Dynator Plus 10 Mg/20 Mg/40 Mg/80 Mg Tablets

Primary Hypercholesterolaemia

DYNATOR PLUS, administered with an HMG-CoA reductase inhibitor (statin) or alone, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C), in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia.

Homozygous Familial Hypercholesterolaemia (HoFH)

DYNATOR PLUS is indicated as adjunctive therapy to diet for use in adults to reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolaemia (HoFH).

Posology

The patient should be on an appropriate lipid - lowering diet and weight loss programme where indicated and should continue on this diet during treatment with DYNATOR PLUS. The usual starting dose of DYNATOR PLUS is 10/10 mg once a day and atorvastatin dosage should be individualised according to the baseline LDL-C levels, the goal of therapy, and patient response. Adjustment of dosage should only be made after an interval of 4 weeks or more. The maximum recommended dose will depend on the indication (see below).

Primary Hypercholesterolaemia and Combined (mixed) Hyperlipidaemia

The majority of patients are controlled with 10/10 mg DYNATOR PLUS once a day. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy.

Homozygous Familial Hypercholesterolaemia

The dose of DYNATOR PLUS in patients with homozygous familial hypercholesterolaemia is 10/10 to 10/40 mg daily. DYNATOR PLUS may be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Dosing of DYNATOR PLUS should occur either 2 or more hours before or 4 or more hours after administration of a bile acid sequestrant.

Co-administration with other medicines

In patients taking hepatitis C antiviral medicines elbasvir/grazoprevir concomitantly with DYNATOR PLUS, the dose of DYNATOR PLUS should not exceed 10/20 mg/day (see sections 4.4 and 4.5).

Special populations

Elderly

No dosage adjustment is required for elderly patients (see section 5.2).

Hepatic Impairment

No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with DYNATOR PLUS is contraindicated in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score > 9) liver dysfunction due to unknown effects (see sections 4.3 and 5.2). In patients with moderate to severe hepatic dysfunction, the therapeutic response to atorvastatin is unaffected but serum levels of the atorvastatin are greatly increased. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Child-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. Therefore, caution with dosage should be exercised in patients who consume substantial quantities of alcohol and/or have a history of liver disease (see sections 4.3 and 5.2).

Renal Impairment

Renal disease has no influence on the plasma concentrations or on the lipid effects of DYNATOR PLUS; thus, no adjustment of dose is required.

Paediatric population

No clinical data on safety and efficacy are available; therefore, treatment with DYNATOR PLUS is contraindicated.

Method of administration

DYNATOR PLUS is for oral administration and can be administered at any time of the day, with or without food.

• hypersensitivity to atorvastatin, ezetimibe or to any of the ingredients of DYNATOR PLUS listed in section 6.1
• pregnancy, as no clinical data on exposed pregnancies is available
• lactation, as it is not known whether ezetimibe is excreted into human breast milk
• women of childbearing potential not using appropriate contraceptive measures
• moderate to severe hepatic impairment (Child Pugh score 7 or more) and active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal (see section 4.4)
• patients with Child-Pugh B and C (liver cirrhosis)
• concomitant use with rifampicin, diltiazem and grapefruit juice (see section 4.4)
• DYNATOR PLUS is contraindicated in patients treated with the hepatitis C antivirals glecaprevir/pibrentasvir.

Liver effects

Persistent elevations (u02c3 3 times the upper limit of normal (ULN) which occurred on 2 or more occasions) in serum transaminases occurred in 0,7 % of patients who received atorvastatin, as in DYNATOR PLUS, in clinical trials. The incidence of these abnormalities was 0,2 %, 0,2 %, 0,6 % and 2,3 % for 10, 20, 40 and 80 mg respectively.

