Tryzetor Plus 10/10 mg, 10/20 mg, 10/40 mg Tablets.

Reduction in the risk of Cardiovascular Events

TRYZETOR PLUS is indicated to reduce the risk of cardiovascular events in patients with coronary artery heart disease (CHD) and a history of acute coronary syndrome (ACS), either previously treated with a statin or not. Benefits have been shown for this group of patients when their LDL-C was above 1,2 mmol/L. No statistically significant benefit was demonstrated for risk reduction of stroke, hospitalisation for unstable angina pectoris and for coronary artery revascularisation procedures.

Primary Hypercholesterolaemia

TRYZETOR PLUS is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG) and non-high-density lipoprotein cholesterol (non- HDL-C) and to moderately increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia.

Homozygous Familial Hypercholesterolaemia (HoFH)

TRYZETOR PLUS is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH.

The patient should be placed on a standard cholesterol lowering diet before receiving TRYZETOR PLUS and should continue on this diet during treatment with TRYZETOR PLUS. The dosage should be individualised according to the baseline LDL-C level, the recommended goal of therapy, and the patientu2019s response.

Hypercholesterolaemia

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

Patients with Coronary Heart Disease and ACS Event History

The starting dose is 10/40 mg once a day in the evening. An 10/80 mg dose is only recommended in patients who have not achieved a suitable reduction in LDL-C, in which case, the patient should be changed to an alternately available product.

Dosage in patients with homozygous familial hypercholesterolaemia

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

In patients taking lomitapide concomitantly with TRYZETOR PLUS, the dose of TRYZETOR PLUS should not exceed 10/40 mg/day (see sections 4.4 Myopathy/Rhabdomyolysis and 4.5).

Special populations

Use in the elderly

No dosage adjustment is required for elderly patients. Because advanced age (u2265 65 years) is a predisposing factor for myopathy, TRYZETOR PLUS should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients u2265 65 years of age had an increased risk of myopathy compared to patients < 65 years of age.

Use in hepatic impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6). Treatment with TRYZETOR PLUS is contraindicated in patients with moderate (Child-Pugh score 7 to 9) or severe (Child-Pugh score greater than 9) liver dysfunction as safety and efficacy have not been demonstrated (see sections 4.3 and 4.4).

Use in renal impairment

No dosage adjustment is required for patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance less than or equal to 30 mL/min) is deemed necessary, dosages above 10/10 mg/day should be implemented cautiously (see section 5.2).

Paediatric population

Treatment with TRYZETOR PLUS is contraindicated as safety and efficacy have not been demonstrated (see section 4.3).

Co-administration with other medicines

Dosing of TRYZETOR PLUS should occur either 2 or more hours before or 4 or more hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol or greater than or equal to 1 g/day of niacin concomitantly with TRYZETOR PLUS, the dose of TRYZETOR PLUS should not exceed 10/10 mg/day (see sections 4.4 and 4.5). In patients taking amiodarone, verapamil or diltiazem, or products containing elbasvir or grazoprevir concomitantly with TRYZETOR PLUS, the dose of TRYZETOR PLUS should not exceed 10/20 mg/day (see sections 4.4 and 4.5). In patients taking amlodipine concomitantly with TRYZETOR PLUS, the dose of TRYZETOR PLUS should not exceed 10/40 mg/day (see sections 4.4 and 4.5).

Method of administration

TRYZETOR PLUS is for oral use and should be taken as a single daily dose in the evening, with or without food.

• hypersensitivity to ezetimibe, simvastatin or to any of the ingredients of TRYZETOR PLUS (see section 6.1)
• active liver disease or unexplained persistent elevations of serum transaminases; moderate to severe hepatic impairment
• pregnancy and lactation (see section 4.6)
• children, as safety and efficacy have not been demonstrated
• concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicines containing cobicistat) (see sections 4.4 and 4.5)
• concomitant administration of gemfibrozil, ciclosporin, or danazol (see sections 4.4 and 4.5)
• in patients with HoFH, concomitant administration of lomitapide with doses > 10/40 mg TRYZETOR PLUS (see sections 4.2, 4.4 and 4.5).

