.4 and 5.2.).

Use in renal impairment

No dosage adjustment is required for renally impaired patients (see section 5.2).

Paediatric population

Initiation of treatment must be performed under review of a specialist.

Children and adolescents ≥ 6 years: The safety and efficacy of Ezetimibe Taj Pharma in children aged 6 to 17 years has not been established. Current available data are described in sections 4.4, 4.8, 5.1 and 5.2 but no recommendation on posology can be made.

When Ezetimibe Taj Pharma is administered with a statin, the dosage instructions for the statin, in children should be consulted.

Children <6 years: The safety and efficacy of Ezetimibe Taj Pharma in children aged <6 years has not been established. No data are available.

Method of administration

For oral administration. Ezetimibe Taj Pharma can be administered at any time of the day, with or without food.

  • Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

When Ezetimibe Taj Pharma is co-administered with a statin, please refer to the SmPC for that particular medicinal product.

Therapy with Ezetimibe Taj Pharma co-administered with a statin is contraindicated during pregnancy and breast-feeding.

Ezetimibe Taj Pharma co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

  • Special warnings and precautions for use

When Ezetimibe Taj Pharma is co-administered with a statin, please refer to the SmPC for that particular medicinal product.

Liver enzymes

In controlled co-administration trials in patients receiving Ezetimibe Taj Pharma with a statin, consecutive transaminase elevations (≥3 X the upper limit of normal [ULN]) have been observed. When Ezetimibe Taj Pharma is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin (see section 4.8).

In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE- IT), 18,144 patients with coronary heart disease and ACS event history were randomised to receive Ezetimibe Taj Pharma/simvastatin 10/40mg daily (n=9067) or simvastatin 40mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for Ezetimibe Taj Pharma/simvastatin and 2.3% for simvastatin. (See section 4.8).

In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe Taj Pharma 10mg combined with simvastatin 20mg daily (n=4650) or placebo (n=4620). (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for Ezetimibe Taj Pharma combined with simvastatin and 0.6% for placebo (see section 4.8).

Skeletal muscle

In post-marketing experience with Ezetimibe Taj Pharma, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with Ezetimibe Taj Pharma. However, rhabdomyolysis has been reported very rarely with Ezetimibe Taj Pharma monotherapy and very rarely with the addition of Ezetimibe Taj Pharma to other agents known to be associated with increased risk of rhabdomyolysis. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level >10 times the ULN, Ezetimibe Taj Pharma, any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Ezetimibe Taj Pharma should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).

In IMPROVE-IT, 18,144 patients with coronary heart disease and ACS event history were randomised to receive Ezetimibe Taj Pharma/simvastatin 10/40mg daily (n=9067) or simvastatin 40mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for Ezetimibe Taj Pharma/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Ezetimibe Taj Pharma/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury (see section 4.8.).

In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Ezetimibe Taj Pharma 10mg combined with simvastatin 20mg daily (n=4650) or placebo (n=4620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Ezetimibe Taj Pharma combined with simvastatin and 0.1% for placebo. (See section 4.8)

Hepatic insufficiency

Due to the unknown effects of the increased exposure to Ezetimibe Taj Pharma in patients with moderate or severe hepatic insufficiency, Ezetimibe Taj Pharma is not recommended (see section 5.2).

Paediatric population

Efficacy and safety of Ezetimibe Taj Pharma in patients 6 to10 years of age with heterozygous familial or non-familial hypercholesterolemia have been evaluated in a 12-week placebo-controlled clinical trial. Effects of Ezetimibe Taj Pharma for treatment periods > 12 weeks have not been studied in this age group (see sections 4.2, 4.8, 5.1 and 5.2).

Ezetimibe Taj Pharma has not been studied in patients younger than 6 years of age. (see sections 4.2 and 4.8).

Efficacy and safety of Ezetimibe Taj Pharma co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys (Tanner stage II or above) and in girls who were at least one year post-menarche.

In this limited controlled study, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of Ezetimibe Taj Pharma for a treatment period > 33 weeks on growth and sexual maturation have not been studied (see sections 4.2 and 4.8)

The safety and efficacy of Ezetimibe Taj Pharma co-administered with doses of simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age.

The safety and efficacy of Ezetimibe Taj Pharma co-administered with simvastatin have not been studied in paediatric patients < 10 years of age. (see sections 4.2 and 4.8).

The long-term efficacy of therapy with Ezetimibe Taj Pharma in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Fibrates

The safety and efficacy of Ezetimibe Taj Pharma administered with fibrates have not been established.

If cholelithiasis is suspected in a patient receiving Ezetimibe Taj Pharma and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).

Ciclosporin

Caution should be exercised when initiating Ezetimibe Taj Pharma in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe Taj Pharma and ciclosporin (see section 4.5).

Anticoagulants

If Ezetimibe Taj Pharma is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).

Excipient

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

  • Interaction with other medicinal products and other forms of interaction

In preclinical studies, it has been shown that Ezetimibe Taj Pharma does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between Ezetimibe Taj Pharma and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

In clinical interaction studies, Ezetimibe Taj Pharma had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with Ezetimibe Taj Pharma, had no effect on the bioavailability of Ezetimibe Taj Pharma.

Antacids

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

Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total Ezetimibe Taj Pharma (Ezetimibe Taj Pharma + Ezetimibe Taj Pharma glucuronide) approximately 55%. The incremental low-density lipoprotein cholesterol (LDL-C) reduction due to adding Ezetimibe Taj Pharma to cholestyramine may be lessened by this interaction (see section 4.2).

Fibrates

In patients receiving fenofibrate and Ezetimibe Taj Pharma, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see section 4.4 and 4.8).

If cholelithiasis is suspected in a patient receiving Ezetimibe Taj Pharma and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8).

Concomitant fenofibrate or gemfibrozil administration modestly increased total Ezetimibe Taj Pharma concentrations (approximately 1.5- and 1.7-fold respectively).

Co-administration of Ezetimibe Taj Pharma with other fibrates has not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, Ezetimibe Taj Pharma sometimes increased cholesterol in the gallbladder bile, but not in all species (see section 5.3). A lithogenic risk associated with the therapeutic use of Ezetimibe Taj Pharma cannot be ruled out.