It is recommended that liver function tests be performed before the initiation of treatment and repeated as clinically indicated. In controlled co-administration trials in patients receiving ezetimibe with a statin, as in DYNATOR PLUS, consecutive transaminase elevations ( u2265 3 x ULN) have been observed. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice occurs during treatment with DYNATOR PLUS, promptly interrupt therapy. If an alternate aetiology is not found, do not restart DYNATOR PLUS. DYNATOR PLUS should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of DYNATOR PLUS (see section 4.3).

Skeletal Muscle

Risk of myasthenia gravis and ocular myasthenia. In clinical trials the incidence of (creatine phosphokinase) CPK > 10 x ULN was 0,2 % for ezetimibe, as in DYNATOR PLUS, versus 0,1 % for placebo and 0,1 % for ezetimibe co-administered with a statin versus 0,4 % for statins alone. Cases of myopathy and rhabdomyolysis have been reported. All patients starting therapy with DYNATOR PLUS should be advised of the risk of myopathy and to report promptly any unexplained muscle pain (diffuse myalgias), tenderness or weakness, particularly if accompanied by malaise or fever. DYNATOR PLUS should be immediately discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level greater than 10 times the ULN indicates myopathy. Myalgia has been reported in patients treated with atorvastatin (see section 4.8). Rhabdomyolysis with or without renal impairment has also been reported with the use of atorvastatin. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.

The risk of myopathy during treatments with DYNATOR PLUS is increased with concurrent administration of immunosuppressive medicines including ciclosporin, fibric acid derivatives, nicotinic acid, azole antifungals or erythromycin, colchicine, the hepatitis C protease inhibitor telaprevir, boceprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir and cytochrome P450 inhibitors (see section 4.5). Medical practitioners considering combined therapy with DYNATOR PLUS and fibric acid derivatives, erythromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, immunosuppressive medicines, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either medicine. Muscle-related adverse events have been reported with concomitant DYNATOR PLUS and fusidic acid. Temporary suspension of DYNATOR PLUS may be appropriate during fusidic acid therapy (see section 4.5). DYNATOR PLUS therapy should be withdrawn in any patient having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Haemorrhagic Stroke

In a post-hoc analysis of a clinical study, patients without coronary heart disease (CHD) who had a stroke or transient ischaemic attack (TIA) within the preceding 6 months who were initiated on atorvastatin 80 mg, revealed a higher incidence of haemorrhagic stroke compared to placebo. Patients with haemorrhagic stroke on entry appeared to be at increased risk for recurrent haemorrhagic stroke.

Fibrates

The safety and efficacy of DYNATOR PLUS administered with fibrates have not been established. The co-administration of DYNATOR PLUS with fibrates other than fenofibrate has not been studied.

Fenofibrate

If cholelithiasis is suspected in a patient receiving DYNATOR PLUS and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered (see section 4.5 and the Professional Information for fenofibrate).

Ciclosporin

Caution should be exercised when initiating DYNATOR PLUS in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving DYNATOR PLUS and ciclosporin (see section 4.5).

Anticoagulants

If DYNATOR PLUS is added to warfarin or another coumarin anticoagulant, the international normalised ratio (INR) should be appropriately monitored (see section 4.5).

Protease inhibitors

Co-administration of atorvastatin, as in DYNATOR PLUS, and protease inhibitors was associated with increased plasma concentrations of atorvastatin.

Daptomycin

Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. atorvastatin and ezetimibe/atorvastatin) co-administered with daptomycin. Caution should be used when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent can cause myopathy and/or rhabdomyolysis when given alone. Consideration should be given to temporarily suspend DYNATOR PLUS in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. Consult the prescribing information of daptomycin to obtain further information about this potential interaction with HMG-CoA reductase inhibitors (e.g. atorvastatin and ezetimibe/atorvastatin) and for further guidance related to monitoring.

Endocrine function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including DYNATOR PLUS.

Interstitial lung disease

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.

Lactose

DYNATOR PLUS contains lactose. Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take DYNATOR PLUS.

