Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: AstraZeneca Pharmaceuticals (Pty) Ltd, Building 2, Northdowns Office Park, 17 Georgian Crescent West, Bryanston, Johannesburg, 2191, South Africa
ZUVAMOR is contraindicated in:
(See sections 4.4, 4.5 and 5.2)
ZUVAMOR should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. It is recommended that liver enzyme tests be performed before the initiation of ZUVAMOR, 3 months following, the initiation of treatment and if signs or symptoms of liver injury occur. The reporting rate for serious hepatic events (consisting mainly of increased hepatic transaminases) in post-marketing use is higher at the 40 mg dose.
There have been rare post marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including ZUVAMOR. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with ZUVAMOR, promptly interrupt therapy. If an alternate aetiology is not found, do not restart ZUVAMOR.
Proteinuria, detected by dipstick testing and mostly tubular in origin, has been observed in patients treated with higher doses of ZUVAMOR, 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). The reporting rate for serious renal events in post-marketing use is higher at the 40 mg dose. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40 mg.
Effects on skeletal muscles e.g. myalgia, myopathy and rhabdomyolysis, have been reported in patients treated with ZUVAMOR. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose. Patients who develop any signs or symptoms suggestive of myopathy should have their Creatine kinase (CK) levels measured. ZUVAMOR therapy should be discontinued if myopathy is diagnosed or suspected.
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 (>5 x ULN) a confirmatory test should be carried out within 5–7 days. If the repeat test confirms a baseline CK >5 x ULN, treatment should not be started.
ZUVAMOR 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 (>5 x ULN) 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 (>5 x ULN) or if muscular symptoms are severe and cause daily discomfort (even if CK levels are ≤5 x ULN). If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing ZUVAMOR or an alternative HMG-CoA reductase inhibitor at the lowest dose with close monitoring. Routine monitoring of CK levels in asymptomatic patients is not warranted.
There have been reports of an immune-mediated necrotizing myopathy clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase during treatment or following discontinuation of statins, including ZUVAMOR. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required.
An increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with ciclosporin, fibric acid derivatives, including gemfibrozil, nicotinic acid, azole antifungals and macrolide antibiotics.
ZUVAMOR 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). Patients 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 coadministration of ZUVAMOR and fusidic acid should only be considered on a case by case basis and under close medical supervision.
ZUVAMOR should be prescribed with caution in patients with pre-disposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism or situations where an increase in plasma levels may occur (see section 4.5 and section 5.2).
ZUVAMOR 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).
Increases in HbA1c and serum glucose levels have been observed in patients treated with ZUVAMOR and in some instances these increases may exceed the threshold for the diagnosis of diabetes mellitus. This was observed primarily in patients already at high risk for developing diabetes (see section 4.8). Patients at risk (fasting glucose 5.6 to 6.9 mmol/l, BMI >30 kg/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 (100-124 md/dL).
Pharmacokinetic studies show an increase in exposure in Asian subjects compared with Caucasians (see section 4.2 and section 5.3).
The evaluation of linear growth (height), weight, BMI (body mass index), and secondary characteristics of sexual maturation by Tanner staging in paediatric patients taking rosuvastatin is limited to a 1 year period (see section 5.1)
ZUVAMOR should be used with caution in patients taking various protease inhibitors in combination with ritonavir as pharmacokinetic studies have shown an increase in the AUC and Cmax of rosuvastatin (see section 4.2 and section 4.4).
ZUVAMOR contains lactose. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take ZUVAMOR.
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.
Transporter protein inhibitors: Rosuvastatin is a substrate for certain transporter proteins including the hepatic uptake transporter OATP1B1 and efflux transporter BCRP. Concomitant administration of ZUVAMOR with medicines 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 1).
Ciclosporin: During concomitant treatment with ZUVAMOR and ciclosporin, rosuvastatin AUC values were on average 7 times higher than those observed in healthy volunteers (see Table 1). ZUVAMOR is contraindicated in patients receiving concomitant ciclosporin (see section 4.3). Concomitant administration did not affect plasma concentrations of ciclosporin.
Protease inhibitors: Although the exact mechanism of interaction is unknown, concomitant protease inhibitor use may strongly increase rosuvastatin exposure (see Table 1). 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 sevenfold increase in rosuvastatin AUC and Cmax, respectively. The concomitant use of ZUVAMOR and some protease inhibitor combinations may be considered after careful consideration of ZUVAMOR dose adjustments based on the expected increase in rosuvastatin exposure (see sections 4.2, 4.4 and 4.5 Table 1).
Gemfibrozil and other lipid-lowering products: Concomitant use of ZUVAMOR and gemfibrozil resulted in a 2-fold increase in rosuvastatin Cmax and AUC (see section 4.4).
Based on data from specific interaction studies no pharmacokinetic relevant interaction with fenofibrate is expected, however a pharmacodynamic interaction may occur. Gemfibrozil, fenofibrate, other fibrates and lipid lowering doses (> or equal to 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when given concomitantly with HMGCoA reductase inhibitors, probably because they can produce myopathy when given alone. The 40 mg dose is contraindicated with concomitant use of a fibrate (see sections 4.3 and 4.4). These patients should also start with the 5 mg dose.