Statins

No clinically significant pharmacokinetic interactions were seen when Ezetimibe Taj Pharma was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.

Ciclosporin

In a study of eight post-renal transplant patients with creatinine clearance of >50 ml/min on a stable dose of ciclosporin, a single 10mg dose of Ezetimibe Taj Pharma resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in the mean AUC for total Ezetimibe Taj Pharma compared to a healthy control population, receiving Ezetimibe Taj Pharma alone, from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total Ezetimibe Taj Pharma compared to concurrent controls receiving Ezetimibe Taj Pharma alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20mg Ezetimibe Taj Pharma for 8 days with a single 100mg dose of ciclosporin on Day 7 resulted in a mean 15 % increase in ciclosporin AUC (range 10 % decrease to 51 % increase) compared to a single 100mg dose of ciclosporin alone. A controlled study on the effect of co-administered Ezetimibe Taj Pharma on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating Ezetimibe Taj Pharma in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe Taj Pharma and ciclosporin (see section 4.4).

Anticoagulants

Concomitant administration of Ezetimibe Taj Pharma (10mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had Ezetimibe Taj Pharma added to warfarin or fluindione. If Ezetimibe Taj Pharma is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).

Paediatric population

Interaction studies have only been performed in adults.

  • Fertility, pregnancy and lactation

Ezetimibe Taj Pharma co-administered with a statin is contraindicated during pregnancy and breast-feeding (see section 4.3), please refer to the SmPC for that particular statin.

Pregnancy

Ezetimibe Taj Pharma should be given to pregnant women only if clearly necessary. No clinical data are available on the use of Ezetimibe Taj Pharma during pregnancy. Animal studies on the use of Ezetimibe Taj Pharma in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).

Breast-feeding

Ezetimibe Taj Pharma should not be used during breast-feeding. Studies on rats have shown that Ezetimibe Taj Pharma is secreted into breast milk. It is not known if Ezetimibe Taj Pharma is secreted into human breast milk.

Fertility

No clinical trial data are available on the effects of Ezetimibe Taj Pharma on human fertility. Ezetimibe Taj Pharma had no effect on the fertility of male or female rats (see section 5.3).

  • Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.

  • Undesirable effects

Clinical studies and post-marketing experience:

In clinical studies of up to 112 weeks duration, Ezetimibe Taj Pharma 10mg daily was administered alone in 2396 patients, or with a statin in 11,308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between Ezetimibe Taj Pharma and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between Ezetimibe Taj Pharma and placebo.

Ezetimibe Taj Pharma administered alone or co-administered with a statin:

The following adverse reactions were observed in patients treated with Ezetimibe Taj Pharma (N=2396) and at a greater incidence than placebo (N=1159) or in patients treated with Ezetimibe Taj Pharma co-administered with a statin (N=11308) and at a greater incidence than statin administered alone (N=9361). Post-marketing adverse reactions were derived from reports containing Ezetimibe Taj Pharma either administered alone or with a statin.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (- cannot be estimated from the available data).

Ezetimibe Taj Pharma monotherapy

CommonUncommon
Metabolism and nutrition disorders• decreased appetite
Vascular disorders• hot flush

• hypertension

Respiratory, thoracic and mediastinal disorders• cough
Gastrointestinal disorders• abdominal pain

• diarrhoea

• flatulence

• dyspepsia

• gastrooesophageal reflux disease

• nausea

Musculoskeletal and connective tissue disorders• arthralgia

• muscle spasms

• neck pain

General disorders and administration site conditions• fatigue• chest pain

• pain

Investigations• ALT and/or AST increased

• blood CPK increased

• gamma-glutamyltransferase increased

• liver function test abnormal

Additional adverse reactions with Ezetimibe Taj Pharma co-administered with a statin

CommonUncommon
Nervous system disorders• headache• paraesthesia
Gastrointestinal disorders• dry mouth

• gastritis

Skin and subcutaneous tissue disorders• pruritus

• rash

• urticaria

Musculoskeletal and connective tissue disorders• myalgia• back pain

• muscular weakness

• pain in extremity

General disorders and administration site conditions• asthenia

• oedema peripheral

Investigations• ALT and/or AST increased

Post-marketing Experience (with or without a statin)

Not known
Blood and lymphatic system disorders• thrombocytopenia
Immune system disorders• hypersensitivity, including rash, urticaria, anaphylaxis and angio-oedema
Psychiatric disorders• depression
Nervous system disorders• dizziness

• paraesthesia

Respiratory, thoracic and mediastinal disorders• dyspnoea
Gastrointestinal disorders• pancreatitis

• constipation

Hepatobiliary disorders• hepatitis

• cholelithiasis

• cholecystitis

Skin and subcutaneous tissue disorders• erythema multiforme
Musculoskeletal and connective tissue disorders• myalgia

• myopathy/rhabdomyolysis (see section 4.4).

General disorders and administration site conditions• asthenia

Ezetimibe Taj Pharma co-administered with fenofibrate:

Common
Gastrointestinal disorders• abdominal pain

In a multicentre, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidaemia, 625 patients were treated for up to 12 weeks and 576 patients for up to 1 year. In this study, 172 patients treated with Ezetimibe Taj Pharma and fenofibrate completed 12 weeks of therapy, and 230 patients treated with Ezetimibe Taj Pharma and fenofibrate (including 109 who received Ezetimibe Taj Pharma alone for the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups for infrequent events.

Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and Ezetimibe Taj Pharma co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and Ezetimibe Taj Pharma co-administered with fenofibrate, respectively (see sections 4.4 and 4.5).

Paediatric patients (6 to 17 years of age)

In a study involving paediatric (6 to10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n = 138), elevations of ALT and/or AST (≥ 3X ULN, consecutive) were observed in 1.1% (1 patient) of the Ezetimibe Taj Pharma patients compared to 0% in the placebo group. There were no elevations of CPK (≥ 10X ULN). No cases of myopathy were reported.

In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of ALT and/or AST (≥3X ULN, consecutive) were observed in 3% (4 patients) of the Ezetimibe Taj Pharma/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥ 10X ULN). No cases of myopathy were reported.

