Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Organon Pharma Pty Limited, Building A, 26 Talavera Road, Macquarie Park NSW 2113
ZIENT is contraindicated in patients with hypersensitivity to any component of this medication.
When ZIENT is to be administered with a statin, please refer to the Product Information for that particular statin.
ZIENT in combination with fenofibrate is contraindicated in patients with gall bladder disease.
Therapy with ZIENT in combination with a statin is contraindicated during pregnancy and lactation.
The combination of ZIENT with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.
When ZIENT is to be administered with a statin or fenofibrate, please refer to the Product Information for that particular product.
In controlled co-administration trials in patients receiving ZIENT with a statin, consecutive transaminase elevations (≥3 X the upper limit of normal [ULN]) have been observed. When ZIENT 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 Adverse Effects (Undesirable Effects)).
In the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg 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/simvastatin and 2.3% for simvastatin. (See Section 4.8 Adverse Effects (Undesirable Effects)).
In a controlled clinical study in which over 9,000 patients with chronic kidney disease were randomised to receive ZIENT 10 mg with simvastatin 20 mg daily (n=4,650) or placebo (n=4,620) (median follow-up period of 4.9 years), the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for ZIENT combined with simvastatin and 0.6% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).
In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZIENT compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of CPK >10 X ULN was 4 of 1674 (0.2%) patients administered ZIENT alone vs. 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ZIENT and a statin vs. 4 of 929 (0.4%) patients administered a statin alone.
In post-marketing experience with ZIENT, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ZIENT. However, rhabdomyolysis has been reported very rarely with ZIENT monotherapy and very rarely with the addition of ZIENT to agents known to be associated with increased risk of rhabdomyolysis. All patients starting therapy with ZIENT should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. ZIENT and any statin that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level >10 times the ULN indicates myopathy.
In IMPROVE-IT, 18,144 patients with CHD were randomized to receive ezetimibe/simvastatin 10/40 mg daily (n=9067) or simvastatin 40 mg daily (n=9077). During a median follow-up of 6.0 years, the incidence of myopathy was 0.2% for ezetimibe/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/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness, pain or tenderness with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 X ULN and <10 X 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 Adverse Effects (Undesirable Effects).)
In a clinical trial in which over 9,000 patients with chronic kidney disease were randomised to receive ZIENT 10 mg combined with simvastatin 20 mg daily (n=4,650) or placebo (n=4,620) (median follow-up 4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for ZIENT combined with simvastatin and 0.1% for placebo (see Section 4.8 Adverse Effects (Undesirable Effects)).
The co-administration of ezetimibe with fibrates, other than fenofibrate, has not been studied and is therefore not recommended. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fibrates may increase cholesterol excretion from the bile, and ezetimibe increased cholesterol in the gallbladder bile in a preclinical study in dogs. Given the potential for cholelithiasis, and the numerically higher incidence of cholecystectomies in patients administered ezetimibe and fenofibrate in a clinical study (see Section 5.1 Pharmacodynamic Properties, Clinical trials and Section 4.8 Adverse Effects (Undesirable Effects)), coadministration of ezetimibe and fenofibrate is not recommended in patients with pre-existing gallbladder disease (see Section 4.3 Contraindications).
Caution should be exercised when initiating ezetimibe in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving ZIENT and ciclosporin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If ZIENT is added to warfarin, another coumarin anticoagulant or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Due to unknown effects of the increased exposure of ezetimibe in patients with moderate to severe hepatic insufficiency, ZIENT is not recommended in these patients (see Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations)).
(See Section 4.2 Dose and Method of Administration, Use in patients with renal impairment/chronic kidney disease and Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations), Renal insufficiency.)
(See Section 4.2 Dose and Method of Administration, Use in the elderly and Section 5.2 Pharmacokinetic Properties, Characteristics in patients (special populations), Geriatric patients.)
