1. Name Of The Medicinal Product
INEGY® 10 mg/20 mg, 10 mg/40 mg, or 10 mg/80 mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 10 mg ezetimibe and 20, 40 or 80 mg of simvastatin.
Excipient(s):
Each 10/20 mg tablet contains 126.5 mg of lactose monohydrate.
Each 10/40 mg tablet contains 262.9 mg of lactose monohydrate.
Each 10/80 mg tablet contains 535.8 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Tablet.
White to off-white capsule-shaped tablets with code “312”, “313”, or “315” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Hypercholesterolaemia
INEGY is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate:
• patients not appropriately controlled with a statin alone
• patients already treated with a statin and ezetimibe
INEGY contains ezetimibe and simvastatin. Simvastatin (20-40 mg) has been shown to reduce the frequency of cardiovascular events (see section 5.1). A beneficial effect of INEGY or ezetimibe on cardiovascular morbidity and mortality has not yet been demonstrated.
Homozygous Familial Hypercholesterolaemia (HoFH)
INEGY is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g., low-density lipoprotein [LDL] apheresis).
4.2 Posology And Method Of Administration
Hypercholesterolaemia
The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with INEGY.
Route of administration is oral. The dosage range of INEGY is 10/10 mg/day through 10/80 mg/day in the evening. All dosages may not be available in all member states. The typical dose is 10/20 mg/day or 10/40 mg/day given as a single dose in the evening. The 10/80 mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1). The patient's low-density lipoprotein cholesterol (LDL-C) level, coronary heart disease risk status, and response to current cholesterol-lowering therapy should be considered when starting therapy or adjusting the dose.
The dose of INEGY should be individualised based on the known efficacy of the various dose strengths of INEGY (see section 5.1, Table 1) and the response to the current cholesterol-lowering therapy. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks. INEGY can be administered with or without food. The tablet should not be split.
Homozygous Familial Hypercholesterolaemia
The recommended dosage for patients with homozygous familial hypercholesterolaemia is INEGY 10/40 mg/day or 10/80 mg/day in the evening. INEGY may be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Coadministration with other medicines
Dosing of INEGY should occur either
In patients taking diltiazem or amlodipine concomitantly with INEGY the dose of INEGY should not exceed 10/40 mg/day (see sections 4.4 and 4.5).
In patients taking amiodarone or verapamil concomitantly with INEGY, the dose of INEGY should not exceed 10/20 mg/day (see sections 4.4 and 4.5).
In patients taking lipid-lowering doses (
In patients taking ciclosporin or danazol concomitantly with INEGY, the dose of INEGY should not exceed 10/10 mg/day (see sections 4.4 and 4.5).
Use in the Elderly
No dosage adjustment is required for elderly patients (see section 5.2).
Use in Children and adolescents
INEGY is not recommended for use in children due to a lack of data on safety and efficacy (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 INEGY 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 modification of dosage should be necessary in patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance
4.3 Contraindications
Hypersensitivity to ezetimibe, simvastatin, or to any of the excipients.
Pregnancy and lactation (see section 4.6).
Active liver disease or unexplained persistent elevations in serum transaminases.
Concomitant administration of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir) and nefazodone) (see sections 4.4 and 4.5).
4.4 Special Warnings And Precautions For Use
Myopathy/Rhabdomyolysis
In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis.
INEGY contains simvastatin. Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%. (See sections 4.8 and 5.1.)
Creatine Kinase measurement
Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (>5 X ULN), levels should be re-measured within 5 to 7 days later to confirm the results.
Before the treatment
All patients starting therapy with INEGY, or whose dose of INEGY is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.
Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting treatment in the following situations:
• Elderly (age
• Female gender
• Renal impairment
• Uncontrolled hypothyroidism
• Personal or familial history of hereditary muscular disorders
• Previous history of muscular toxicity with a statin or fibrate
• Alcohol abuse.
In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with any statin-containing product (such as INEGY) should only be initiated with caution. If CK levels are significantly elevated at baseline (>5 X ULN), treatment should not be started.
Whilst on treatment
If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with INEGY, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (>5 X ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are <5 X ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.
If symptoms resolve and CK levels return to normal, then re-introduction of INEGY or introduction of another statin-containing product may be considered at the lowest dose and with close monitoring.
A higher rate of myopathy has been observed in patients titrated to the 80 mg dose of simvastatin (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.