These trials were not suited for comparison of rare adverse drug reactions.

Patients with Coronary Heart Disease and ACS Event History

In the IMPROVE-IT study (see section 5.1), involving 18,144 patients treated with either Ezetimibe Taj Pharma/simvastatin 10/40mg (n=9067; of whom 6% were uptitrated to Ezetimibe Taj Pharma/simvastatin 10/80mg) or simvastatin 40mg (n=9077; of whom 27% were uptitrated to simvastatin 80mg), the safety profiles were similar during a median follow-up period of 6.0 years. Discontinuation rates due to adverse experiences were 10.6% for patients treated with Ezetimibe Taj Pharma/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for Ezetimibe Taj Pharma/simvastatin and 0.1% for simvastatin, where myopathy was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN or two consecutive observations of CK ≥5 and <10 times ULN. The incidence of rhabdomyolysis was 0.1% for Ezetimibe Taj Pharma/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness or pain with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 times ULN and <10 times ULN on two consecutive occasions with evidence of renal injury or CK ≥10,000 IU/L without evidence of renal injury. The incidence of consecutive elevations of transaminases (≥3 X ULN) was 2.5% for Ezetimibe Taj Pharma/simvastatin and 2.3% for simvastatin (see section 4.4.). Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to Ezetimibe Taj Pharma/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalisations was 1.5% in both treatment groups. Cancer (defined as any new malignancy) was diagnosed during the trial in 9.4% vs 9.5%, respectively.

Patients with Chronic Kidney Disease

In the Study of Heart and Renal Protection (SHARP) (see section 5.1), involving over 9000 patients treated with a fixed dose combination of Ezetimibe Taj Pharma 10mg with simvastatin 20mg daily (n=4650) or placebo (n=4620), the safety profiles were comparable during a median follow-up period of 4.9 years. In this trial, only serious adverse events and discontinuations due to any adverse events were recorded. Discontinuation rates due to adverse events were comparable (10.4% in patients treated with Ezetimibe Taj Pharma combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with Ezetimibe Taj Pharma combined with simvastatin and 0.1% in patients treated with placebo. Consecutive elevations of transaminases (> 3X ULN) occurred in 0.7% of patients treated with Ezetimibe Taj Pharma combined with simvastatin compared with 0.6% of patients treated with placebo (see section 4.4). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for Ezetimibe Taj Pharma combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.

Laboratory values

In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3 X ULN, consecutive) was similar between Ezetimibe Taj Pharma (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with Ezetimibe Taj Pharma co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (see section 4.4.).

In clinical trials, CPK >10 X ULN was reported for 4 of 1,674 (0.2%) patients administered Ezetimibe Taj Pharma alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered Ezetimibe Taj Pharma and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with Ezetimibe Taj Pharma compared with the relevant control arm (placebo or statin alone) (see section 4.4.).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

  • Overdose

In clinical studies, administration of Ezetimibe Taj Pharma, 50mg/day, to 15 healthy subjects for up to 14 days, or 40mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5,000mg/kg of Ezetimibe Taj Pharma in rats and mice and 3,000mg/kg in dogs.

A few cases of overdosage with Ezetimibe Taj Pharma have been reported: most have not been associated with adverse experiences.

Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: Other lipid modifying agents.

Mechanism of action

Ezetimibe Taj Pharma is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezetimibe Taj Pharma 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 Taj Pharma is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.

Ezetimibe Taj Pharma 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 Taj Pharma inhibited intestinal cholesterol absorption by 54%, compared with placebo.

Pharmacodynamic effects

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

Epidemiologic studies 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.

Administration of Ezetimibe Taj Pharma with a statin is effective in reducing the risk of cardiovascular events in patients with coronary heart disease and ACS event history.

Clinical efficacy and safety

In controlled clinical studies, Ezetimibe Taj Pharma, either as monotherapy or co-administered with a statin significantly reduced total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglyceride (TG) and increased high-density lipoprotein cholesterol (HDL-C) in patients with hypercholesterolaemia.

Primary hypercholesterolaemia

In a double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL-C goal (2.6 to 4.1 mmol/l [100 to 160mg/dl], depending on baseline characteristics) were randomised to receive either Ezetimibe Taj Pharma 10mg or placebo in addition to their on-going statin therapy.

Among statin-treated patients not at LDL-C goal at baseline (~82%), significantly more patients randomised to Ezetimibe Taj Pharma achieved their LDL-C goal at study endpoint compared to patients randomised to placebo, 72% and 19% respectively. The corresponding LDL-C reductions were significantly different (25% and 4% for Ezetimibe Taj Pharma versus placebo, respectively). In addition, Ezetimibe Taj Pharma, added to on-going statin therapy, significantly decreased total-C, Apo B, TG and increased HDL-C, compared with placebo. Ezetimibe Taj Pharma or placebo added to statin therapy reduced median C-reactive protein by 10% or 0% from baseline, respectively.

In two, double-blind, randomised placebo-controlled, 12-week studies in 1,719 patients with primary hypercholesterolaemia, Ezetimibe Taj Pharma 10mg significantly lowered total-C (13%), LDL-C (19%), Apo B (14%), and TG (8%) and increased HDL-C (3%) compared to placebo. In addition, Ezetimibe Taj Pharma had no effect on the plasma concentrations of the fat-soluble vitamins A, D, and E, no effect on prothrombin time, and, like other lipid-lowering agents, did not impair adrenocortical steroid hormone production.

In a multicenter, double-blind, controlled clinical study (ENHANCE), 720 patients with heterozygous familial hypercholesterolemia were randomized to receive Ezetimibe Taj Pharma 10mg in combination with simvastatin 80mg (n = 357) or simvastatin 80mg (n = 363) for 2 years. The primary objective of the study was to investigate the effect of Ezetimibe Taj Pharma/simvastatin combination therapy on carotid artery intima-media thickness (IMT) compared to simvastatin monotherapy. The impact of this surrogate marker on cardiovascular morbidity and mortality is still not demonstrated.