The use of ZIENT co-administered with simvastatin in children and adolescent patients (10-17 years old) is recommended only for patients with Heterozygous Familial Hypercholesterolaemia (HeFH) or Homozygous Familial Hypercholesterolaemia (HoFH).
However, clinical efficacy/safety study experience in paediatric and adolescent patients (10-17 years old) has been mostly limited to patients with Heterozygous Familial Hypercholesterolaemia (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There are also no long-term (>1 year) safety data in this population.
The clinical safety and efficacy of ZIENT co-administered with simvastatin in children and adolescents (10-17 years old) with hypercholesterolaemia other than Heterozygous Familial Hypercholesterolaemia have not been studied.
Safety and effectiveness of ZIENT co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys and girls who were at least one year post-menarche. Doses greater than 10 mg ZIENT with 40 mg simvastatin have not been studied in this population and are not recommended. 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 for a treatment period >33 weeks on growth, sexual maturation, intellectual and psychosocial development have not been studied. (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); and Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients). Adolescent females should be counselled on appropriate contraceptive methods while on co-administered ZIENT and simvastatin therapy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use and Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
The safety and efficacy of ZIENT co-administered with simvastatin doses above 40 mg daily have not been studied in children and adolescents (10-17 years old) and are not recommended. The long-term efficacy of therapy with ZIENT in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
ZIENT co-administered with simvastatin has not been studied in pre-menarchal girls or in prepubertal boys and is not recommended.
ZIENT is not recommended in children <10 years of age.
Safety and effectiveness of ZIENT in patients 6 to 10 years of age with heterozygous familial or non-familial hypercholesterolaemia have been evaluated in a 12-week controlled clinical trial. Children treated with ZIENT had an adverse experience profile similar to that of adult patients treated with ZIENT. In this study, there was generally no detectable effect on growth or sexual maturation in either boys or girls. However, the effects of ezetimibe for a treatment period greater than 12 weeks on growth, sexual maturation, intellectual and psychosocial development have not been studied. The use of ZIENT in combination with statins has not been studied in children <10 years of age. ZIENT has not been studied in patients younger than 6 years of age (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); and Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
(See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory values.)
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
Ezetimibe 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, had no effect on the bioavailability of ezetimibe.
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.
Concomitant colestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55 %. The incremental LDL-C reduction due to adding ezetimibe to colestyramine may be lessened by this interaction. Therefore, dosing of ezetimibe and a bile acid binding sequestrant should take place several hours apart. However, efficacy of such combination has not been studied.
The effect of ciclosporin on ezetimibe was studied in eight post-renal transplant patients with creatinine clearance of >50 mL/min who were on a stable dose of ciclosporin. 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 group of historical healthy volunteers (n=17) who had taken a single 10-mg dose of ezetimibe alone.
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 ciclosporin, 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 dose 100 mg 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 100 mg dose of ciclosporin alone (see Section 4.3 Contraindications and see Section 4.4 Special Warnings and Precautions for Use).
In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.
In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available.
No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin.
Concurrent administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability and prothrombin time in a study of twelve healthy adult males administered a single dose of warfarin. There have been post-marketing reports of increased International Normalised Ratio in patients who had ZIENT added to warfarin, or fluindione. Most of these patients were also on other medications (see Section 4.4 Special Warnings and Precautions for Use).
Ezetimibe had no effects on fertility in male and female rats at doses up to 1000mg/kg/day by oral gavage, corresponding to exposures of approximately 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively.
[Pregnancy Category B3]
No clinical data on exposed pregnancies are available. Ezetimibe crossed the placenta in rats and rabbits. There was no evidence of foetal abnormalities in rats dosed with up to 1000 mg/kg/day of ezetimibe by oral gavage during organogenesis, corresponding to exposures of about 1 and 7 times the adult human exposure for ezetimibe and total ezetimibe respectively, based on AUC. There was an increase in the incidence of extra thoracic ribs in rabbits at doses of 250 to 1000 mg/kg/day, corresponding to exposures of 0.5 to 1 times and 100 to 150 times the adult human exposure for ezetimibe and total ezetimibe, respectively. The relevance of this finding to humans is not known. ZIENT should be used in pregnancy only if the potential benefit exceeds the potential risk. When ZIENT is to be administered with a statin, please refer to the Product Information for that particular statin.
