Presentation and Status in Health Basket
30 X 10 mg
The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetrol. Route of administration is oral. The recommended dose is one Ezetrol 10 mg tablet daily. Ezetrol can be administered at any time of the day, with or without food. When Ezetrol 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.
Co-administration with bile acid sequestrants: Dosing of Ezetrol should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
Use in the Elderly: No dosage adjustment is required for elderly patients.
Use in Paediatric Patients: Initiation of treatment must be performed under review of a specialist. Adolescents ≥ 10 years (pubertal status: boys Tanner Stage II and above and girls who are at least one year post–menarche): No dosage adjustment is required. The clinical experience in paediatric and adolescent patients (aged 10-17 years old) is, however, limited. When Ezetrol is administered with simvastatin, the dosage instructions for simvastatin, in adolescents should be consulted.
Children < 10 years: Ezetrol is not recommended for use in children below age 10 due to insufficient data on safety and efficacy.
Use in Hepatic Impairment: No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6). Treatment with Ezetrol is not recommended in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score > 9) liver dysfunction.
Use in Renal Impairment: No dosage adjustment is required for renally impaired patients.
For full details see prescribing information.
Primary hypercholesterolemia: Co-administered with an HMG-CoA reductase inhibitor (statin) it is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia who are not appropriately controlled with statin alone. Monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia in whom statin is considered inappropriate or is not tolerated. Homozygous familial hypercholesterolemia (HoFH): Co-administered with a statin, it is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).
Homozygous sitosterolemia (phytosterolemia): As adjunctive therapy to diet for use in patients with homozygous familial sitosterolemia.
Hypersensitivity to the active substance or to any of the excipients. When co-administered with a statin, please refer to the approved physician circular for that particular statin. Therapy co-administered with a statin is contraindicated during pregnancy and lactation. Co-administration with a statin in patients with active liver disease or unexplained elevations in serum transaminases.
When Ezetrol is co-administered with a statin, please refer to the SPC for that particular medicinal product.
Liver Enzymes: In controlled co-administration trials in patients receiving Ezetrol with a statin, consecutive transaminase elevations (≥ 3 X the upper limit of normal [ULN]) have been observed. When Ezetrol is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin. In a controlled clinical study in which over 9000 patients with chronic kidney disease were randomized to receive Ezetrol 10 mg combined with simvastatin 20 mg 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 Ezetrol combined with simvastatin and 0.6% for placebo.
Skeletal Muscle: In post-marketing experience with Ezetrol, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with Ezetrol. However, rhabdomyolysis has been reported very rarely with Ezetrol monotherapy and very rarely with the addition of Ezetrol 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, Ezetrol, any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Ezetrol should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. In a clinical trial in which over 9000 patients with chronic kidney disease were randomized to receive Ezetrol 10 mg combined with simvastatin 20 mg daily (n=4650) or placebo (n=4620) (median follow-up
4.9 years), the incidence of myopathy/rhabdomyolysis was 0.2% for Ezetrol combined with simvastatin
and 0.1% for placebo.
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, Ezetrol is not recommended.
Paediatric (10 to 17 Years of Age) Patients: Efficacy and safety of Ezetrol 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 for a treatment period > 33 weeks on growth and sexual maturation have not been studied The safety and efficacy of Ezetrol co-administered with doses simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age.Ezetrol has not been studied in patients younger than 10 years of age or in pre-menarchal girls. The long-term efficacy of therapy with Ezetrol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.
Fibrates: The safety and efficacy of Ezetrol administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving Ezetrol and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued.
Ciclosporin: Caution should be exercised when initiating Ezetrol in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetrol and ciclosporin.
Anticoagulants: If Ezetrol is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored.
Excipient: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
Clinical studies have demonstrated that ezetimibe was generally well tolerated, adverse reactions were usually mild and transient. The overall incidence of side effects reported with ezetimibe was similar between ezetimibe and placebo.
For full details see prescribing information.
Lercanidipine is known to be methabolised by the CYP3A4 enzyme and therefore inhibitors and inducers of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine. Co-prescription of Vasodip with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided. An interaction study with a strong CYP3A4 inhibitor, Ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S-lercanidipine).
Cyclosporin and lercanidipine should not be administered together. Increased plasma levels of both lercanidipine and cyclosporin have been observed following concomitant administration. A study in young healthy volunteers has shown that when cyclosporin was administered 3 hours after the lercanidipine intake the plasma levels of lercanidipine did not change, while the AUC of cyclosporin increased by 27%. However, the co-administration of Vasodip with cyclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the cyclosporin AUC. Lercanidipine should not be taken with grapefruit juice. As for other dihydropiridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect. When concominantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers, lercanidipine’s absorption was increased (by approximately 40%) and the rate of absorption was decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified. Caution should be exercised when Vasodip is co-prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone and quinidine. Co-administration of Vasodip with CYP3A4 inducers like anticonvulsants (e.g. phenytoin,carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual. When Vasodip was co-administered with metoprolol, a β-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine may be safely administered with beta-adrenoceptor blocking drugs, but dose adjustment may be required. An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine. Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased.Co-administration of 20 mg lercanidipine in patients chronically treated with β-methyldigoxin showed no evidence of pharmacokinetic interaction. Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted, showed a mean increase of 33 % in digoxin Cmax while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.m When a dose of 20 mg of Vasodip was repeatedly co-administered with 40 mg of simvastatin, the AUC of lercanidipine was not significantly modified, while simvastatin’s AUC increased by 56% and that of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such drug. The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin. Vasodip has been safely administered with diuretics and ACE inhibitors. Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs.
For full details see prescribing information.
Pregnancy and Lactation
Ezetrol co-administered with a statin is contraindicated during pregnancy and lactation, please refer to the SPC for that particular statin.
Pregnancy: Ezetrol should be given to pregnant women only if clearly necessary. No clinical data are available on the use of Ezetrol during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development.
Lactation: Ezetrol should not be used during lactation. Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk.
Fertility: No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the fertility of male or female rats.
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5000 mg/kg of ezetimibe in rats and mice and 3000 mg/kg in dogs. A few cases of overdose with Ezetrol 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.