The primary endpoint, the change in the mean IMT of all six carotid segments, did not differ significantly (p=0.29) between the two treatment groups as measured by B-mode ultrasound. With Ezetimibe Taj Pharma 10mg in combination with simvastatin 80mg or simvastatin 80mg alone, intima-medial thickening increased by 0.0111 mm and 0.0058 mm, respectively, over the study’s 2 year duration (baseline mean carotid IMT 0.68 mm and 0.69 mm respectively).

Ezetimibe Taj Pharma 10mg in combination with simvastatin 80mg lowered LDL-C, total-C, Apo B, and TG significantly more than simvastatin 80mg. The percent increase in HDL-C was similar for the two treatment groups. The adverse reactions reported for Ezetimibe Taj Pharma 10mg in combination with simvastatin 80mg were consistent with its known safety profile.

Paediatric population

In a multicentre, double-blind, controlled study, 138 patients (59 boys and 79 girls), 6 to 10 years of age (mean age 8.3 years) with heterozygous familial or non-familial hypercholesterolaemia (HeFH) with baseline LDL-C levels between 3.74 and 9.92 mmol/l were randomised to either Ezetimibe Taj Pharma 10mg or placebo for 12 weeks.

At week 12, Ezetimibe Taj Pharma significantly reduced total-C (-21% vs. 0%), LDL-C (-28% vs. -1%), Apo-B (-22% vs. -1%), and non-HDL-C (-26% vs. 0%) compared to placebo. Results for the two treatment groups were similar for TG and HDL-C (-6% vs. +8%, and +2% vs. +1%, respectively).

In a multicentre, double-blind, controlled study, 142 boys (Tanner stage II and above) and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years) with heterozygous familial hypercholesterolaemia (HeFH) with baseline LDL-C levels between 4.1 and 10.4 mmol/l were randomised to either Ezetimibe Taj Pharma 10mg co-administered with simvastatin (10mg, 20mg or 40mg) or simvastatin (10mg, 20mg or 40mg) alone for 6 weeks, co-administered Ezetimibe Taj Pharma and 40mg simvastatin or 40mg simvastatin alone for the next 27 weeks, and open-label co-administered Ezetimibe Taj Pharma and simvastatin (10mg, 20mg or 40mg) for 20 weeks thereafter.

At Week 6, Ezetimibe Taj Pharma co-administered with simvastatin (all doses) significantly reduced total-C (38 % vs 26 %), LDL-C (49 % vs 34 %), Apo B (39 % vs 27 %), and non-HDL-C (47 % vs 33 %) compared to simvastatin (all doses) alone. Results for the two treatment groups were similar for TG and HDL-C (-17 % vs -12 % and +7 % vs +6 %, respectively). At Week 33, results were consistent with those at Week 6 and significantly more patients receiving Ezetimibe Taj Pharma and 40mg simvastatin (62 %) attained the NCEP AAP ideal goal (< 2.8 mmol/L [110mg/dL]) for LDL-C compared to those receiving 40mg simvastatin (25 %). At Week 53, the end of the open label extension, the effects on lipid parameters were maintained.

The safety and efficacy of Ezetimibe Taj Pharma co-administered with doses of simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age. The safety and efficacy of Ezetimibe Taj Pharma co-administered with simvastatin have not been studied in paediatric patients < 10 years of age.

The long-term efficacy of therapy with Ezetimibe Taj Pharma in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.

Prevention of cardiovascular events

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) was a multicenter, randomised, double-blind, active-control study of 18,144 patients enrolled within 10 days of hospitalization for acute coronary syndrome (ACS; either acute myocardial infarction [MI] or unstable angina [UA]). Patients had an LDL-C ≤125mg/dL (≤3.2 mmol/L) at the time of presentation with ACS if they had not been taking lipid-lowering therapy, or ≤100mg/dL (≤2.6 mmol/L) if they had been receiving lipid-lowering therapy. All patients were randomized in a 1:1 ratio to receive either Ezetimibe Taj Pharma/simvastatin 10/40mg (n=9067) or simvastatin 40mg (n=9077) and followed for a median of 6.0 years.

Patients had a mean age of 63.6 years; 76% were male, 84% were Caucasian, and 27% were diabetic. The average LDL-C value at the time of study qualifying event was 80mg/dL (2.1 mmol/L) for those on lipid-lowering therapy (n=6390) and 101mg/dL (2.6 mmol/L) for those not on previous lipid-lowering therapy (n=11594). Prior to the hospitalisation for the qualifying ACS event, 34% of the patients were on statin therapy. At one year, the average LDL-C for patients continuing on therapy was 53.2mg/dL (1.4 mmol/L) for the Ezetimibe Taj Pharma/simvastatin group and 69.9mg/dL (1.8 mmol/L) for the simvastatin monotherapy group. Lipid values were generally obtained for patients who remained on study therapy.

The primary endpoint was a composite consisting of cardiovascular death, major coronary events (MCE; defined as non-fatal myocardial infarction, documented unstable angina that required hospitalization, or any coronary revascularization procedure occurring at least 30 days after randomized treatment assignment) and non-fatal stroke. The study demonstrated that treatment with Ezetimibe Taj Pharma when added to simvastatin provided incremental benefit in reducing the primary composite endpoint of cardiovascular death, MCE, and non-fatal stroke compared with simvastatin alone (relative risk reduction of 6.4%, p=0.016). The primary endpoint occurred in 2572 of 9067 patients (7-year Kaplan-Meier [KM] rate 32.72%) in the Ezetimibe Taj Pharma/simvastatin group and 2742 of 9077 patients (7-year KM rate 34.67%) in the simvastatin alone group. (See Figure 1 and Table 1.) This incremental benefit is expected to be similar with coadministration of other statins shown to be effective in reducing the risk of cardiovascular events. Total mortality was unchanged in this high risk group (see Table 1).

There was an overall benefit for all strokes; however there was a small non-significant increase in haemorrhagic stroke in the Ezetimibe Taj Pharma-simvastatin group compared with simvastatin alone (see Table 1). The risk of haemorrhagic stroke for Ezetimibe Taj Pharma coadministered with higher potency statins in long-term outcome studies has not been evaluated.