Ezetimibe in combination with statins in rats and rabbits resulted in higher exposures to ezetimibe and/or statins than either drug administered alone. Skeletal malfunctions (hemivertebrae in rats and shortened/filamentous tail associated with fused and reduced number of caudal vertebrae in rabbits) and other less severe foetal abnormalities were observed in rats and rabbits dosed with ezetimibe/statin combinations during organogenesis. HMG-CoA reductase inhibitors (statins) are contraindicated during pregnancy, therefore, ezetimibe in combination with statins should not be used in pregnancy (see Section 4.3 Contraindications).
Embryofoetal studies in rats showed no adverse foetal effects of oral ezetimibe/fenofibrate doses corresponding to 5 times (total ezetimibe) and 38 times (fenofibric acid) the anticipated human plasma exposure at the maximum recommended doses. In similar studies in rabbits, a No Effect Level for embryotoxicity was established at ca. 90 times (total ezetimibe) and 32 times (fenofibric acid) anticipated human exposure levels.
Studies in rats have shown that ezetimibe is excreted in milk. Ezetimibe had no effects on pup development in rats treated with up to 1000 mg/kg/day of ezetimibe during late pregnancy and lactation. Drug exposures (based on AUC) in pups were approximately 1.5% and 50% of maternal exposures for ezetimibe and total ezetimibe respectively. It is not known whether ezetimibe is excreted into human breast milk. ZIENT should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
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 ZIENT may affect some patients' ability to drive or operate machinery. Individual responses to ZIENT may vary (see Section 4.8 Adverse Effects (Undesirable Effects)).
Clinical studies of 8 to 14 weeks duration in which ZIENT 10 mg daily was administered alone, with a statin, or with fenofibrate in 3551 patients demonstrated: ZIENT was generally well tolerated, adverse reactions were usually mild and transient, the overall incidence of side effects reported with ZIENT was similar to that reported with placebo, and the discontinuation rate due to adverse experiences was comparable between ZIENT and placebo.
There were no drug-related adverse experiences reported occurring in 2% of patients taking ZIENT alone (n=1691).
The following drug-related adverse experiences were reported occurring in 2% in patients taking ZIENT co-administered with a statin (n=1675).
Table 1:
| All Statins (%) N=1676 | ZIENT 10 mg Co-administered with a statin (%) N=1675 | |
|---|---|---|
| Musculoskeletal and connective tissue disorders | ||
| Myalgia | 2.4 | 3.2 |
In addition, the following common or uncommon drug-related adverse experiences were reported in clinical trials in patients taking ZIENT alone and at a greater incidence than placebo, or in patients taking ZIENT co-administered with a statin and at a greater incidence than statin administered alone.
ZIENT administered alone:
Uncommon: gamma-glutamyltransferase increased; liver function test abnormal
Uncommon: cough
Common: abdominal pain; diarrhea; flatulence
Uncommon: dyspepsia; gastroesophageal reflux disease
Uncommon: muscle spasms; neck pain
Uncommon: decreased appetite
Uncommon: hot flush; hypertension
Common: fatigue
Uncommon: chest pain; pain
ZIENT co-administered with a statin:
Common: ALT and/or AST increased
Common: headache
Uncommon: dry mouth; gastritis
Uncommon: pruritus
Common: myalgia
Uncommon: back pain; muscular weakness; pain in extremity
Uncommon: asthenia; edema peripheral
ZIENT co-administered with fenofibrate:
Common: abdominal pain
In a co-administration study with fenofibrate (see Section 5.1 Pharmacodynamic Properties, Clinical trials), in which 292 patients were exposed for ≥24 weeks and 120 exposed for ≥52 weeks, the incidence rate of cholecystectomy in the coadministration group was 1.7% (95% CI 0.6, 4.0) per 100 patient years compared to 0 (95% CI 0, 9.2) per 100 PY for the ezetimibe group and 0.6% (95% CI 0, 3.1) per 100 PY for the fenofibrate group. Longer term safety outcomes have not been studied.
