Simvotin 10/20/40 10/20/40 mg Tablets

Hypercholesterolaemia

SIMVOTIN is indicated, in combination with diet, to decrease elevated serum total cholesterol and LDL-cholesterol in patients with:

• Primary hypercholesterolaemia
• Heterozygous familial hypercholesterolaemia
• Combined (mixed) hyperlipidaemia when response to diet or other non-pharmacological measures alone are not adequate.

Coronary heart disease

SIMVOTIN is indicated in patients with coronary heart disease and hypercholesterolaemia unresponsive to diet, to:

• Reduce the risk of total mortality by reducing coronary death
• Reduce the risk of non-fatal myocardial infarction
• Reduce the risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty); and
• Slow the progression of coronary atherosclerosis.

Posology

The patient should be placed on a standard cholesterol-lowering diet before receiving SIMVOTIN and should continue on this diet during treatment with SIMVOTIN.

Hypercholesterolaemia

The usual starting dose is 10 mg/day as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg daily given as a single dose in the evening. If LDL-cholesterol levels fall below 1,94 mmol/l (75 mg/dL) or total plasma cholesterol levels fall below 3,6 mmol/l (140 mg/dL) the dose of SIMVOTIN should be reduced.

Coronary Heart Disease

Patients with coronary heart disease can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Dosing adjustments, if required, should be made at intervals of not less than 4 weeks, up to a maximum of 80 mg daily as a single dose in the evening.

Dosage in Renal Insufficiency

SIMVOTIN does not undergo significant renal excretion, therefore, modification of dosage should not be necessary in patients with mild to moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 mL/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Concomitant therapy

SIMVOTIN is effective alone or in combination with bile acid sequestrants. When both medicines are prescribed, SIMVOTIN should be given 1 hour before or 4 hours after cholestyramine administration. A maximum daily dosage of 10 mg SIMVOTIN is recommended in patients taking ciclosporin, fibrates (other than gemfibrozil) or niacin concomitantly (see section 4.4-Muscle Effects). The dose should not exceed 20 mg daily in patients receiving concomitant medicines such as amiodarone, verapamil, diltiazem or amlodipine (see section 4.5).

Elderly population

No dosage adjustment is required for this population.

Paediatric population

Use in paediatric patients is not recommended, as safety and efficacy have not been established.

Method of administration

For oral use.

• Hypersensitivity to simvastatin, other HMG-CoA reductase inhibitors or any of the excipients listed in section 6.1.
• Acute or chronic liver diseases.
• Unexplained persistent elevations of serum transaminases.
• Pregnancy and lactation (see section 4.6).
• Concomitant administration of strong CYP3A4 inhibitors (medicines that increase AUC approximately 5-fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, such as ritonavir, saquinavir, nelfinavir, boceprevir and telaprevir; erythromycin, clarithromycin, telithromycin; nefazodone and medicines containing cobicistat) (see sections 4.4 and 4.5).
• In patients with HoFH, concomitant administration of lomitapide with doses > 40 mg SIMVOTIN (see section 4.2, section 4.4 and section 4.5)
• Concomitant administration of gemfibrozil, ciclosporin or danazol (see sections 4.4 and 4.5).
• Porphyria: Safety has not been established.

Myopathy/Rhabdomyolysis

SIMVOTIN, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times 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 (i.e., elevated SIMVOTIN and simvastatin acid plasma levels), which may be due, in part, to interacting medicines that interfere with SIMVOTIN metabolism and/or transporter pathways (see section 4.5).

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. The risk of myopathy is greater in patients on simvastatin 80 mg compared with other statin-based therapies with similar LDL-C-lowering efficacy. Therefore, the 80-mg dose of SIMVOTIN should only be used in patients with severe hypercholesterolaemia and at 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. In patients taking simvastatin 80 mg for whom an interacting medicine is needed, a lower dose of simvastatin or an alternative statin-based regimen with less potential for medicine-medicine interactions should be used (see below Measures to reduce the risk of myopathy caused by medicine interactions and sections 4.2, 4.3, and 4.5).

