Lypstaplus Special Precautions

Skeletal Muscle Effects: Effects on skeletal muscle e.g. myalgia, myopathy, and, rarely rhabdomyolysis have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20 mg.
Cases of de novo or aggravated pre-existing myasthenia gravis or ocular myasthenia have been observed with statins (see Adverse Reactions). LYPSTAPLUS should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.
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. All patients starting should be told to report promptly any unexplained muscle pain, tenderness or weakness (see Adverse Reactions).
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 (>10xULN) a confirmatory test should be carried out within 5-7 days. If the repeat test confirms a baseline CK>10xULN, treatment should not be started.
Before treatment: LYPSTAPLUS, as other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include: renal impairment; hypothyroidism; personal or family history of hereditary muscular disorders; previous history of muscular toxicity with another HMG-CoA reductase inhibitor, fibrate or niacin; alcohol abuse; age ≥65 years; situations where an increase in plasma levels may occur (see Pharmacology: Pharmacokinetics under Actions); concomitant use of fibrates or niacin.
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 (>10xULN) treatment should not be started.
In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with LYPSTAPLUS.
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 (>10xULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤10xULN). Routine monitoring of CK levels in asymptomatic patients is not warranted.
The risk of myopathy during treatment with rosuvastatin may be increased in circumstances which increase rosuvastatin drug levels (see Pharmacology: Pharmacokinetics under Actions).
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, 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 LYPSTAPLUS and gemfibrozil is not recommended. The benefit of further alterations in lipid levels by the combined use of LYPSTAPLUS with fibrates should be carefully weighed against the potential risks of such combinations.
LYPSTAPLUS should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures).
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 functions tests be carried out 3 months following the initiation of rosuvastatin treatment and any increase of dose, and periodically (semi-annually) thereafter. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is greater than 3 times the upper limit of normal.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, LYPSTAPLUS is not recommended (see Pharmacology: Pharmacokinetics under Actions).
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. Proteinuria has not been shown to be predictive of acute or progressive renal disease (see Adverse Reactions).
An assessment of renal function is recommended during routine follow-up of patients treated with a rosuvastatin dose of 40mg.
Severe cutaneous adverse reactions: Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions and be closely monitored. If signs and symptoms suggestive of this reaction appears, LYPSTAPLUS should be discontinued immediately and an alternative treatment should be considered.
If the patient has developed a serious reaction such as SJS or DRESS with the use of LYPSTAPLUS, treatment with LYPSTAPLUS must not be restarted in this patient at any time.
Fusidic acid: LYPSTAPLUS 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. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see Interactions). 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 fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of LYPSTAPLUS and fusidic acid should only be considered on a case by case basis and under close medical supervision.
Race: Rosuvastatin pharmacokinetic studies show an increase in exposure in Asian subjects, including subjects of Japanese, Chinese, Malay and Indian ancestry, compared with Caucasians (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of LYPSTAPLUS in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose is adjusted (see Dosage & Administration and Interactions).
Interstitial lung disease: Exceptional cases of interstitial lung disease have been reported with some statins, especially with long term therapy (see Adverse Reactions). 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, statin therapy should be discontinued.
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 statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.
In the JUPITER study, the reported overall frequency of diabetes mellitus was 2.8% in rosuvastatin and 2.3% in placebo, mostly in patients with fasting glucose 5.6 to 6.9 mmol/L.
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established.
If cholelithiasis is suspected in a patient receiving LYPSTAPLUS and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Interactions and Adverse Reactions).
Anticoagulants: If LYPSTAPLUS is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see Interactions).
Ciclosporin: See Contraindications and Interactions.
Liver disease and alcohol: LYPSTAPLUS should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.
Effects on ability to drive and use machines: LYPSTAPLUS has no or negligible influence on the ability to drive and use machines. Studies to determine the effect of rosuvastatin and/or ezetimibe on the ability to drive and use machines have not been conducted. However, when driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.
Use in Children: The safety and efficacy of LYPSTAPLUS in children below the age of 18 years has not yet been established, therefore its use is not recommended in this age group.