Therapy with INEGY should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5)
The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of INEGY with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), nefazodone), as well as ciclosporin, danazol and gemfibrozil (see section 4.2).
Due to the simvastatin component of INEGY, the risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates, lipid-lowering doses (
Consequently, regarding CYP3A4 inhibitors, the use of INEGY concomitantly with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin, and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with INEGY must be suspended during the course of treatment. Moreover, caution should be exercised when combining INEGY with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and INEGY should be avoided.
The dose of INEGY should not exceed 10/10 mg daily in patients receiving concomitant medication with ciclosporin, or danazol. The benefits of the combined use of INEGY 10 mg/10 mg daily with ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.)
The combined use of INEGY at doses higher than 10/20 mg daily with lipid-lowering doses (
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (
Physicians contemplating combined therapy with simvastatin and lipid-modifying doses (
In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. There was no apparent contribution by ezetimibe to the increased incidence of myopathy. Therefore, caution should be used when treating Chinese patients with INEGY (particularly doses of 10/40 mg or higher) co-administered with lipid-modifying doses (
The combined use of INEGY at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).
The combined use of INEGY at doses higher than 10/40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5).
The safety and efficacy of INEGY administered with fibrates have not been studied. There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, the concomitant use of INEGY with fibrates is not recommended (See section 4.5.).
Patients on fusidic acid and INEGY should be closely monitored (see section 4.5). Temporary suspension of INEGY treatment may be considered.
Liver Enzymes
In controlled coadministration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (
It is recommended that liver function tests be performed before treatment with INEGY begins and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 X ULN and are persistent, the drug should be discontinued.
INEGY should be used with caution in patients who consume substantial quantities of alcohol.
Hepatic Insufficiency
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, INEGY is not recommended (see section 5.2).
Fibrates
The safety and efficacy of ezetimibe administered with fibrates have not been established; therefore, coadministration of INEGY and fibrates is not recommended (see section 4.5).
Ciclosporin
Caution should be exercised when initiating INEGY in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving INEGY and ciclosporin (see section 4.5).
Anticoagulants
If INEGY is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).
Interstitial lung disease
Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, INEGY therapy should be discontinued.
Excipient
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Pharmacodynamic interactions
Interactions with lipid-lowering medicinal products that can cause myopathy when given alone
The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates. Additionally, there is a pharmacokinetic interaction of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions). Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see section 5.3). Although the relevance of this preclinical finding to humans is unknown, coadministration of INEGY with fibrates is not recommended (see section 4.4).
Pharmacokinetic interactions
Prescribing recommendations for interacting agents are summarised in the table below (further details are provided in the text; see also sections 4.2, 4.3, and 4.4).
| |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Effects of other medicinal products on INEGY
INEGY
Niacin: In a study of 15 healthy adults, concomitant INEGY (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%). These increases are not considered clinically significant. (See sections 4.2 and 4.4).
Drug interaction studies with higher doses of simvastatin have not been investigated.
Ezetimibe
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.
Colestyramine: Concomitant colestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding INEGY to colestyramine may be lessened by this interaction (see section 4.2).
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 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe 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 compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of 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. A controlled study on the effect of coadministered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating INEGY in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving INEGY and ciclosporin (see section 4.4).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5- and 1.7-fold, respectively. Although these increases are not considered clinically significant, coadministration of INEGY with fibrates is not recommended (see section 4.4).
Simvastatin
Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.
Therefore, combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin, and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with INEGY must be suspended during the course of treatment. Caution should be exercised when combining INEGY with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil, or diltiazem (see sections 4.2 and 4.4).
Fluconazole: Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported. (see section 4.4).
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of INEGY (see sections 4.2 and 4.4). Therefore, the dose of INEGY should not exceed 10/10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of INEGY (see section 4.2 and 4.4).
Gemfibrozil: Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway.
Amiodarone: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
Calcium Channel Blockers
•Verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration of simvastatin with verapamil resulted in 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of INEGY should not exceed 10/20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
•Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem (see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem with simvastatin caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of INEGY should not exceed 10/40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
•Amlodipine
Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of INEGY should not exceed 10/40 mg daily in patients receiving concomitant medication with amlodipine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by concomitant administration of fusidic acid with INEGY (see section 4.4). Specific pathways of fusidic acid metabolism in the liver are not known, however, an interaction between fusidic acid and HMG-CoA reductase inhibitors, which are metabolised by CYP-3A4, can be suspected.