The dose of TRYZETOR PLUS should not exceed 10/10 mg daily in patients receiving concomitant medicine with ciclosporin, danazol or u2265 1 g/day of niacin. The combined use of TRYZETOR PLUS with these medicines should be avoided (see section 4.5). Ciclosporin concentrations should be monitored in patients receiving TRYZETOR PLUS and ciclosporin (see section 4.5).

Other Fibrates (especially gemfibrozil)

There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates, especially gemfibrozil. The safety and effectiveness of ezetimibe administered with fibrates, except fenofibrate, have not been formally studied. Therefore, the concomitant use of TRYZETOR PLUS and fibrates, except fenofibrate, should be avoided. Concomitant use of gemfibrozil is contraindicated (see sections 4.3 and 4.5).

Amiodarone, verapamil

The dose of TRYZETOR PLUS should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of TRYZETOR PLUS at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided.

Myopathy/rhabdomyolysis

All patients starting therapy with TRYZETOR PLUS, or whose dose of TRYZETOR PLUS is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. TRYZETOR PLUS should be discontinued immediately if myopathy is diagnosed or suspected. Caution should be exercised in patients with predisposing factors for rhabdomyolysis. In order to establish a reference baseline value, a creatine kinase (CK) level should be measured before starting treatment in the following situations:

• elderly (age u2265 65 years)
• 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.

If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with any statin-containing product (such as TRYZETOR PLUS) should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 X ULN), treatment should not be started.

Simvastatin may cause myopathy manifested as muscle pain, tenderness or weakness with CK above 10 times the ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. The presence of symptoms, and/or a CK level greater than 10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting TRYZETOR PLUS treatment or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

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 remeasured within 5 to 7 days later to confirm the results.

Cases of myopathy and rhabdomyolysis have been reported in ezetimibe treatment. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to other medicines known to be associated with increased risk of rhabdomyolysis.

The risk of myopathy/rhabdomyolysis is increased by use of TRYZETOR PLUS with the following:

Contraindicated medicines

Potent inhibitors of CYP3A4

Concomitant use with medicines labelled as having a potent inhibitory effect on CYP3A4 at therapeutic doses, including itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone or medicines containing cobicistat, is contraindicated (see section 4.3). If short-term treatment with potent CYP3A4 inhibitors is unavoidable, therapy with TRYZETOR PLUS should be suspended during the course of treatment (see sections 4.3, 4.5 and 5.2).

Gemfibrozil, ciclosporin or danazol

Concomitant use with TRYZETOR PLUS is contraindicated (see sections 4.3 and 4.5).

Other medicines

Niacin (1 g or more per day): Concomitant use of simvastatin and lipid modifying doses (greater than or equal to 1 g/day) of niacin, has resulted in cases of myopathy/rhabdomyolysis being reported. Co- administration of TRYZETOR PLUS with lipid-modifying doses of niacin (u2265 1 g/day) in Asian patients is not recommended (see section 4.5).

Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.

Amlodipine: The dose of TRYZETOR PLUS should not exceed 10/40 mg in patients receiving concomitant amlodipine therapy.

Diltiazem: The risk of myopathy in patients taking simvastatin 40 mg with diltiazem is similar to that in patients taking simvastatin 40 mg without diltiazem (see section 4.5).

Fusidic acid: Patients on fusidic acid treated concomitantly with TRYZETOR PLUS may have an increased risk of myopathy and rhabdomyolysis (see section 4.5). Patients should be closely monitored; temporary suspension of TRYZETOR PLUS treatment may be considered.

For patients with HoFH, this risk may be increased by concomitant use of lomitapide with TRYZETOR PLUS (see section 4.5). Patients should be closely monitored; temporary suspension of TRYZETOR PLUS treatment may be considered.

Many patients who developed rhabdomyolysis on therapy with simvastatin had complicated medical histories, including renal insufficiency, usually as a consequence of long-standing diabetes mellitus. Such patients taking TRYZETOR PLUS need closer monitoring. Therapy with TRYZETOR PLUS should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Daptomycin: Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) co-administered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to temporarily suspend TRYZETOR PLUS in patients taking daptomycin. Consult the prescribing information of Daptomycin to obtain further information about this potential interaction with HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and for further guidance related to monitoring (see section 4.5).