Ezetimibe: Concomitant use of 10 mg ZUVAMOR and 10 mg ezetimibe resulted in a 1.2-fold increase in AUC of rosuvastatin in hypercholesterolaemic subjects (Table 1). A pharmacodynamic interaction, in terms of adverse effects, between ZUVAMOR and ezetimibe cannot be ruled out (see section 4.4).
Antacids: The simultaneous dosing of ZUVAMOR 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 ZUVAMOR. The clinical relevance of this interaction has not been studied.
Erythromycin: Concomitant use of ZUVAMOR and erythromycin resulted in a 20% decrease in AUC and a 30% decrease in Cmax of rosuvastatin. This interaction may be caused by the increase in gut motility caused by erythromycin.
Cytochrome P450 enzymes: 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).
When it is necessary to co-administer ZUVAMOR with other medicines known to increase exposure to rosuvastatin, doses of ZUVAMOR should be adjusted. Start with a 5 mg once daily dose of ZUVAMOR if the expected increase in exposure (AUC) is approximately 2-fold or higher. The maximum daily dose of ZUVAMOR should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40 mg daily dose of ZUVAMOR taken without interacting medicines, for example a 20 mg dose of ZUVAMOR with gemfibrozil (1,9-fold increase), and a 10 mg dose of ZUVAMOR with combination ritonavir/atazanavir (3,1-fold increase).
If medicine is observed to increase rosuvastatin AUC less than 2-fold, the starting dose need not be decreased but caution should be taken if increasing the ZUVAMOR dose above 20 mg.
Table 1. Effect of co-administered medicinal products on rosuvastatin exposure (AUC; in order of decreasing magnitude) from published clinical trials:
| 2-fold or greater than 2-fold increase in AUC of rosuvastatin | ||
| Interacting medicine dose regimen | Rosuvastatin dose regimen | Change in rosuvastatin AUC* |
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg-100 mg-100 mg) + Voxilaprevir (100 mg) once daily for 15 days | 10 mg single dose | 7,4 -fold ↑ |
| Ciclosporin 75 mg BID to 200 mg BID, 6 months | 10 mg OD, 10 days | 7,1-fold ↑ |
| Darolutamide 600 mg BID, 5 days | 5 mg, single dose | 5,2-fold ↑ |
| Regorafenib 160 mg OD, 14 days | 5 mg single dose | 3,8 -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 ↑ |
| Velpatasvir 100 mg OD | 10 mg single dose | 2,7-fold ↑ |
| Ombitasvir 25 mg/ paritaprevir 150 mg/ ritonavir 100 mg/dasabuvir 400 mg BID | 5 mg single dose | 2,6-fold ↑ |
| Grazoprevir 200 mg/elbasvir 50 mg OD | 10 mg single dose | 2,3-fold ↑ |
| Glecaprevir 400 mg/pibrentasvir 120 mg OD for 7 days | 5 mg once daily | 2,2-fold ↑ |
| Lopinavir 400 mg/ritonavir 100 mg BID, 17 days | 20 mg OD, 7 days | 2,1-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 ↑ |
| Less than 2-fold increase in AUC of rosuvastatin | ||
| Interacting medicine dose regimen | Rosuvastatin dose regimen | Change in rosuvastatin AUC* |
| 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 or 80 mg, single dose | **1,4-fold ↑ |
| Ezetimibe 10 mg OD, 14 days | 10 mg, OD, 14 days | **1,2-fold ↑ |
| Decrease in AUC of rosuvastatin | ||
| Interacting medicine dose regimen | Rosuvastatin dose regimen | Change in rosuvastatin AUC* |
| Erythromycin 500 mg QID, 7 days | 80 mg, single dose | 20% ↓ |
| Baicalin 50 mg TID, 14 days | 20 mg, single dose | 47% ↓ |
* 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 “↑”, decrease as “↓”.
** Several interaction studies have been performed at different ZUVAMOR dosages, the table shows the most significant ratio
AUC = area under curve; OD = once daily; BID = twice daily; TID = three times daily; QID = four times daily
The following medical product/combinations did not have a clinically significant effect on the AUC ratio of rosuvastatin at coadministration:
Aleglitazar 0.3 mg 7 days dosing; Fenofibrate 67 mg 7 days TID dosing; Fluconazole 200mg 11 days OD dosing; Fosamprenavir 700 mg/ritonavir 100 mg 8 days BID dosing; Ketoconazole 200 mg 7 days BID dosing; Rifampin 450 mg 7 days OD dosing; Silymarin 140 mg 5 days TID dosing.
The pharmacokinetics of warfarin are not significantly affected following co-administration with ZUVAMOR. However, as with other HMG-CoA reductase inhibitors, co-administration of ZUVAMOR and warfarin may result in a rise in INR compared to warfarin alone. In patients taking warfarin monitoring of INR is recommended both at initiation or cessation of therapy with ZUVAMOR or following dose adjustment.