The treatment effect of Ezetimibe Taj Pharma/simvastatin was generally consistent with the overall results across many subgroups, including sex, age, race, medical history of diabetes mellitus, baseline lipid levels, prior statin therapy, prior stroke, and hypertension.

Figure 1: Effect of Ezetimibe Taj Pharma/simvastatin on the primary composite endpoint of cardiovascular death, major coronary event, or non-fatal stroke

Table 1: Major cardiovascular events by treatment group in all randomised patients in IMPROVE-IT

OutcomeEzetimibe Taj Pharma/Simvastatin 10/40mga (N=9067)Simvastatin 40mgb (N=9077)Hazard Ratio (95% CI)p-value
nK-M%cnK-M%c
Primary composite efficacy endpoints
CV death, major coronary events and non-fatal stroke257232.72%274234.67%0.936 (0.887, 0.988)0.016
Secondary composite efficacy endpoints
CHD death, non-fatal MI, urgent coronary revascularisation after 30 days132217.52%144818.88%0.912 (0.847, 0.983)0.016
MCE, non-fatal stroke, death (all causes)308938.65%324640.25%0.948 (0.903, 0.996)0.035
CV death, non-fatal MI, unstable angina requiring hospitalisation, any revascularisation, non-fatal stroke271634.49%286936.20%0.945 (0.897, 0.996)0.035
Components of primary composite endpoint and select efficacy endpoints

(first occurrences of specified events at any time)

Cardiovascular death5376.89%5386.84%1.000 (0.887, 1.127)0.997
Major coronary event:
Non-fatal MI94512.77%108314.41%0.871 (0.798, 0.950)0.002
Unstable angina requiring hospitalisation1562.06%1481.92%1.059 (0.846, 1.326)0.618
Coronary revascularisation after 30 days169021.84%179323.36%0.947 (0.886, 1.012)0.107
Non-fatal stroke2453.49%3054.24%0.802 (0.678, 0.949)0.010
All MI (fatal and non-fatal)97713.13%111814.82%0.872 (0.800, 0.950)0.002
All stroke (fatal and non-fatal)2964.16%3454.77%0.857 (0.734, 1.001)0.052
Non-haemorrhagic stroked2423.48%3054.23%0.793 (0.670, 0.939)0.007
Haemorrhagic stroke590.77%430.59%1.377 (0.930, 2.040)0.110
Death from any cause121515.36%123115.28%0.989 (0.914, 1.070)0.782

a 6% were uptitrated to Ezetimibe Taj Pharma/simvastatin 10/80mg

b 27% were uptitrated to simvastatin 80mg

c Kaplan-Meier estimate at 7 years

d includes ischaemic stroke or stroke of undetermined type

Prevention of major vascular events in Chronic Kidney Disease (CKD)

The Study of Heart and Renal Protection (SHARP) was a multi-national, randomized, placebo-controlled, double-blind study conducted in 9438 patients with chronic kidney disease, a third of whom were on dialysis at baseline. A total of 4650 patients were allocated to a fixed dose combination of Ezetimibe Taj Pharma 10mg with simvastatin 20mg and 4620 to placebo, and followed for a median of 4.9 years. Patients had a mean age of 62 and 63% were male, 72% Caucasian, 23% diabetic and, for those not on dialysis, the mean estimated glomerular filtration rate (eGFR) was 26.5 ml/min/1.73 m2. There were no lipid entry criteria. Mean LDL-C at baseline was 108mg/dL. After one year, including patients no longer taking study medication, LDL-C was reduced 26% relative to placebo by simvastatin 20mg alone and 38% by Ezetrol 10mg combined with simvastatin 20mg.

The SHARP protocol-specified primary comparison was an intention-to-treat analysis of “major vascular events” (MVE; defined as nonfatal MI or cardiac death, stroke, or any revascularization procedure) in only those patients initially randomized to the Ezetimibe Taj Pharma combined with simvastatin (n=4193) or placebo (n=4191) groups. Secondary analyses included the same composite analyzed for the full cohort randomized (at study baseline or at year 1) to Ezetimibe Taj Pharma combined with simvastatin (n=4650) or placebo (n=4620) as well as the components of this composite.

The primary endpoint analysis showed that Ezetimibe Taj Pharma combined with simvastatin significantly reduced the risk of major vascular events (749 patients with events in the placebo group vs. 639 in the Ezetimibe Taj Pharma combined with simvastatin group) with a relative risk reduction of 16% (p=0.001).

Nevertheless, this study design did not allow for a separate contribution of the monocomponent Ezetimibe Taj Pharma to efficacy to significantly reduce the risk of major vascular events in patients with CKD.

The individual components of MVE in all randomized patients are presented in Table 1. Ezetimibe Taj Pharma combined with simvastatin significantly reduced the risk of stroke and any revascularization, with non-significant numerical differences favouring Ezetimibe Taj Pharma combined with simvastatin for nonfatal MI and cardiac death.

Table 2: Major Vascular Events by Treatment Group in all randomized patients in SHARPa

OutcomeEzetimibe Taj Pharma 10mg combined with simvastatin 20mg

(N=4650)

Placebo

(N=4620)

Risk Ratio

(95% CI)

P-value
Major Vascular Events701 (15.1%)814 (17.6%)0.85 (0.77-0.94)0.001
Nonfatal MI134 (2.9%)159 (3.4%)0.84 (0.66-1.05)0.12
Cardiac Death253 (5.4%)272 (5.9%)0.93 (0.78-1.10)0.38
Any Stroke171 (3.7%)210 (4.5%)0.81 (0.66-0.99)0.038
Non-hemorrhagic Stroke131 (2.8%)174 (3.8%)0.75 (0.60-0.94)0.011
Hemorrhagic Stroke45 (1.0%)37 (0.8%)1.21 (0.78-1.86)0.40
Any Revascularization284 (6.1%)352 (7.6%)0.79 (0.68-0.93)0.004
Major Atherosclerotic Events (MAE)b526 (11.3%)619 (13.4%)0.83 (0.74-0.94)0.002

Intention-to-treat analysis on all SHARP patients randomized to Ezetimibe Taj Pharma combined with simvastatin or placebo either at baseline or year 1

b MAE; defined as the composite of nonfatal myocardial infarction, coronary death, non-haemorrhagic stroke, or any revascularization

The absolute reduction in LDL cholesterol achieved with Ezetimibe Taj Pharma combined with simvastatin was lower among patients with a lower baseline LDL-C (<2.5 mmol/l) and patients on dialysis at baseline than the other patients, and the corresponding risk reductions in these two groups were attenuated.