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicines (e.g. ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype. Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of simvastatin acid and increased risk of myopathy. Simvastatin (as contained in TRYZETOR PLUS) is a substrate of the breast cancer resistant protein (BCRP) efflux transporter. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy; therefore, a dose adjustment of TRYZETOR PLUS should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with simvastatin has not been studied; however, the dose of TRYZETOR PLUS should not exceed 10/20 mg daily in patients receiving TRYZETOR PLUS concomitantly with medicines containing elbasvir or grazoprevir (see section 4.5).

Anticoagulants: If TRYZETOR PLUS is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored (see section 4.5).

Liver enzymes

In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (greater than or equal to 3 times the ULN) have been observed (see section 4.8). It is recommended that liver function tests be performed before treatment with TRYZETOR PLUS begins and thereafter when clinically indicated. 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 times the ULN and are persistent, TRYZETOR PLUS should be discontinued. Note that alanine aminotransferase (ALT) may emanate from muscle, therefore ALT rising with CK may indicate myopathy.

There have been reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with TRYZETOR PLUS, promptly interrupt therapy. If an alternate aetiology is not found, do not restart TRYZETOR PLUS.

TRYZETOR PLUS should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of TRYZETOR PLUS (see section 4.3).

Skeletal muscle effects

Risk of myasthenia gravis and ocular myasthenia. Statins have been reported to either induce new onset, or aggravate pre-existing myasthenia gravis or ocular myasthenia (see section 4.8), should these conditions occur, TRYZETOR PLUS should be discontinued. There have been reports of recurrences of these conditions when the same or a different statin was (re-) administered.

Hepatic impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, TRYZETOR PLUS is contraindicated (see section 4.3).

Diabetes mellitus

Some evidence suggests that statins as a class raise blood glucose and, in some patients at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping TRYZETOR PLUS treatment. Patients at risk (fasting glucose 5,6 to 6,9 mmol/L, BMI > 30 kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including simvastatin (as contained in TRYZETOR PLUS), 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, TRYZETOR PLUS therapy should be discontinued.

Porphyria

Simvastatin has been classified as probably porphyrinogenic and should therefore only be prescribed for compelling reasons and precautions should be considered in all patients.

Paediatric population

The safety and efficacy of ezetimibe co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients aged 10 - 17 years. Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarche girls (see sections 4.2 and 4.5).

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

Lactose

TRYZETOR PLUS contains lactose. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No clinically significant pharmacokinetic interaction was seen when ezetimibe was co-administered with simvastatin. TRYZETOR PLUS is bioequivalent to co-administered ezetimibe and simvastatin.

CYP3A4 interactions

No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9 and 3A4, or N-acetyltransferase. Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity, therefore it is not expected to affect the plasma concentrations of other medicines metabolised by CYP3A4.

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 and sections 4.3 and 4.4). Cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (u2265 1 g/day) of niacin (see section 4.4). Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of TRYZETOR PLUS with fibrates is not recommended (see section 4.4).

Pharmacokinetic Interactions

Prescribing recommendations for interacting agents are summarised in the table below:

Medicine Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting medicines Prescribing recommendations

Potent CYP3A4 inhibitors, e.g. Itraconazole* *If treatment is unavoidable, then TRYZETOR PLUS should be discontinued. All other potent CYP3A4 inhibitors should be avoided.

Other fibrates

Fusidic acid

Not recommended with TRYZETOR PLUS

Niacin (nicotinic acid) (u2265 1 g/day)

For Asian patients, not recommended with TRYZETOR PLUS

Amiodarone

Amlodipine

Verapamil

Diltiazem

Niacin (u2265 1 g/day)

Elbasvir

Grazoprevir

Do not exceed 10/20 mg TRYZETOR PLUS daily

Lomitapide

Daptomycin

For patients with HoFH, do not exceed 10/40 mg TRYZETOR PLUS daily

Grapefruit juice

Avoid grapefruit juice when taking TRYZETOR PLUS

EZETIMIBE:

Gemfibrozil

In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1,7-fold. Co-administration with TRYZETOR PLUS is contraindicated. No clinical data are available (see sections 4.3 and 4.4).