Ezetimibe does not induce cytochrome P450 medicine metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and medicines known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Ezetimibe had no significant effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, midazolam or warfarin during co-administration. However, there have been post-marketing reports of increased international normalised ratio in patients who had ezetimibe added to warfarin. Most of these patients were also on other medication. If ezetimibe is added to warfarin or another coumarin anticoagulant, the international normalised ratio (INR) should be appropriately monitored (see section 4.4). Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe. The risk of myopathy during treatment with DYNATOR PLUS is increased with concurrent administration of immunosuppressive medicines, including ciclosporin, fibric acid derivatives, niacin (nicotinic acid) or cytochrome P450 3A4 inhibitors (macrolide antibiotics e.g. erythromycin, and azole antifungals e.g. clotrimazole).

Inhibitors of cytochrome P450 3A4

Atorvastatin is metabolised by cytochrome P450 3A4. Concomitant administration of DYNATOR PLUS with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. Ticagrelor, for example, is a cytochrome P450 3A4 inhibitor. A study proved that co-administration of atorvastatin and ticagrelor increased atorvastatin acid C max by 23 % and AUC by 36 %. Similar increases in AUC and C max were observed for all atorvastatin acid metabolites. These increases are not considered clinically significant. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4 (see section 4.4).

Inducers of cytochrome P450 3A:

Concomitant administration of DYNATOR PLUS with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin, simultaneous co-administration of DYNATOR PLUS with rifampicin is not recommended, as delayed administration of DYNATOR PLUS after administration of rifampicin has been associated with a significant reduction in atorvastatin plasma concentrations.

Antacids

Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant. Co-administration of an oral antacid suspension containing magnesium and aluminium hydroxides decreased plasma concentrations of atorvastatin by approximately 35 %; however, LDL-C reduction was not altered.

Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe by approximately 55 %. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be lessened by this interaction.

Fibrates

Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1,5 and 1,7-fold respectively, however these increases are not considered clinically significant. The safety and effectiveness of DYNATOR PLUS administered with fibrates have not been established. The safety and effectiveness of ezetimibe co-administered with fenofibrate have been evaluated in a clinical study (see section 4.4). Co-administration of DYNATOR PLUS with other fibrates has not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, co-administration of DYNATOR PLUS with fibrates (other than fenofibrate) is not recommended until use in patients is studied.

Transporter inhibitors

In a study of 8 post renal transplant patients with creatinine clearance of > 50 mL/min on a stable dose of cyclosporin, 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 historical healthy control population. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13,2mL/min/1,73m2) who was receiving multiple medications including cyclosporin, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. 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 cyclosporin 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 (see section 4.4). Inhibitors of the OATP1B1 (e.g. ciclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and ciclosporin 5,2 mg/kg/day resulted in an 8,7-fold increase in exposure to atorvastatin.

Erythromycin/clarithromycin

In healthy individuals, plasma concentrations of atorvastatin increased by approximately 40 % with co-administration of atorvastatin, as in DYNATOR PLUS, and erythromycin, a known inhibitor of cytochrome P450 3A4 (see section 4.4- Skeletal Muscle).

