TWICOR

Posology The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Twicor. Twicor can be administered within the dose range of 10/10 mg to 20/10 mg. The recommended dose is one film-coated tablet of the given strength per day, with or without food.

Twicor is not suitable for initial therapy. Treatment initiation should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Treatment should be individualised according to the target lipid levels, the recommended goal of therapy, and the patient's response.

A dose adjustment can be made after 4 weeks where necessary. Twicor 10 mg/10 mg is not suitable for the treatment of patients requiring 20 mg dose of rosuvastatin. Twicor should be taken either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

Paediatric population The safety and efficacy of Twicor in children below the age of 18 years has not yet been established. 2 but no recommendation on a posology can be made. 4). The fixed dose combination is not suitable for initial therapy.

Treatment initiation should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Dosage in patients with renal insufficiency No dose adjustment is necessary in patients with mild renal impairment.

The recommended start dose is rosuvastatin 5 mg in patients with moderate renal impairment (creatinine clearance <60 ml/min). The fixed dose combination is not suitable for initial therapy. Treatment initiation should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

2). Dosage in patients with hepatic impairment No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). ). 3). 2). The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry.

The fixed dose combination is not suitable for initial therapy. Treatment initiation should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

2). For patients who are known to have such specific types of polymorphisms, a lower daily dose is recommended. 4). The fixed dose combination is not suitable for initial therapy. Treatment initiation should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible.

g. OATP1B1 and BCRP). g. 5). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Twicor therapy. 5). Method of administration For oral use. Twicor should be taken each day once at the same time of the day with or without food.

The film-coated tablet should be swallowed whole with a drink of water.

Summary of the safety profile The adverse reactions seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse reactions. In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2396 patients, or with a statin in 11,308 patients or with fenofibrate in 185 patients.

Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between ezetimibe and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between ezetimibe and placebo.

According to available data 1200 patients took rosuvastatin and ezetimibe combination in clinical studies. As reported in the published literature, the most frequent common adverse events related to rosuvastatin-ezetimibe combination treatment in hypercholesterolemic patients are increased hepatic transaminases, gastrointestinal problems and muscle pain.

These are known undesirable effects of the active substances. 2). Tabulated list of adverse reactions The frequencies of adverse events are ranked according to the following: Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

6 mmol/L, BMI>30kg/m2, raised triglycerides, history of hypertension) – for rosuvastatin. 2 Adverse reaction profile for rosuvastatin based on data from clinical studies and extensive post- marketing experience. 3 Ezetimibe in monotherapy.

Adverse reactions were observed in patients treated with ezetimibe (N=2396) and at a greater incidence than placebo (N=1159) 4 Ezetimibe co-administered with a statin. Adverse reactions were observed in patients with ezetimibe co-administered with a statin (N=11308) and at a greater incidence than statin administered alone (N=9361).

5 Additional adverse reactions of ezetimibe, reported in post-marketing experience. Because these adverse experiences have been identified from spontaneous reports, their true frequencies are not known and cannot be estimated. As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

Renal effects:

Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with rosuvastatin. Shifts in urine protein from none or trace to ++ or more were seen in <1% of patients at some time during treatment with 10 and 20 mg, and in approximately 3% of patients treated with 40 mg.

A minor increase in shift from none or trace to + was observed with the 20 mg dose. In most cases, proteinuria decreases or disappears spontaneously on continued therapy. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or progressive renal disease.

Haematuria has been observed in patients treated with rosuvastatin and clinical trial data show that the occurrence is low. g. myalgia, myopathy (including myositis), and, rarely, rhabdomyolysis with and without acute renal failure have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg.

A dose-related increase in CK levels has been observed in patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient. 4).

Liver Effects:

As with other HMG-CoA reductase […]

g. myalgia, myopathy, and, rarely rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported.

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. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine kinase level, ezetimibe, any statin, and any of these agents known to be associated with increased risk of rhabdomyolysis, that the patient is taking concomitantly should be immediately discontinued.

8). Liver effects In controlled co-administration trials in patients receiving ezetimibe with a statin, consecutive transaminase elevations (≥3x the upper limit of normal [ULN]) have been observed. It is recommended that liver function tests be carried out 3 months following the initiation of rosuvastatin treatment.

Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with Twicor.

2). Liver disease and alcohol Twicor should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. Renal effects Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of rosuvastatin, in particular 40 mg, where it was transient or intermittent in most cases.

8). Creatine Kinase Measurement Creatine kinase (CK) should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase, which may confound interpretation of the results. If CK levels are significantly elevated at baseline (>5xULN) a confirmatory test should be carried out within 5-7 days.

If the repeat test confirms a baseline CK>5xULN, treatment should not be started. Before treatment Twicor, as other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis.

2) – concomitant use of fibrates. In such patients the risk of treatment should be considered in relation to possible benefit and clinical monitoring is recommended. If CK levels are significantly elevated at baseline (>5xULN) treatment should not be started.

Whilst on treatment Patients should be asked to report inexplicable muscle pain, weakness or cramps immediately, particularly if associated with malaise or fever. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are <5xULN).

Routine monitoring of CK levels in asymptomatic patients is not warranted. There have been very rare reports of an immune-mediated necrotising myopathy (IMNM) during or after treatment with statins, including rosuvastatin. IMNM is clinically characterized by proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

In clinical trials there was no evidence of increased skeletal muscle effects in the small number of patients dosed with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives including gemfibrozil, ciclosporin, nicotinic acid, azole antifungals, protease inhibitors and macrolid antibiotics.

Gemfibrozil increases the risk of myopathy when given concomitantly with some HMG-CoA reductase inhibitors. Therefore, the combination of Twicor and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of Twicor with fibrates should be carefully weighed against the potential risks of such combinations.

g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Fusidic acid Twicor must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment.

In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. 5). The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness.

Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic […]

1. 4). 6). 2). 4). 5).