Ciclosporin or danazol

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin or danazol, particularly with higher doses of TRYZETOR PLUS (see sections 4.3 and 4.4). In a study of 8 post-renal transplant patients with creatinine clearance of greater than 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 healthy patients. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13,2 mL/min/1,73 m2) receiving multiple medicines, including ciclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. In a two-period crossover study in 12 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 (see section 4.4).

Antacids

Concomitant antacid administration with TRYZETOR PLUS 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.

Cholestyramine

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

Fibrates

Concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1,5 and 1,7-fold respectively, however these increases are not considered clinically significant. The safety and effectiveness of TRYZETOR PLUS administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of TRYZETOR PLUS with fibrates is not recommended until use in patients is studied.

Pregnancy

TRYZETOR PLUS is contraindicated during pregnancy (see section 4.3.). No controlled clinical trials with simvastatin have been conducted in pregnant women. Reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. The safety of TRYZETOR PLUS in pregnant women has not been established. Maternal treatment with TRYZETOR PLUS may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. For this reason, TRYZETOR PLUS should not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with TRYZETOR PLUS should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.

No clinical data on exposed pregnancies are available for ezetimibe.

Breastfeeding

TRYZETOR PLUS is contraindicated during lactation (see section 4.3.). Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether the active ingredients of TRYZETOR PLUS are excreted into human breast milk; therefore, women who are nursing should not take TRYZETOR PLUS.

Fertility

No clinical trial data are available on the effects of ezetimibe or simvastatin on human fertility.

No studies on the effects on 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 when taking TRYZETOR PLUS.

Summary of the safety profile

The most common adverse effects include headache, abdominal pain and diarrhoea. The commonest adverse effect with simvastatin is gastrointestinal disturbances.

Tabulated list of adverse effects

Adverse effects with TRYZETOR PLUS

System Organ Class Frequency Side effects

Blood and lymphatic system disorders Frequency unknown Thrombocytopenia, anaemia

Immune system disorders Frequency unknown Hypersensitivity, anaphylaxis, hypersensitivity syndrome

Metabolism and nutrition disorders Less frequent Frequency unknown Decreased weight Decreased appetite

Psychiatric disorders Less frequent Frequency unknown Sleep disorder, insomnia Depression, memory loss, forgetfulness, amnesia, memory impairment, confusion, sleep disturbances, nightmares

Nervous system disorders Frequent Less frequent Frequency unknown Headache Dizziness, paraesthesia Peripheral neuropathy, memory impairment

Eye disorders Less frequent Vision blurred, visual impairment

Vascular disorders Frequency unknown Hot flush, hypertension

Respiratory, thoracic and mediastinal disorders Frequency unknown Cough, dyspnoea, interstitial lung disease

Gastrointestinal disorders Frequent Less frequent Frequency unknown Flatulence Abdominal pain, abdominal discomfort, upper abdominal pain, dyspepsia, nausea, vomiting, abdominal distension, diarrhoea, dry mouth, gastroesophageal reflux disease Constipation, pancreatitis, gastritis

Hepatobiliary disorders Frequency unknown Hepatitis, jaundice, fatal and non-fatal hepatic failure, cholelithiasis, cholecystitis

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Pruritus, rash, urticaria, lichenoid drug eruptions Alopecia, erythema multiforme, angioedema

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Frequency unknown Myalgia, pain in limb Arthralgia, muscle spasms, muscular weakness, musculoskeletal pain and discomfort, neck pain, pain in extremity, back pain, muscle rupture Muscle cramps, myopathy, myositis, rhabdomyolysis (with or without renal failure), tendinopathy, tendon rupture, immune-mediated necrotising myopathy

Reproductive system and breast disorders Less frequent Frequency unknown Gynaecomastia Erectile dysfunction, sexual dysfunction

General disorders and administrative site conditions Less frequent Frequency unknown Asthenia, fatigue, malaise, peripheral oedema, chest pain Pain

Investigations Frequent Less frequent Frequency unknown Increased ALT and/or aspartate aminotransferase (AST); increased blood creatinine kinase (CK) Increased blood bilirubin blood uric acid, gamma-glutamyl transferase and international normalised ratio, protein present in the urine, weight decreased Elevated alkaline phosphatase, abnormal liver function test results, increases in HbA1c and fasting serum glucose levels, diabetes mellitus