In the IMPROVE-IT study (see Section 5.1 Pharmacodynamic Properties, Clinical trials), involving 18,144 patients treated with either ezetimibe/simvastatin 10/40 mg (n=9067; of whom 6% were uptitrated to ezetimibe/simvastatin 10/80 mg) or simvastatin 40 mg (n=9077; of whom 27% were uptitrated to simvastatin 80 mg), 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/simvastatin and 10.1% for patients treated with simvastatin. The incidence of myopathy was 0.2% for ezetimibe/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/simvastatin and 0.2% for simvastatin, where rhabdomyolysis was defined as unexplained muscle weakness, pain or tenderness with a serum CK ≥10 times ULN with evidence of renal injury, ≥5 X ULN and <10 X 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/simvastatin and 2.3% for simvastatin. (See Section 4.4 Special Warnings and Precautions for Use.) Gallbladder-related adverse effects were reported in 3.1% vs 3.5% of patients allocated to ezetimibe/simvastatin and simvastatin, respectively. The incidence of cholecystectomy hospitalizations 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.
In the Study of Heart and Renal Protection (SHARP) (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Prevention of Major Vascular Events in Chronic Kidney Disease (CKD)), involving over 9,000 patients treated with a fixed dose combination of ZIENT 10 mg with simvastatin 20 mg daily (n=4,650) or placebo (n=4,620), 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 ZIENT combined with simvastatin, 9.8% in patients treated with placebo). The incidence of myopathy/rhabdomyolysis was 0.2% in patients treated with ZIENT 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 ZIENT combined with simvastatin compared with 0.6% of patients treated with placebo (see Section 4.4 Special Warnings and Precautions for Use). In this trial, there were no statistically significant increases in the incidence of pre-specified adverse events, including cancer (9.4% for ZIENT combined with simvastatin, 9.5% for placebo), hepatitis, cholecystectomy or complications of gallstones or pancreatitis.
In a 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/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 (see Section 4.4 Special Warnings and Precautions for Use, (Paediatric (6 to 17 years of age) patients; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
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 ZIENT co-administered with simvastatin for a treatment period > 33 weeks on growth, sexual maturation intellectual and psychosocial development have not been studied (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; and Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
The study was not of sufficient duration to detect long term adverse effects.
In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n=138), the safety and tolerability profile of the group treated with ZIENT was similar to that of adult patients treated with ZIENT. Elevations of ALT and/or AST (≥3 ULN, consecutive) were observed in 1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of CPK (≥10X ULN). No cases of myopathy were observed. The duration of this study was 12 weeks and safety data from this study is therefore limited (see Section 4.4 Special Warnings and Precautions for Use, (Paediatric (6 to 17 years of age) patients; Section 5.1 Pharmacodynamic Properties, Clinical trials, Clinical studies in paediatric (6 to 17 years of age) patients).
ZIENT is not recommended in children <10 years of age.
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 ZIENT (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ZIENT 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 Special Warnings and Precautions for Use).
Clinically important elevations of CPK (≥10 X ULN) in patients treated with ZIENT administered alone or co-administered with a statin were similar to elevations seen with placebo or statin administered alone, respectively.
The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment:
Hypersensitivity reactions, including anaphylaxis, angioedema, rash and urticaria; erythema multiforme; arthralgia; myalgia; increased CPK; elevations of liver transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea; dizziness; paraesthesia; depression; cholelithiasis; cholecystitis; constipation; asthenia and, very rarely myopathy/rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use).
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