Combination of protease inhibitors

Plasma concentrations of atorvastatin increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor, telaprevir, compared to that of atorvastatin alone. Therefore, in patients taking the HIV protease inhibitor, tipranavir plus ritonavir, or the hepatitis C protease inhibitor, telaprevir, concomitant use of DYNATOR PLUS should be avoided. Concomitant administration of atorvastatin 10 mg single dose with tipranavir 500 mg twice daily plus ritonavir 200 mg twice daily for seven days, resulted in a 9,4-fold increase in atorvastatin AUC and 8,6-fold increase in atorvastatin C max. Atorvastatin did not result in a change in pharmacokinetics of tipranavir plus ritonavir. Concomitant administration of atorvastatin 20 mg single dose with telaprevir 750 mg every eight hours, for 10 days, resulted in a 7,9-fold increase in atorvastatin AUC and 10,6-fold increase in atorvastatin C max. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing DYNATOR PLUS and the lowest dose necessary should be used. Concomitant administration of atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5,9-fold increase in atorvastatin AUC. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of DYNATOR PLUS should not exceed 10/20 mg and should be used with caution. Concomitant administration of atorvastatin 40 mg once a day for 4 days with saquinavir 400 mg twice daily plus ritonavir 400 mg twice daily for 15 days resulted in a 3,9-fold increase in atorvastatin AUC and 4,3-fold increase in atorvastatin C max. The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. Concomitant administration of atorvastatin 10 mg once a day for 4 days with darunavir 300 mg twice daily plus ritonavir 100 mg twice daily for 9 days resulted in a 3,4-fold increase in atorvastatin AUC and 2,3-fold increase in atorvastatin C max. Concomitant administration of atorvastatin 10 mg once a day for 4 days with fosamprenavir 1 400 mg twice a day for 14 days resulted in a 2,3-fold increase in atorvastatin AUC and 4,0-fold increase in atorvastatin C max. Atorvastatin resulted in a 1,27-fold increase in fosamprenavir. Concomitant administration of atorvastatin 10 mg once a day for 4 days with fosamprenavir 700 mg twice a day plus ritonavir 100 mg twice a day for 14 days resulted in a 2,5-fold increase in atorvastatin AUC and 2,8-fold increase in atorvastatin C max. Atorvastatin did not result in a change in pharmacokinetics of fosamprenavir 700 mg plus ritonavir.

In patients taking nelfinavir, the dose of DYNATOR PLUS should not exceed 10/40 mg daily. Concomitant administration of atorvastatin 10 mg once a day for 28 days with nelfinavir 1 250 mg twice a day for 14 days resulted in a 74 % increase in atorvastatin AUC and 2,2-fold increase in atorvastatin C max. Concomitant administration of atorvastatin 40 mg single dose with boceprevir 800 mg three times a day for 7 days resulted in a 2,3-fold increase in atorvastatin AUC and 2,66-fold increase in atorvastatin C max (see section 4.4 u2013 Skeletal muscle).

Inhibitors of breast cancer resistant Protein (BCRP): Concomitant administration of products that are inhibitors of BCRP (e.g. elbasvir and grazoprevir) may lead to increased plasma concentrations of atorvastatin and an increased risk of myopathy; therefore, a dose adjustment of atorvastatin should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with atorvastatin increases plasma concentrations of atorvastatin 1,9-fold; therefore, the dose of DYNATOR PLUS should not exceed 10/20 mg daily in patients receiving concomitant medications with products containing elbasvir or grazoprevir (see sections 4.2.).

Diltiazem hydrochloride

Co-administration of DYNATOR PLUS, with diltiazem was associated with an increase in AUC of 51 % of atorvastatin (see section 4.3).

Cimetidine

Cimetidine co-administered with DYNATOR PLUS, had no effect on the bioavailability of ezetimibe and the atorvastatin plasma concentrations and LDL-C reduction were not altered.

Itraconazole

Co-administration of atorvastatin 40 mg, single dose and itraconazole 200 mg, once daily, was associated with a 3,3-fold increase in AUC and a 20 % increase in C max.

Grapefruit juice

Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin by 2,5- to 3,3-fold and the combination should be avoided (see section 4.3).

Antipyrine

Because DYNATOR PLUS does not affect the pharmacokinetics of antipyrine interactions with other drugs metabolised via the same cytochrome isoenzymes are not expected.

Colestipol

Plasma concentrations of atorvastatin decreased approximately 25 % when colestipol and atorvastatin were co-administered. However, LDL-C reduction was greater when atorvastatin, as in DYNATOR PLUS, and colestipol were co-administered than when either medicine was given alone.

Digoxin

Co-administration of multiple doses of atorvastatin, as in DYNATOR PLUS, and digoxin increased steadystate plasma digoxin concentrations by approximately 20 %. Patients taking digoxin should be monitored appropriately (see section 4.4).