Homozygous Familial Hypercholesterolaemia (HoFH)

A double-blind, randomised, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, who were receiving atorvastatin or simvastatin (40mg) with or without concomitant LDL apheresis. Ezetimibe Taj Pharma co-administered with atorvastatin (40mg or 80mg) or simvastatin (40mg or 80mg), significantly reduced LDL-C by 15% compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40mg to 80mg.

Aortic stenosis

The Simvastatin and Ezetimibe Taj Pharma for the Treatment of Aortic Stenosis (SEAS) study was a multi-center, double-blind, placebo controlled study with a median duration of 4.4 years conducted in 1873 patients with asymptomatic aortic stenosis (AS), documented by Doppler-measured aortic peak flow velocity within the range of 2.5 to 4.0 m/s. Only patients who were considered not to require statin treatment for purposes of reducing atherosclerotic cardiovascular disease risk were enrolled. Patients were randomised 1:1 to receive placebo or co-administered Ezetimibe Taj Pharma 10mg and simvastatin 40mg daily.

The primary endpoint was the composite of major cardiovascular events (MCE) consisting of cardiovascular death, aortic valve replacement (AVR) surgery, congestive heart failure (CHF) as a result of progression of AS, nonfatal myocardial infarction, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), hospitalization for unstable angina, and nonhaemorrhagic stroke. The key secondary endpoints were composites of subsets of the primary endpoint event categories.

Compared to placebo, Ezetimibe Taj Pharma/simvastatin 10mg/40mg did not significantly reduce the risk of MCE. The primary outcome occurred in 333 patients (35.3%) in the Ezetimibe Taj Pharma / simvastatin group and in 355 patients (38.2%) in the placebo group (hazard ratio in the Ezetimibe Taj Pharma / simvastatin group, 0.96; 95% confidence interval, 0.83 to 1.12; p = 0.59). Aortic valve replacement was performed in 267 patients (28.3%) in the Ezetimibe Taj Pharma / simvastatin group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; p = 0.97). Fewer patients had ischemic cardiovascular events in the Ezetimibe Taj Pharma / simvastatin group (n=148) than in the placebo group (n=187) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; p = 0.02), mainly because of the smaller number of patients who underwent coronary artery bypass grafting.

Cancer occurred more frequently in the Ezetimibe Taj Pharma / simvastatin group (105 versus 70, p= 0.01). The clinical relevance of this observation is uncertain as in the bigger SHARP trial the total number of patients with any incident cancer (438 in the Ezetimibe Taj Pharma / simvastatin versus 439 placebo group) did not differ. In addition, in the IMPROVE-IT trial the total number of patients with any new malignancy (853 in the Ezetimibe Taj Pharma/simvastatin group versus 863 in the simvastatin group) did not differ significantly and therefore the finding of the SEAS trial could not be confirmed by SHARP or IMPROVE-IT.

  • Pharmacokinetic properties

Absorption

After oral administration, Ezetimibe Taj Pharma is rapidly absorbed and extensively conjugated to a pharmacologically-active phenolic glucuronide (Ezetimibe Taj Pharma-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for Ezetimibe Taj Pharma-glucuronide and 4 to 12 hours for Ezetimibe Taj Pharma. The absolute bioavailability of Ezetimibe Taj Pharma 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 Taj Pharma when administered as Ezetimibe Taj Pharma 10mg tablets. Ezetimibe Taj Pharma can be administered with or without food.

Distribution

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

Biotransformation

Ezetimibe Taj Pharma 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 Taj Pharma and Ezetimibe Taj Pharma-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both Ezetimibe Taj Pharma and Ezetimibe Taj Pharma-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for Ezetimibe Taj Pharma and Ezetimibe Taj Pharma glucuronide is approximately 22 hours.

Elimination

Following oral administration of 14C-Ezetimibe Taj Pharma (20mg) to human subjects, total Ezetimibe Taj Pharma 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.

Special populations:

Paediatric patients

The pharmacokinetics of Ezetimibe Taj Pharma are similar between children ≥6 years and adults. Pharmacokinetic data in the paediatric population <6 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH, HeFH.

Elderly

Plasma concentrations for total Ezetimibe Taj Pharma 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 Taj Pharma. Therefore, no dosage adjustment is necessary in the elderly.

Hepatic insufficiency

After a single 10-mg dose of Ezetimibe Taj Pharma, the mean AUC for total Ezetimibe Taj Pharma 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 (10mg daily) in patients with moderate hepatic insufficiency (Child Pugh score 7 to 9), the mean AUC for total Ezetimibe Taj Pharma 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 Taj Pharma in patients with moderate or severe (Child Pugh score >9) hepatic insufficiency, Ezetimibe Taj Pharma is not recommended in these patients (see section 4.4).

Renal insufficiency

After a single 10mg dose of Ezetimibe Taj Pharma in patients with severe renal disease (n=8; mean CrCl ≤ 30ml/min /1.73m2), the mean AUC for total Ezetimibe Taj Pharma was increased approximately 1.5-fold, compared to healthy subjects (n=9). This result is not considered clinically significant. No dosage adjustment is necessary for renally impaired patients.

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

Gender

Plasma concentrations for total Ezetimibe Taj Pharma are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with Ezetimibe Taj Pharma. Therefore, no dosage adjustment is necessary on the basis of gender.

  • Preclinical safety data

Animal studies on the chronic toxicity of Ezetimibe Taj Pharma identified no target organs for toxic effects. In dogs treated for four weeks with Ezetimibe Taj Pharma (≥0.03mg/kg/day) the cholesterol concentration in the cystic bile was increased by a factor of 2.5 to 3.5. However, in a one-year study on dogs given doses of up to 300mg/kg/day no increased incidence of cholelithiasis or other hepatobiliary effects were observed. The significance of these data for humans is not known. A lithogenic risk associated with the therapeutic use of Ezetimibe Taj Pharma cannot be ruled out.

