Source: Medicines Authority (MT) Revision Year: 2023 Publisher: Viatris Healthcare Limited, Damastown Industrial Park, Mulhuddart, Dublin 15, DUBLIN, Ireland
TWICOR is contraindicated
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. 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 section 4.8).
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 ROSUVASTATINE/EZETIMIBE MYLAN HEALTHCARE.
Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, TWICOR is not recommended (see section 5.2).
TWICOR should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease.
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 section 4.8).
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.
ROSUVASTATINE/EZETIMIBE-MYLAN HEALTHCARE, as other HMG-CoA reductase inhibitors, should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include:
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.
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 ROSUVASTATINE/ EZETIMIBE MYLAN HEALTHCARE with fibrates should be carefully weighed against the potential risks of such combinations.
TWICOR 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).
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. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination (see section 4.5). 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 fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of ROSUVASTATINE/ EZETIMIBE MYLAN HEALTHCARE and fusidic acid should only be considered on a case by case basis and under close medical supervision.
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 TWICOR 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 sections 4.2 and 4.5).
The safety and efficacy of ezetimibe administered with fibrates have not been established.
If cholelithiasis is suspected in a patient receiving TWICOR and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).
If TWICOR is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).
See section 4.3 and 4.5.
Rosuvastatin pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see sections 4.2 and 5.2).
Exceptional cases of interstitial lung disease have been reported with some statins, 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, statin therapy should be discontinued.
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.
The safety and efficacy of TWICOR in children below the age of 18 years has not yet been established, therefore its use is not recommended in this age group. 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 appear, TWICOR 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 TWICOR, treatment with TWICOR must not be restarted in this patient at any time.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodiumfree”.
During concomitant treatment with rosuvastatin and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see section 4.3).
Concomitant administration did not affect plasma concentrations of ciclosporin. Co-administration of TWICOR with ciclosporin is contraindicated (see section 4.3). In a study of eight post-renal transplant patients with creatinine clearance of >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 a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in twelve 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. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted.
Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see section 4.5 Table). For instance, in a pharmacokinetic study, co-administration of 10 mg rosuvastatin and a combination product of two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was associated with an approximately three-fold and seven-fold increase in rosuvastatin AUC and Cmax respectively. The concomitant use of rosuvastatin and some protease inhibitor combinations may be considered after careful consideration of rosuvastatin dose adjustments based on the expected increase in rosuvastatin exposure (see Sections 4.2, 4.4, and 4.5 Table). 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.
Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of TWICOR with medicinal products that are inhibitors of these transporter proteins may result in increased rosuvastatin plasma concentrations and an increased risk of myopathy (see Sections 4.2, 4.4, and 4.5 Table).
Concomitant use of rosuvastatin and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see section 4.4). Concomitant gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.7-fold).
Based on data from specific interaction studies no pharmacokinetic relevant interaction between rosuvastatin and fenofibrate is expected, however a pharmacodynamic interaction may occur. Concomitant fenofibrate administration modestly increased total ezetimibe concentrations (approximately 1.5-fold).
Fenofibrate and other fibrates increase the risk of myopathy when given concomitantly with HMGCoA reductase inhibitors, probably because they can produce myopathy when given alone. In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see section 4.4 and 4.8). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8). Co-administration of ezetimibe with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol in the gallbladder bile, but not all species (see section 5.3). A lithogenic risk associated with the therapeutic use of ezetimibe cannot be ruled out.
The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamic or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with systemic fusidic acid is necessary, rosuvastatin treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.
The simultaneous dosing of rosuvastatin with an antacid suspension containing aluminium and magnesium hydroxide resulted in a decrease in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when the antacid was dosed 2 hours after rosuvastatin. The clinical relevance of this interaction has not been studied. Concomitant antacid administration 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.
Concomitant use of rosuvastatin and eryhtromycin resulted in a 20% decrease in AUC0-t and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).
In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
As with other HMG-CoA reductase inhibitors, the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin or another coumarin anticoagulant) may result in an increase in International Normalised Ratio (INR). Discontinuation or down-titration of rosuvastatin may result in a decrease in INR. In such situations, appropriate monitoring of INR is desirable.
Concomitant administration of ezetimibe (10 mg once daily) had no effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been postmarketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If TWICOR is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see section 4.4).
Concomitant use of rosuvastatin and oral contraceptive resulted in an increase in ethinyl estradiol and norgestrel AUC of 26% and 34%, respectively. These increased plasma levels should be considered when selecting oral contraceptive doses. There are no pharmacokinetic data available in subjects taking concomitant rosuvastatin and HRT and therefore a similar effect cannot be excluded. However, the combination has been extensively used in women in clinical trials and was well tolerated.
In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).
Concomitant colestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental low-density lipoprotein cholesterol (LDL-C) reduction due to adding ezetimibe to colestyramine may be lessened by this interaction (see section 4.2).
No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.
