ZENON

Posology The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Zenon. Zenon is not suitable for initial therapy. When Zenon is indicated for patients not controlled by statin alone, the dose of Zenon should be individualised according to the target lipid levels and the patient’s response.

When Zenon is indicated for patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed dose combination, but as separate product, treatment initiation or dose adjustment, if necessary, 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.

Patient should use the strength corresponding to their previous treatment. The recommended dose is one Zenon tablet daily. 5). Paediatric population The safety and efficacy of Zenon in children below the age of 18 years have not yet been established.

2 but no recommendation on a posology can be made. 4). The combination is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, 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.

Hepatic impairment No dosage adjustment is required in patients with mild hepatic impairment (Child- Pugh score 5 – 6). 2). 3). Renal impairment 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 40 mg/10 mg dose is contraindicated in patients with moderate renal impairment. 2). 2). The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry. The fixed dose combination is not suitable for initial therapy.

Monocomponent preparations should be used to start the treatment or to modify the dose. 2). 2). For patients who are known to have such specific types of polymorphisms, a lower daily dose of Zenon is recommended. 4). The fixed dose combination is not suitable for initial therapy.

Monocomponent preparations should be used to start the treatment or to modify the dose. 3). g. OATP1B1 and BCRP). g. 5). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Zenon therapy.

Summary of safety profile Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Zenon. In clinical studies of up to 112 weeks duration, ezetimibe 10 mg daily was administered alone in 2,396 patients, 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.

The adverse events seen with rosuvastatin are generally mild and transient. In controlled clinical trials, less than 4% of rosuvastatin-treated patients were withdrawn due to adverse events. Tabulated list of adverse reactions The frequencies of adverse reactions are ranked according to the following convention: very common (≥1/10); 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) and not known (cannot be estimated from the available data).

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

Adverse reactions were observed in patients treated with ezetimibe (N=2,396) and at a greater incidence than placebo (N=1,159). 4 Ezetimibe co-administered with a statin. Adverse reactions were observed in patients with ezetimibe co-administered with a statin (N=11,308) and at a greater incidence than statin administered alone (N=9,361).

5 Additional adverse reactions of ezetimibe, reported in post-marketing experience (with or without statin). As with other HMG-CoA reductase inhibitors, the incidence of adverse drug reactions tends to be dose dependent.

g. myalgia, myopathy and, rarely, rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg. As with other HMG-CoA reductase inhibitors, the reporting rate for rhabdomyolysis associated with rosuvastatin in post-marketing use is higher at the 40 mg dose.

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 phosphokinase (CPK) level, Zenon and any of these other agents that the patient is taking concomitantly should be immediately discontinued. 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 result.

If CK levels are significantly elevated at baseline (>5x ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5x ULN, treatment should not be started. Before treatment Caution should be exercised 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 (>5x ULN) 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 (>5x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are </=5x ULN).

1. 6). 4). 4). 4). 5). 5). 5). The 40 mg/10 mg dose is contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: • Moderate renal impairment (creatinine clearance <60 ml/min). • Hypothyroidism.

• Personal or family history of hereditary muscular disorders. • Previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate. • Alcohol abuse. • Situations where an increase in plasma levels of rosuvastatin may occur.

• Asian patients. • Concomitant use of fibrates. 2)