Adverse effects with Ezetimibe

System Organ Class Frequency Side effects

Infections and Infestations Frequent Viral infection, pharyngitis, sinusitis, upper respiratory tract infection

Blood and lymphatic system disorders Frequency unknown Thrombocytopenia*

Immune system disorders Frequency unknown Hypersensitivity reactions*, anaphylaxis* and angioedema*

Metabolism and nutrition disorders Less frequent Decreased appetite

Psychiatric disorders Frequency unknown Depression*

Nervous system disorders Frequent Less frequent Headache Dizziness, paraesthesia

Vascular disorders Less frequent Hot flush, hypertension

Respiratory, thoracic and mediastinal disorders Frequent Coughing

Gastrointestinal disorders Frequent Less frequent Frequency unknown Abdominal pain and diarrhoea Nausea Constipation*, pancreatitis*

Hepatobiliary disorders Frequency unknown Hepatitis*/jaundice*, cholelithiasis*, cholecystitis*, raised liver enzymes*

Skin and subcutaneous tissue disorders Frequency unknown Rash*, urticaria*, erythema multiforme*

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Frequency unknown Back pain, myalgia Arthralgia Myopathy/rhabdomyolysis* (see section 4.4)

General disorders and administrative site conditions Frequent Less frequent Fatigue, chest pain Pain

Investigations Less frequent Increased creatine phosphokinase (CPK), elevations of liver transaminases

*Post marketing

Adverse effects with Simvastatin:

System Organ Class Frequency Side effects

Blood and lymphatic system disorders Less frequent Frequency unknown Thrombocytopenia Anaemia*

Immune system disorders Less frequent Hypersensitivity syndrome (including angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea, malaise)

Psychiatric disorders Less frequent Frequency unknown Insomnia Reversible cognitive impairment, depression

Nervous system disorders Less frequent Frequency unknown Dizziness, paraesthesia, memory impairment, headache Myasthenia gravis*, peripheral neuropathy*

Eye disorders Frequency unknown Ocular myasthenia*

Respiratory, thoracic and mediastinal disorders Frequency unknown Dyspnoea*, interstitial lung disease*

Gastrointestinal disorders Frequent Less frequent Gastrointestinal disturbances Constipation, abdominal pain, dyspepsia, diarrhoea, nausea, vomiting and pancreatitis

Hepatobiliary disorders Frequency unknown Hepatitis/jaundice*, fatal and non-fatal hepatic failure*

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Pruritus and rash Amyopathic dermatomyositis, vesiculobullous eruptions, alopecia*, lichen planus*

Musculoskeletal, connective tissue and bone disorders Less frequent Frequency unknown Myopathy, rhabdomyolysis, dermatomyositis, polymyositis, myasthenia gravis Muscle cramps*

Renal and urinary disorders Frequency unknown Proteinuria, renal failure

Reproductive system and breast disorders Frequency unknown Sexual dysfunction, erectile dysfunction, impotence, decreased libido, testicular pain

General disorders and administrative site conditions Frequency unknown Asthenia

Investigations Frequency unknown Hyperglycaemia, diabetes mellitus

* Post marketing. There have been reports of immune-mediated necrotising myopathy (IMNM), an autoimmune myopathy associated with statin use. IMNM is characterised by: proximal muscle weakness and elevated serum creatine kinase, which persists despite discontinuation of statin treatment; muscle biopsy showing necrotising myopathy without significant inflammation; improvement with immunosuppressive agents (see section 4.4 Myopathy/Rhabdomyolysis).

Signs and symptoms:

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to healthy subjects for up to 14 days, or 40 mg/day to patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. A few cases of overdosage have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious.

Simvastatin

A few cases of overdosage have been reported; the maximum dose taken was 3,6 g. All patients recovered without sequelae.

Management of overdose:

No specific treatment of overdosage with TRYZETOR PLUS can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed. Co-administration of ezetimibe (1 000 mg/kg) and simvastatin (1 000 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 greater than or equal to 1 000 mg/kg and simvastatin greater than or equal to 1 000 mg/kg.