Ticagrelor might affect renal excretion of rosuvastatin, increasing the risk for rosuvastatin accumulation. Although the exact mechanism is not known, in some cases, concomitant use of ticagrelor and rosuvastatin led to renal function decrease, increased CPK level and rhabdomyolysis.
Based on data from specific interaction studies no clinically relevant interaction between rosuvastatin and digoxin is expected. In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.
When it is necessary to co-administer rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted. Start with a 5 mg once daily dose of rosuvastatin if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of rosuvastatin taken without interacting medicinal products, for example a 20 mg dose of rosuvastatin with gemfibrozil (1.9-fold increase), and a 10 mg dose of rosuvastatin with combination atazanavir/ritonavir (3.1-fold increase).
Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials:
| Interacting drug dose regimen | Rosuvastatin dose regimen | Change in rosuvastatin AUC* |
|---|---|---|
| Ciclosporin 75 mg BID to 200 mg BID, 6 months | 10 mg OD, 10 days | 7.1-fold ↑ |
| Atazanavir 300 mg/ritonavir 100 mg OD, 8 days | 10 mg, single dose | 3.1-fold ↑ |
| Simeprevir 150 mg OD, 7 days | 10 mg, single dose | 2.8-fold ↑ |
| Lopinavir 400 mg/ritonavir 100 mg BID, 17 days | 20 mg OD, 7 days | 2.1-fold ↑ |
| Velpatasvir 100 mg OD | 10 mg, single dose | 2.7-fold ↑ |
| Ombitasvir 25 mg/paritaprevir 150 mg/ Ritonavir 100 mg OD/ dasabuvir 400 mg BID, 14 days | 5 mg, single dose | 2.6-fold ↑ |
| Grazoprevir 200 mg/elbasvir 50 mg OD, 11 days | 10 mg, single dose | 2.3-fold ↑ |
| Glecaprevir 400 mg/pibrentasvir 120 mg OD, 7 days | 5 mg OD, 7 days | 2.2-fold ↑ |
| Clopidogrel 300 mg loading, followed by 75 mg at 24 hours | 20 mg, single dose | 2-fold ↑ |
| Gemfibrozil 600 mg BID, 7 days | 80 mg, single dose | 1.9-fold ↑ |
| Eltrombopag 75 mg OD, 5 days | 10 mg, single dose | 1.6-fold ↑ |
| Darunavir 600 mg/ritonavir 100 mg BID, 7 days | 10 mg OD, 7 days | 1.5-fold ↑ |
| Tipranavir 500 mg/ritonavir 200 mg BID, 11 days | 10 mg, single dose | 1.4-fold ↑ |
| Dronedarone 400 mg BID | Not available | 1.4-fold ↑ |
| Itraconazole 200 mg OD, 5 days | 10 mg, single dose | 1.4-fold ↑** |
| Fosamprenavir 700 mg/ritonavir 100 mg BID, 8 days | 10 mg, single dose | ↔ |
| Aleglitazar 0.3 mg, 7 days | 40 mg, 7 days | ↔ |
| Silymarin 140 mg TID, 5 days | 10 mg, single dose | ↔ |
| Fenofibrate 67 mg TID, 7 days | 10 mg, 7 days | ↔ |
| Rifampin 450 mg OD, 7 days | 20 mg, single dose | ↔ |
| Ketoconazole 200 mg BID, 7 days | 80 mg, single dose | ↔ |
| Fluconazole 200 mg OD, 11 days | 80 mg, single dose | ↔ |
| Erythromycin 500 mg QID, 7 days | 80 mg, single dose | 20% ↓ |
| Baicalin 50 mg TID, 14 days | 20 mg, single dose | 47% ↓ |
| Regorafenib 160 mg OD, 14 days | 5 mg, single dose | 3.8-fold ↑ |
* Data given as x-fold change represent a simple ratio between co-administration and rosuvastatin alone. Data given as % change represent % difference relative to rosuvastatin alone. Increase is indicated as “↑” no change as “↔” decrease as "↓"
** Several interaction studies have been performed at different rosuvastatin dosages, the table shows the most significant ratio
OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily
TWICOR is contraindicated in pregnancy and breast-feeding.
Women of childbearing potential should use appropriate contraceptive measures.
Since cholesterol and other products of cholesterol biosynthesis are essential for the development of the foetus, the potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. Animal studies provide limited evidence of reproductive toxicity (see section 5.3). If a patient becomes pregnant during use of TWICOR, treatment should be discontinued immediately.
No clinical data are available on the use of ezetimibe during pregnancy.
Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).
Rosuvastatin is excreted in the milk of rats. There are no data with respect to excretion of rosuvastatin in milk in humans (see section 4.3).
Studies on rats have shown that ezetimibe is secreted into milk. It is not known if ezetimibe is secreted into human breast milk.
No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the fertility of male or female rats (see section 5.3).
TWICOR 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.
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. However, a pharmacodynamic interaction, in terms of adverse effects, between rosuvastatin and ezetimibe cannot be ruled out (see section 5.2).