In co-administration studies with Ezetimibe Taj Pharma and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).

In a series of in vivo and in vitro assays Ezetimibe Taj Pharma, given alone or co-administered with statins, exhibited no genotoxic potential. Long-term carcinogenicity tests on Ezetimibe Taj Pharma were negative.

Ezetimibe Taj Pharma had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe Taj Pharma crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000mg/kg/day. The co-administration of Ezetimibe Taj Pharma and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of Ezetimibe Taj Pharma with lovastatin resulted in embryolethal effects.

  1. Pharmaceutical particulars
    • List of excipients

Lactose monohydrate

Sodium laurilsulfate

Croscarmellose sodium

Hypromellose

Crospovidone (Type B)

Cellulose, microcrystalline

Magnesium stearate

  • Incompatibilities

Not applicable.

  • Shelf life

3 years.

Bottles: Use within 100 days of opening.

  • Special precautions for storage

This medicinal product does not require any special storage conditions.

  • Nature and contents of container

The product is presented in the following pack types:

  • Clear/transparent Blister pack PVC-Aclar Aluminium foil blisters in cardboard cartons containing 14, 28, 30, 56, 84, 90, 98 and 100 tablets, calendar packs of 28 and 30 tablets and perforated unit dose blisters containing 30 x 1, 50 x 1 & 90 x 1 tablets.
  • Clear/transparent Blister pack PVC-PVdC Aluminium foil blisters in cardboard cartons containing 14, 28, 30, 56, 84, 90, 98 and 100 tablets and perforated unit dose blisters containing 30 x 1, 50 x 1 & 90 x 1 tablets.
  • HDPE bottle with polypropylene (PP) screw cap closure with induction sealing liner and absorbent cotton containing 14, 28, 50, 56, 84, 100 tablets.
  • Each carton contains: 100, 200, 250, 360, 400 and 500 Tablets.

The HDPE bottle pack may either be placed in an outer cardboard carton or provided without a carton based on market requirement.

Not all pack sizes may be marketed.

  • Special precautions for disposal and other handling

No special requirements for disposal.

Manufactured by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Ezetimibe Tablets USP 10mg Taj Pharma

Package leaflet: Information for the patient

Ezetimibe Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Ezetimibe Taj Pharma is and what it is used for
  2. What you need to know before you take Ezetimibe Taj Pharma
  3. How to take Ezetimibe Taj Pharma
  4. Possible side effects
  5. How to store Ezetimibe Taj Pharma
  6. Contents of the pack and other information
  7. What Ezetimibe Taj Pharma is and what it is used for

Ezetimibe Taj Pharma contains the active substance Ezetimibe Taj Pharma. Ezetimibe Taj Pharma is a medicine used to lower increased levels of cholesterol. Ezetimibe Taj Pharma lowers levels of total cholesterol, “bad” cholesterol (LDL cholesterol), and fatty substances called triglycerides in the blood. In addition, Ezetimibe Taj Pharma raises levels of “good” cholesterol (HDL cholesterol).

LDL cholesterol is often called “bad” cholesterol because it can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries. This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke.

HDL cholesterol is often called “good” cholesterol because it helps keep the bad cholesterol from building up in the arteries and protects against heart disease.

Triglycerides are another form of fat in your blood that may increase your risk for heart disease.

Ezetimibe Taj Pharma works by reducing the cholesterol absorbed in your digestive tract. Ezetimibe Taj Pharma does not help you lose weight.

Ezetimibe Taj Pharma adds to the cholesterol-lowering effect of statins, a group of medicines that reduce the cholesterol your body makes by itself.

Ezetimibe Taj Pharma is used for patients who cannot control their cholesterol levels by cholesterol lowering diet alone. You should stay on your cholesterol lowering diet while taking this medicine.

Ezetimibe Taj Pharma is used in addition to your cholesterol-lowering diet if you have:

  • a raised cholesterol level in your blood (primary hypercholesterolaemia [heterozygous familial and non-familial])
    • together with a statin, when your cholesterol level is not well controlled with a statin alone
    • alone, when statin treatment is inappropriate or is not tolerated
  • a hereditary illness (homozygous familial hypercholesterolaemia) that increases the cholesterol level in your blood. You will also be prescribed a statin and may also receive other treatments.

If you have heart disease, Ezetimibe Taj Pharma combined with cholesterol-lowering medicines called statins reduces the risk of heart attack, stroke, surgery to increase heart blood flow, or hospitalisation for chest pain.

Ezetimibe Taj Pharma does not help you lose weight.

  1. What you need to know before you take Ezetimibe Taj Pharma

If you use Ezetimibe Taj Pharma together with a statin, please read the package leaflet of that particular medicine.

Do not take Ezetimibe Taj Pharma:

  • if you are allergic to Ezetimibe Taj Pharma or any of the other ingredients of this medicine (listed in section 6).

Do not take Ezetimibe Taj Pharma together with a statin:

  • if you currently have liver problems
  • if you are pregnant or breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist before taking Ezetimibe Taj Pharma.

Tell your doctor about all your medical conditions including allergies.

Your doctor should do a blood test before you start taking Ezetimibe Taj Pharma with a statin. This is to check how well your liver is working.

Your doctor may also want you to have blood tests to check how well your liver is working after you start taking Ezetimibe Taj Pharma with a statin.

If you have moderate or severe liver problems, Ezetimibe Taj Pharma is not recommended.

The safety and efficacy of the combined use of Ezetimibe Taj Pharma and certain lowering medicines, the fibrates have not been established.

If you have unexplained muscular pain, tenderness or weakness while taking these tablets, particularly if this is associated with a high temperature, please tell your doctor.

Children and adolescents

Do not give this medicine to children and adolescents aged 6 to 17 years unless it is prescribed by a specialist because there are limited data on safety and efficacy.

Do not give this medicine to children less than 6 years old because there is no information in this age group.