Azithromycin

Co-administration of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.

Oral contraceptives

Co-administration of atorvastatin and an oral contraceptive increased AUC-values of norethindrone and ethinyl estradiol by approximately 30 % and 20 %, respectively. These increases should be considered when selecting an oral contraceptive for a woman taking DYNATOR PLUS.

Anticoagulants

There have been reports of increased international normalised ratio in patients who had ezetimibe added to warfarin. Most of these patients were also on other medication. Atorvastatin had no clinically significant effect on prothrombin/INR time when administered to patients receiving combined atorvastatin and warfarin therapy for two weeks. If DYNATOR PLUS is added to warfarin or another coumarin anticoagulant, the international normalised ratio (INR) should be appropriately monitored (see section 4.4).

Colchicine

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing DYNATOR PLUS with colchicine.

Amlodipine

Atorvastatin pharmacokinetics were not altered by the co-administration of atorvastatin 80 mg and amlodipine 10 mg at steady state.

Fusidic acid

Although interaction studies with DYNATOR PLUS and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored, and temporary suspension of DYNATOR PLUS treatment may be appropriate.

Other concomitant therapy

In clinical studies, atorvastatin was used concomitantly with antihypertensive medicine and oestrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific medicine have not been conducted.

Women of childbearing potential / Contraception in males and females

DYNATOR PLUS should be administered to women of childbearing age only when such patients are using adequate contraception and have been informed of the potential hazards to the foetus. An interval of one month should be allowed from stopping DYNATOR PLUS treatment to conception in the event of planning a pregnancy.

Pregnancy

DYNATOR PLUS is contraindicated in pregnancy as no clinical data on exposed pregnancies are available (see section 4.3).

Breastfeeding

The use of DYNATOR PLUS is not recommended during lactation, as it is not known whether ezetimibe is excreted into human breast milk (see section 4.3).

Fertility

No fertility studies were conducted.

No studies of the effects on the ability to drive and use of machines have been performed. However, certain side effects such as dizziness that have been reported with DYNATOR PLUS may affect some patients' ability to drive or operate machinery. Individual responses to DYNATOR PLUS may vary (see section 4.8).

a. Tabulated list of adverse effects

Ezetimibe

System Organ Class Frequency Side effects

Infections and Infestations Less frequent Viral infection, pharyngitis, sinusitis, upper respiratory tract infection

Blood and lymphatic system disorders Frequency unknown Thrombocytopenia

Immune system disorders Frequency unknown Hypersensitivity reactions, including anaphylaxis, rash, urticaria, angioedema

Psychiatric disorders Frequency unknown Depression

Nervous system disorders Frequency unknown Paraesthesia

Respiratory, thoracic and mediastinal disorders Less frequent Coughing

Gastrointestinal disorders Frequent Frequency unknown Abdominal pain, diarrhoea Nausea, pancreatitis

Hepatobiliary disorders Frequency unknown Hepatitis, cholelithiasis cholecystitis

Skin and subcutaneous tissue disorders Frequency unknown Erythema multiforme

Musculoskeletal and connective tissue disorders Less frequent Frequency unknown Arthralgia, back pain, myalgia Myopathy, rhabdomyolysis

General disorders and administrative site conditions Frequent Less frequent Headache Fatigue, chest pain, dizziness

Investigations Frequency unknown increased transaminases, increased CPK

Atorvastatin

System Organ Class Frequency Side effects

Infections and infestations Less frequent Infection, flu syndrome, sinusitis, pharyngitis

Blood and lymphatic system disorders Less frequent Thrombocytopenia

Immune system disorders Frequent Allergic reaction (including anaphylaxis)

Metabolism and nutrition disorders Less frequent Hypoglycaemia, hyperglycaemia, anorexia, weight gain

Psychiatric disorders Frequent Frequency unknown Insomnia Cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion)