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).
| MedDRA system organ class | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|
| Blood and lymphatic system disorders | thrombo-cytopenia2 | thrombo-cytopenia5 | |||
| Immune system disorders | hypersensitivity reactions including angioedema2 | hypersensitivity (including rash, urticaria, anaphylaxis and angioedema)5 | |||
| Endocrine disorders | diabetes mellitus1,2 | ||||
| Metabolism and Nutrition Disorders | decreased appetite3 | ||||
| Psychiatric disorders | depression2,5 | ||||
| Nervous system disorders | headache2,4, dizziness2 | paraesthesia4 | polyneuropathy2, memory loss2 | peripheral neuropathy2, sleep disturbances (including insomnia and nightmares)2, dizziness5, paraesthesia5 | |
| Vascular Disorders | hot flush3; hypertension3 | ||||
| Respiratory, thoracic and mediastinal disorders | cough3 | cough2, dyspnoea2,5 | |||
| Gastrointestinal disorders | constipation2, nausea2, abdominal pain2,3 diarrhoea3, flatulence3 | dyspepsia3; gastro-oesophageal reflux disease3; nausea3 dry mouth4; gastritis | pancreatitis2 | diarrhoea2 pancreatitis5; constipation5 | |
| Hepatobiliary disorders | increased hepatic transaminases2 | jaundice2, hepatitis2 | hepatitis5, cholelithiasis5, cholecystitis5 | ||
| Skin and subcutaneous tissue disorders | pruritus2,4, rash2,4, urticaria2,4 | Stevens-Johnson syndrome2, erythema multiforme5, drug reaction with eosinophilia and systemic symptoms (DRESS) | |||
| Musculoskeletal and connective tissue disorders | myalgia2,4 | arthralgia3; muscle spasms3; neck pain3; back pain4; muscular weakness4; pain in extremity4 | myopathy (including myositis)2, rhabdomyolysis2, lupuslike syndrome, muscle rupture | arthralgia2 | immune-mediated necrotising myopathy2, tendon disorders, sometimes complicated by rupture2, arthralgia5, myalgia5; myopathy/ rhabdomyolysis5 (see section 4.4) |
| Renal and urinary disorders | haematuria2 | ||||
| Reproductive system and breast disorders | gynecomastia2 | ||||
| General disorders and administration site conditions | asthenia2, fatigue3 | chest pain3, pain3, asthenia4; oedema peripheral4 | oedema2, asthenia5 | ||
| Investigations | ALT and/or AST increased4 | ALT and/or AST increased3; blood CPK increased3; gamma- glutamyl- transferase increased3; liver function test abnormal3 |
1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥5.6 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.
Skeletal Muscle Effects: Effects on skeletal muscle e.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. If CK-levels are elevated (>5xULN), the treatment should be discontinued (see section 4.4).
Liver Effects: As with other HMG-CoA reductase inhibitors, a dose-related increase in transaminases has been observed in a small number of patients taking rosuvastatin; the majority of cases were mild, asymptomatic and transient.
The following adverse events have been reported with some statins:
The reporting rates for rhabdomyolysis, serious renal events and serious hepatic events (consisting mainly of increased hepatic transaminases) are higher at the 40 mg rosuvastatin dose.
In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST ≥3X ULN, consecutive) was similar between ezetimibe (0.5%) and placebo (0.3%). In co-administration trials, the incidence was 1.3% for patients treated with ezetimibe co-administered with a statin and 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment (see section 4.4).
In clinical trials, CPK >10X ULN was reported for 4 of 1,674 (0.2%) patients administered ezetimibe alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered ezetimibe and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or statin alone) (see section 4.4).
The safety and efficacy of TWICOR in children below the age of 18 years has not yet been established (see section 5.1).
Creatine kinase elevations >10x ULN and muscle symptoms following exercise or increased physical activity were observed more frequently in a 52-week clinical trial of children and adolescents compared to adults. In other respects, the safety profile of rosuvastatin was similar in children and adolescents compared to adults.
In a study involving paediatric (6 to 10 years of age) patients with heterozygous familial or non-familial hypercholesterolaemia (n=138), elevations of ALT and/or AST (≥3X ULN, consecutive) were observed in 1.1% (1 patient) of the ezetimibe patients compared to 0% in the placebo group. There were no elevations of CPK (≥10X ULN). No cases of myopathy were reported.
In a separate study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n=248), elevations of ALT and/or AST (≥3X ULN, consecutive) were observed in 3% (4 patients) of the ezetimibe/simvastatin patients compared to 2% (2 patients) in the simvastatin monotherapy group; these figures were respectively 2% (2 patients) and 0% for elevation of CPK (≥10X ULN). No cases of myopathy were reported. These trials were not suited for comparison of rare adverse drug reactions.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel +353 1 6764971: Fax +353 1 6762517. Website: www.hpra.ie; email: medsafety@hpra.ie For Malta Website: www.medicinesauthority.gov.mt /adrportal.
Not applicable.
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