Reducing the risk of myopathy

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. The risk of high dose (80 mg) simvastatin related myopathy is about 1 % in general, without genetic testing. The corresponding risk is 0,3 % in patients having the most common genotype (TT) (see section 5.2). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg simvastatin for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

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.

General measures:

All patients starting therapy with SIMVOTIN or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and should report, promptly, any unexplained muscle pain, tenderness or weakness. A creatine kinase (CK) level above 10 times the Upper Limit of Normal (ULN) in a patient, with unexplained symptoms, indicates myopathy. SIMVOTIN should be discontinued if myopathy is diagnosed or suspected.

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 a 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 of 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 a different member of the class 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 a statin, 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.

There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterised by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment (see section 4.8). If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin 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 (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 SIMVOTIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes. There have been reports of cognitive impairment (such as memory loss, forgetfulness, amnesia and confusion) associated with statins such as SIMVOTIN. These were generally not serious, with variable time-to-symptom onset (between 1 day to years) and symptom resolution (median 3 weeks). Increased glycosylated haemoglobin, fasting serum glucose levels and worsening of glycaemic control have been reported with statins such as SIMVOTIN. SIMVOTIN should be used with caution in patients with Type 2 diabetes.

Multiple mechanisms may contribute to potential interactions with HMG-CoA reductase inhibitors. Medicines including herbal medicines that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g.OATP1B) pathways may increase SIMVOTIN and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis. Consult the professional information of all concomitantly used medicines to obtain further information about their potential interactions with SIMVOTIN and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.

Pharmacodynamic interaction

Interactions with lipid-lowering medicines that can cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased SIMVOTIN plasma levels (see below Pharmacokinetic interactions and sections 4.3 and 4.4). When SIMVOTIN and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each medicine. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with SIMVOTIN co-administered with lipid-modifying doses (u2265 1 g/day) of niacin (see section 4.4).

Pharmacokinetic interactions

Prescribing recommendations for interacting medicines are summarised in the table below (further details are provided in the text; see also section 4.3 and section 4.4).

Medicine Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting medicines

Prescribing recommendations

• Potent CYP3A4 inhibitors, e.g. Itraconazole, Ketoconazole, Posaconazole, Voriconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease inhibitors (e.g. nelfinavir), Boceprevir, Telaprevir, Nefazodone, Cobicistat, Cyclosporin, Danazol, Gemfibrozil

Contraindicated with SIMVOTIN

• Other fibrates (except fenofibrate)

Do not exceed 10 mg SIMVOTIN daily

• Fusidic acid

Is not recommended with SIMVOTIN

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

For Asian patients, not recommended with SIMVOTIN

• Amiodarone, Amlodipine, Verapamil, Diltiazem, Elbasvir

Do not exceed 20 mg SIMVOTIN daily

• Grazoprevir, Lomitapide

For patients with HoFH, do not exceed 40 mg SIMVOTIN daily

• Daptomycin

It should be considered to temporarily suspend SIMVOTIN in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk (see section 4.4)

• Ticagrelor

Doses greater than 40 mg SIMVOTIN daily are not recommended

• Grapefruit juice

Avoid grapefruit juice when taking SIMVOTIN

The active metabolite of ARROW SIMVASTATIN is fetotoxic and teratogenic in rats and it should therefore not be used in female patients of childbearing potential.

Pregnancy

SIMVOTIN is contraindicated during pregnancy (see section 4.3). Safety in pregnancy and lactation has not been established. No controlled clinical trials with SIMVOTIN have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking SIMVOTIN or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with SIMVOTIN may reduce the foetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicines during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, SIMVOTIN must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with SIMVOTIN must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant (see sections 4.3 and 5.3).

Breastfeeding

It is not known whether SIMVOTIN or its metabolites are excreted in breast milk. Because many medicines are excreted in human milk and because of the potential for serious adverse reactions, women taking SIMVOTIN must not breastfeed their babies (see section 4.3).