Other medicines and Ezetimibe Taj Pharma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines including medicines obtained without a prescription. In particular, tell your doctor or pharmacist if you are taking any of the following:

  • ciclosporin (a medicine often used in organ transplant patients)
  • medicines to prevent blood clots, such as warfarin, phenprocoumon, acenocoumarol or fluindione (anticoagulants)
  • cholestyramine (a medicine for lowering cholesterol), because it affects the way Ezetimibe Taj Pharma works
  • fibrates (medicines for lowering cholesterol).

Pregnancy and breast-feeding

Do not take Ezetimibe Taj Pharma with a statin if you are pregnant, are trying to get pregnant or think you may be pregnant. If you get pregnant while taking Ezetimibe Taj Pharma with a statin, stop taking both medicines immediately and tell your doctor.

There is no experience from the use of Ezetimibe Taj Pharma without a statin during pregnancy.

Do not take Ezetimibe Taj Pharma with a statin if you are breast-feeding, because it is not known if the medicines are passed into breast milk. Ezetimibe Taj Pharma without a statin should not be used if you are breast-feeding.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Ezetimibe Taj Pharma is not expected to interfere with your ability to drive or to use machinery. However, some people may get dizzy after taking Ezetimibe Taj Pharma, if this happens do not drive or use machinery.

Ezetimibe Taj Pharma contains lactose monohydrate

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

  1. How to take Ezetimibe Taj Pharma

Always take this medicine exactly as your doctor or pharmacist has told you. Continue taking your other cholesterol-lowering medicines unless your doctor tells you to stop. Check with your doctor or pharmacist if you are not sure.

Before starting Ezetimibe Taj Pharma, you should be on a diet to lower your cholesterol. You should keep on this cholesterol lowering diet whilst taking Ezetimibe Taj Pharma.

Adults and adolescents (10 to 17 years of age)

The recommended dose is one Ezetimibe Taj Pharma 10mg tablet by mouth once a day.

Take the tablets at any time of the day. You can take them with or without food.

If your doctor has prescribed Ezetimibe Taj Pharma along with a statin, both medicines can be taken at the same time. In this case, please read the dosage instructions in the package leaflet of that particular medicine.

If your doctor has prescribed Ezetimibe Taj Pharma along with cholestyramine or any other bile acid sequestrant (medicines for lowering cholesterol), you should take Ezetimibe Taj Pharma at least 2 hours before or 4 hours after taking the bile acid sequestrant.

If you take more Ezetimibe Taj Pharma than you should

If you take more Ezetimibe Taj Pharma than you have been told to, contact your doctor or pharmacist.

If you forget to take Ezetimibe Taj Pharma

Do not take a double dose to make up for a forgotten dose, just take your normal amount of Ezetimibe Taj Pharma at the usual time the next day.

If you stop taking Ezetimibe Taj Pharma

Talk to your doctor or pharmacist before you stop taking this medicine because your cholesterol levels may increase again.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor or go to your nearest hospital casualty department straight away if you have any of the following serious side effects; these effects are not known (frequency cannot be estimated from the available data) but you may need medical attention:

  • unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems, including muscle breakdown resulting in kidney damage, can be serious and may become a potentially life-threatening condition
  • allergic reactions, including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (which requires treatment right away)
  • inflammation of the pancreas often with severe abdominal pain.
  • gallstones or inflammation of the gallbladder (which may cause abdominal pain, feeling or being sick)
  • raised red rash, sometimes with target shaped lesions
  • inflammation of the liver (which may cause tiredness, fever, feeling or being sick, feeling generally unwell, yellowing of the skin and eyes, light coloured stools and dark coloured urine).

When used alone, the following side effects were reported:

Common (may affect up to 1 in 10 people):

  • abdominal pain
  • diarrhoea
  • wind (flatulence)
  • feeling tired.

Uncommon (may affect up to 1 in 100 people):

  • elevations in some liver and muscle enzymes seen on a blood test
  • cough
  • indigestion
  • heartburn
  • feeling sick
  • joint pain
  • muscle spasms
  • neck pain
  • decreased appetite
  • pain
  • chest pain
  • hot flush
  • high blood pressure.

Additionally, when used with a statin, the following side effects are possible:

Common (may affect up to 1 in 10 people):

  • elevations in some liver enzymes seen on a blood test
  • headache
  • muscle pain.

Uncommon (may affect up to 1 in 100 people):

  • tingling sensation
  • dry mouth
  • stomach pain, feeling sick, vomiting blood, blood in bowel motions
  • itching
  • rash
  • hives
  • back pain
  • muscle weakness
  • pain in arms and legs
  • unusual tiredness or weakness
  • swelling, especially in the hands and feet.

When used with or without a statin, the following side effects are possible:

Not known (frequency cannot be estimated from the available data):

  • dizziness
  • allergic reactions including rash and hives
  • constipation
  • reduction in blood cell counts, which may cause bruising/bleeding (thrombocytopenia)
  • tingling sensation
  • depression
  • unusual tiredness or weakness
  • shortness of breath.

When used with fenofibrate, the following side effect is possible:

Common (may affect up to 1 in 10 people):

  • abdominal pain.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Ezetimibe Taj Pharma

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister, carton or bottle after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Bottles: Use within 100 days of opening.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information

What Ezetimibe Taj Pharma contains

  • The active substance is Ezetimibe Taj Pharma. Each tablet contains 10mg Ezetimibe Taj Pharma.
  • The other ingredients are: lactose monohydrate (see section 2 “Ezetimibe Taj Pharma contains lactose monohydrate”); sodium laurilsulfate; croscarmellose sodium; hypromellose; crospovidone (Type B); cellulose, microcrystalline; magnesium stearate.

What Ezetimibe Taj Pharma looks like and contents of the pack

Ezetimibe Taj Pharma 10mg Tablets are white to off white capsule shaped,

Ezetimibe Taj Pharma 10mg Tablets are available in blister packs of 14, 28, 30, 56, 84, 90, 98 & 100 tablets; perforated unit dose blister packs of 30 x 1, 50 x 1, 90 x 1 tablets, calendar blisters of 28 and 30 tablets and plastic bottles of 14, 28, 50, 56, 84, 100 tablets.

Each carton contains: 100, 200, 250, 360, 400 and 500 Tablets.

Not all pack sizes may be marketed.

Manufactured by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com