Grapefruit juice: Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and administration of simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with INEGY should therefore be avoided.
Colchicine: There have been reports of myopathy and rhabyomyolysis with the concomitant administration of colchicine and simvastatin, in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Rifampicin: Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.
Effects of INEGY on the pharmacokinetics of other medicinal products
Ezetimibe
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.
Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If INEGY is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).
Simvastatin
Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
Oral anticoagulants: In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalised Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting INEGY and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of INEGY is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
4.6 Pregnancy And Lactation
Pregnancy:
Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering drugs during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.
INEGY
INEGY is contraindicated during pregnancy. No clinical data are available on the use of INEGY during pregnancy. Animal studies on combination therapy have demonstrated reproduction toxicity (See section 5.3.).
Simvastatin
The safety of simvastatin in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to simvastatin or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence.
Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking simvastatin or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, INEGY must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with INEGY must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See section 4.3.)
Ezetimibe
No clinical data are available on the use of ezetimibe during pregnancy.
Lactation:
INEGY is contraindicated during lactation. Studies on rats have shown that ezetimibe is excreted into breast milk. It is not known if the active components of INEGY are secreted into human breast milk. (See section 4.3.)
4.7 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.
4.8 Undesirable Effects
INEGY (or coadministration of ezetimibe and simvastatin equivalent to INEGY) has been evaluated for safety in approximately 12,000 patients in clinical trials.
The frequencies of adverse events are ranked according to the following: Very common (
The following adverse reactions were observed in patients treated with INEGY (N=2404) and at a greater incidence than placebo (N=1340).
| ||
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
The following adverse reactions were observed in patients treated with INEGY (N=9595) and at a greater incidence than statins administered alone (N=8883).
| ||
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
Laboratory Values
In coadministration trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST
Clinically important elevations of CK (
Post-marketing Experience
The following additional adverse reactions have been reported in post-marketing use with INEGY or during clinical studies or post-marketing use with one of the individual components.
Blood and lymphatic system disorders: thrombocytopaenia; anaemia
Nervous system disorders: peripheral neuropathy; memory impairment
Respiratory, thoracic and mediastinal disorders: cough; dyspneoa, intersitiial lung disease (see section 4.4).
Gastro-intestinal disorders: constipation; pancreatitis; gastritis
Skin and subcutaneous tissue disorders: alopecia; erythema multiforme; hypersensitivity reactions, including rash, urticaria, anaphylaxis, angio-oedema
Musculoskeletal and connective tissue disorders: muscle cramps; myopathy* (including myositis)/rhabdomyolysis with or without acute renal failure (see section 4.4)
* In a clinical trial, myopathy occurred commonly in patients treated with simvastatin 80 mg/day compared to patients treated with 20 mg/day (1.0 % vs 0.02 %, respectively).
Metabolism and nutrition disorders: decreased appetite
Vascular disorders: hot flush; hypertension
General disorders and administration site conditions: pain
Hepato-biliary disorders: hepatitis/jaundice; hepatic failure; cholelithiasis; cholecystitis
Reproductive system and breast disorders: erectile dysfunction
Psychiatric disorders: depression; insomnia
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angio-oedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopaenia, eosinophilia, red blood cell sedimentation rate increased, arthritis and arthralgia, urticaria, photosensitivity reaction, pyrexia, flushing, dyspnoea and malaise.
Laboratory Values: elevated alkaline phosphatase; liver function test abnormal.
The following adverse events have been reported with some statins:
• sleep disturbances, including nightmares
• memory loss
• sexual dysfunction
4.9 Overdose
INEGY
In the event of an overdose, symptomatic and supportive measures should be employed. Coadministration of ezetimibe (1000 mg/kg) and simvastatin (1000 mg/kg) was well-tolerated in acute, oral toxicity studies in mice and rats. No clinical signs of toxicity were observed in these animals. The estimated oral LD50 for both species was ezetimibe
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. 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.
Simvastatin
A few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: HMG-CoA reductase inhibitors in combination with other lipid modifying agents, ATC code: C10BA02
INEGY (ezetimibe/simvastatin) is a lipid-lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.
Mechanism of action:
INEGY
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. INEGY contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. INEGY reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and
No comments:
Post a Comment