Fertility

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

SIMVOTIN has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

Tabulated list of adverse reactions

MedDRA System Organ Class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Less frequent

Anaemia, thrombocytopenia, increased erythrocyte sedimentation rate, eosinophilia.

Frequency unknown

Neutropenia.

Immune system disorders

Less frequent

Anaphylaxis, reactions may include angioedema, lupus-like syndrome, toxic epidermal necrosis, erythema multiforme, including Stevens-Johnson syndrome.

Endocrine disorders

Less frequent

Increases in HbA1C and fasting glucose levels. Diabetes mellitus.

Metabolism and nutrition disorders

Frequency unknown

Mass gain has been reported.

Psychiatric disorders

Less frequent

Insomnia

Frequency unknown

Depression, sleep disturbances (including nightmares)

Nervous system disorders

Less frequent

Dizziness, headache, paraesthesia, peripheral neuropathy, cognitive impairment such as memory loss, forgetfulness, amnesia, confusion.

Eye disorders

Less frequent

Photosensitivity, vision blurred, visual impairment.

Cardiac disorders

Less frequent

Atrial fibrillation

Vascular disorders

Less frequent

Vasculitis.

Respiratory, thoracic and mediastinal disorders

Less frequent

Dyspnoea, hypersensitivity pneumonitis

Frequency unknown

Interstitial lung disease (see section 4.4), respiratory infections, bronchitis, sinusitis.

Gastro-intestinal disorders

Less frequent

Constipation, diarrhoea, nausea, flatulence, dyspepsia, abdominal pain, cramps, vomiting, pancreatitis, gastritis

Hepato-biliary disorders

Less frequent

Hepatitis/jaundice, fatal and non-fatal hepatic failure.

Skin and subcutaneous tissue disorders

Less frequent

Skin rash, pruritus, alopecia, eczema, urticaria, lichenoid medicine eruptions.

Musculoskeletal and connective tissue disorders

Less frequent

Myalgia, muscle cramps, myopathy (including myositis), arthralgia, rhabdomyolysis (presenting as muscle pain with elevated creatine phosphokinase and myoglobinuria leading to renal failure), muscle rupture, polymyalgia, rheumatic, arthritis, arthralgia.

Frequency unknown

tendinopathy, sometimes complicated by rupture, immune-mediated necrotising myopathy (IMNM) **.

Reproductive system and breast disorders

Less frequent

Gynecomastia

Frequency unknown

Erectile dysfunction.

General disorders and administration site condition

Less frequent

Asthenia***, oedema, swelling, fever, flushing, malaise

Frequency unknown

Fatigue

Investigations

Less frequent: Marked and persistent increases of serum transaminases (alanine aminotransferase, aspartate aminotransferase, u03b3-glutamyl transpeptidase) see section 4.4 Hepatic effects), and elevated alkaline phosphatase. Liver function test abnormalities. Increases in serum creatine kinase (CK) levels derived from skeletal muscle (see section 4.4).

Laboratory Test Findings

Marked and persistent increases of serum transaminases have been reported infrequently. Elevated alkaline phosphatase and gamma-glutamyl transpeptidase have been reported. Liver function test abnormalities have generally been mild and transient. Increases in serum creatine kinase (CK) levels, derived from skeletal muscle, have been reported (see section 4.4).

The following additional adverse events have been reported with some statins:

• Sleep disturbance
• Sexual dysfunction
• Diabetes mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose u2265 5,6 mmol/L, BMI > 30kg/m2, raised triglycerides, history of hypertension).

IMNM** There have been very rare reports of immune-mediated necrotising myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins. IMNM is clinically characterized by: persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotising myopathy without significant inflammation; improvement with immunosuppressive medicines (see section 4.4).

Asthenia***An apparent hypersensitivity syndrome, reactions may include angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, increased erythrocyte sedimentation rate, eosinophilia, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, malaise, and dyspnoea.

(See sections 4.4 and 4.8). General measures should be adopted and liver function should be monitored. Treatment is symptomatic and supportive.