Nervous system disorders Frequent Less frequent Frequency unknown Hypoesthesia, paraesthesia, dizziness Peripheral neuropathy, amnesia, dysgeusia myasthenia gravis

Eye disorders Frequency unknown ocular myasthenia

Gastrointestinal disorders Frequent Less frequent Nausea, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence Vomiting, pancreatitis

Hepato-biliary disorders Less frequent Hepatitis, cholestatic jaundice

Skin and subcutaneous tissue disorders Frequent Less frequent Pruritus, rash Alopecia, urticaria, bullous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Frequency unknown Myalgia, arthralgia, back pain Myositis, muscle cramps, rhabdomyolysis, myopathy Immune-mediated necrotizing myopathy

Reproductive system and breast disorders Less frequent Impotence

General disorders and administrative site conditions Frequent Less frequent Asthenia, chest pain, headache Malaise, peripheral oedema, fatigue

Injury, poisoning and procedural complications Less frequent Tendon rupture, accidental injury

Ezetimibe/atorvastatin combination

System Organ Class Frequency Side effects

Infections and infestations Less frequent Frequency unknown Influenza, bronchitis, sinusitis Nasopharyngitis, urinary tract infection, infection, pharyngitis

Blood and lymphatic system disorders Frequency unknown Thrombocytopenia

Immune system disorders Frequency unknown Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria

Metabolism and nutrition disorders Less frequent Frequency unknown Hyperkalaemia Decreased appetite, anorexia, Hyperglycaemia, hypoglycaemia

Psychiatric disorders Less frequent Frequency unknown Depression, insomnia, sleep disorder Nightmares

Nervous system disorders Less frequent Frequency unknown Dizziness, dysgeusia, paraesthesia, headache Hypoesthesia, amnesia, peripheral neuropathy

Eye disorders Frequency unknown Vision blurred

Ear and labyrinth disorders Frequency unknown Tinnitus, deafness

Cardiac disorders Less frequent Sinus bradycardia

Vascular disorders Less frequent Frequency unknown Hot flushes Hypertension, haemorrhagic stroke

Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Dyspnoea, coughing Pharyngolaryngeal pain, epistaxis, asthma

Gastrointestinal disorders Frequent Less frequent Frequency unknown Abdominal pain, constipation, diarrhoea, flatulence, nausea Abdominal discomfort, frequent bowel movements, stomach discomfort, upset stomach, abdominal distension, dyspepsia, gastritis Pancreatitis, gastroesophageal reflux disease, eructation, vomiting, dry mouth

Hepato-biliary disorders Frequency unknown Hepatitis, cholelithiasis, cholecystitis, hepatic failure, cholestasis

Skin and subcutaneous tissue disorders Less frequent Frequency unknown Acne, urticaria Pruritus, skin rash, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermis necrosis), alopecia

Musculoskeletal, connective tissue and bone disorders Frequent Less frequent Frequency unknown Myalgia Arthralgia, back pain, muscle fatigue, muscle weakness, pain in extremities, muscle spasms, musculoskeletal stiffness Immune mediated necrotising myopathy, myopathy/rhabdomyolysis which may be fatal, neck pain, joint swelling, musculoskeletal pain, myositis

Reproductive system and breast disorders Frequency unknown Gynaecomastia, erectile dysfunction

General disorders and administrative site conditions Frequent Less frequent Frequency unknown Fatigue Asthenia, oedema, malaise, increased weight Chest pain, pain, peripheral oedema, pyrexia

Investigations Frequent Less frequent Frequency unknown Increased alanine transaminase (ALT), increased aspartate transaminase (AST) Increased alkaline phosphatase, gamma-glutamyltransferase, and hepatic enzyme, abnormal liver function test, increased blood creatine kinase (CK) Positive white blood cells in urine

Management of overdose: In the event of an overdose, symptomatic and supportive measures should be employed. In clinical studies administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. Due to extensive drug binding to plasma proteins, haemodialysis is not expected to significantly enhance atorvastatin clearance.