The risk of skeletal muscle effects may be enhanced when ZUVAMOR is used in combination with lipid-modifying doses (≥1 g/day) of niacin; caution should be used when prescribing with ZUVAMOR (see section 4.4).
Consideration should be given both to the benefit of lipid lowering by the use of ZUVAMOR in HIV-infected patients receiving protease inhibitors and the potential risks of this increased rosuvastatin plasma concentrations when initiating and up-titrating ZUVAMOR doses in patients treated with protease inhibitors, as the combination may lead to an increased incidence of adverse events (see section 4.2 and 4.4).
The lowest dose of ZUVAMOR that provides therapeutic benefit to the patient should be used and close monitoring of adverse events is indicated (see section 4.2).
Digoxin: Based on data from specific interaction studies no clinically relevant interaction with digoxin is expected.
Fusidic Acid: Interaction studies with rosuvastatin and fusidic acid have not been conducted. 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, ZUVAMOR treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see section 4.4.
Paediatric population: Interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known.
There were no clinically significant interactions with an oral contraceptive.
In clinical studies ZUVAMOR was co-administered with antihypertensive agents, antidiabetic agents and hormone replacement therapy. These studies did not produce any evidence of clinically significant adverse interactions.
ZUVAMOR is contraindicated in pregnancy and lactation.
The safety of ZUVAMOR during pregnancy and whilst breast feeding has not been established. Women of child-bearing 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 this product, treatment should be discontinued immediately.
Studies to determine the effect of ZUVAMOR on the ability to drive and use machines have not been conducted. However, based on its pharmacodynamic properties, ZUVAMOR is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness may occur during treatment.
In controlled clinical trials less than 4% of ZUVAMOR treated patients were withdrawn due to adverse events.
The incidence of adverse reactions tends to increase with increasing dose.
The frequencies of adverse events are ranked according to the following: common (≥1/100, <1/10); uncommon (≥1/1 000, <1/100); rare (≥1/10 000, <1/1 000); very rare (<1/10 000) not known (cannot be estimated from the available data).
Table 2. Adverse reactions based on data from clinical studies and post-marketing experience:
| System organ class | Frequency | Adverse Event |
|---|---|---|
| Blood and lymphatic system disorders | Rare | Thrombocytopenia |
| Endocrine disorders | Common | Diabetes mellitus1 |
| Psychiatric disorder | Not known | Depression |
| Nervous system disorders | Common | Headache, dizziness |
| Very Rare | Polyneuropathy, memory loss | |
| Not known | Peripheral neuropathy, sleep disturbances (including insomnia and nightmares) | |
| Respiratory, thoracic and mediastinal disorders | Not known | Cough, dyspnoea |
| Gastrointestinal disorders | Common | Constipation, nausea, abdominal pain |
| Rare | Pancreatitis | |
| Hepatobiliary disorders | Rare | Increased hepatic transaminases |
| Very rare | Jaundice, hepatitis | |
| Not known | Fatal and non-fatal hepatic failure | |
| Skin and subcutaneous tissue disorders | Uncommon | Pruritus, rash, urticaria |
| Rare | Hypersensitivity reactions including angio-oedema | |
| Not known | Stevens-Johnson syndrome | |
| Musculoskeletal and connective tissue disorders | Common | Myalgia |
| Rare | Myopathy including (myositis), rhabdomyolysis lupus-like syndrome, muscle rupture, arthralgia | |
| Not known | Tendon disorders, sometimes complicated by rupture, immune-mediated necrotising myopathy | |
| Renal and urinary disorders | Very Rare | Haematuria |
| Reproductive system and breast disorders | Not known | Gynaecomastia |
| General disorders and administration site conditions | Common | Asthenia |
1 Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI >30 kg/m², raised triglycerides, history of hypertension).
There have been post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Rhabdomyolysis, which may occasionally be associated with impairment of renal function, has been reported with ZUVAMOR.
Proteinuria (see “Laboratory effects”).
A dose-related increase in liver transaminases and Creatine kinase (CK) has been observed in patients taking ZUVAMOR. Increases in HbA1c have also been observed in patients treated with ZUVAMOR (see section 4.4). Abnormal urinalysis testing (dipstick-positive proteinuria with haematuria) has been seen in patients taking ZUVAMOR. The protein detected was mostly tubular in origin. In most cases, proteinuria decreases or disappeares spontaneously on continued therapy, and is not predictive of acute or progressive renal disease.
In a long-term controlled clinical trial ZUVAMOR was shown to have no harmful effects on the ocular lens.
In ZUVAMOR treated patients, there was no impairment of adrenocortical function. The reporting rate for rhabdomyolysis in post-marketing use is higher at the highest marketed dose.
The safety profile of ZUVAMOR is similar in children or adolescent patients and adults although CK elevations >10 x ULN and muscle symptoms following exercise or increased physical activity, which resolved with continued treatment, were observed more frequently in clinical trials of children and adolescents. However, the same warnings and special precautions for use in adults also apply to children and adolescents (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Not appliable.
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