Coleflux

Hypercholesterolaemia

Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolaemia (HoFH) as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate.

Cardiovascular prevention

Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy.

Posology

The dosage range is 5-80 mg/day of Coleflux given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80 mg dose is only recommended in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks.

Hypercholesterolaemia

The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Coleflux. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Homozygous familial hypercholesterolaemia

Based on the results of a controlled clinical study, the recommended starting dosage is Coleflux 40 mg/day in the evening Coleflux should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

In patients taking lomitapide concomitantly with Coleflux, the dose of Coleflux must not exceed 40 mg/day.

Cardiovascular prevention

The usual dose of Coleflux is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Medicinal product therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above.

Concomitant therapy

Coleflux is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant.

In patients taking Coleflux concomitantly with fibrates, other than gemfibrozil or fenofibrate, the dose of Coleflux should not exceed 10 mg/day. In patients taking amiodarone, amlodipine, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with Coleflux, the dose of Coleflux should not exceed 20 mg/day.

Renal impairment

No modification of dosage should be necessary in patients with moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 ml/ min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously.

Elderly

No dosage adjustment is necessary.

Paediatric population

For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before Coleflux treatment initiation; this diet should be continued during Coleflux treatment.

The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualised according to the recommended goal of therapy as recommended by the paediatric treatment recommendations. Adjustments should be made at intervals of 4 weeks or more.

The experience of Coleflux in pre-pubertal children is limited.

Method of administration

Coleflux is for oral administration. Coleflux can be administered as a single dose in the evening.

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- Active liver disease or unexplained persistent elevations of serum transaminases

- Pregnancy and lactation

- Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone and medicinal products containing cobicistat

- Concomitant administration of gemfibrozil, ciclosporin, or danazol

- In patients with HoFH, concomitant administration of lomitapide with doses > 40 mg Coleflux.

Myopathy/Rhabdomyolysis

Coleflux, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Coleflux, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

In a clinical trial in which patients with a history of myocardial infarction were treated with Coleflux 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0 % compared with 0.02 % for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %..

The risk of myopathy is greater in patients on Coleflux 80 mg compared with other statin-based therapies with similar LDL-C- lowering efficacy.3 and 4.5).

In a clinical trial in which patients at high risk of cardiovascular disease were treated with Coleflux 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05 % for non-Chinese patients (n = 7367) compared with 0.24 % for Chinese patients (n = 5468). While the only Asian population assessed in this clinical trial was Chinese, caution should be used when prescribing Coleflux to Asian patients and the lowest dose necessary should be employed.

Reduced function of transport proteins

Reduced function of hepatic OATP transport proteins can increase the systemic exposure of Coleflux acid and increase the risk of myopathy and rhabdomyolysis. Reduced function can occur as the result of inhibition by interacting medicinal products (e.g. ciclosporin) or in patients who are carriers of the SLCO1B1 c.521T>C genotype.

Patients carrying the SLCO1B1 gene allele (c.521T>C) coding for a less active OATP1B1 protein have an increased systemic exposure of Coleflux acid and increased risk of myopathy. The risk of high dose (80 mg) Coleflux related myopathy is about 1 % in general, without genetic testing. Based on the results of the SEARCH trial, homozygote C allele carriers (also called CC) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygote C allele carriers (CT) is 1.5%. The corresponding risk is 0.3% in patients having the most common genotype (TT). Where available, genotyping for the presence of the C allele should be considered as part of the benefit-risk assessment prior to prescribing 80 mg Coleflux for individual patients and high doses avoided in those found to carry the CC genotype. However, absence of this gene upon genotyping does not exclude that myopathy can still occur.

Creatine Kinase measurement

Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results.

Before the treatment

All patients starting therapy with Coleflux, or whose dose of Coleflux is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations:

- Elderly (age > 65 years)

- Female gender

- Renal impairment

- Uncontrolled hypothyroidism

- Personal or familial history of hereditary muscular disorders

- Previous history of muscular toxicity with a statin or fibrate

- Alcohol abuse.

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started.

Whilst on treatment

If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

There have been very rare reports of an immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment.

If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring.

A higher rate of myopathy has been observed in patients titrated to the 80 mg dose. Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy.

Therapy with Coleflux should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

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The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of Coleflux with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat), as well as gemfibrozil, ciclosporin and danazol. Use of these medicinal products is contraindicated.

The risk of myopathy and rhabdomyolysis is also increased by concomitant use of amiodarone, amlodipine, verapamil, or diltiazem with certain doses of Coleflux. The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins. For patients with HoFH, this risk may be increased by concomitant use of lomitapide with Coleflux.

Consequently, regarding CYP3A4 inhibitors, the use of Coleflux concomitantly with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated. If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater)is unavoidable, therapy with Coleflux must be suspended (and use of an alternative statin considered) during the course of treatment. Moreover, caution should be exercised when combining Coleflux with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem. Concomitant intake of grapefruit juice and Coleflux should be avoided.

The use of Coleflux with gemfibrozil is contraindicated. Due to the increased risk of myopathy and rhabdomyolysis, the dose of Coleflux should not exceed 10 mg daily in patients taking Coleflux with other fibrates, except fenofibrate.. Caution should be used when prescribing fenofibrate with Coleflux, as either agent can cause myopathy when given alone.

Coleflux 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. 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 Coleflux and fusidic acid should only be considered on a case by case basis and under close medical supervision.

The combined use of Coleflux at doses higher than 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. In patients with HoFH, the combined use of Coleflux at doses higher than 40 mg daily with lomitapide must be avoided.

Patients taking other medicinal products labelled as having a moderate inhibitory effect on CYP3A4 concomitantly with Coleflux, particularly higher Coleflux doses, may have an increased risk of myopathy.

When coadministering Coleflux with a moderate inhibitor of CYP3A4 (agents that increase AUC approximately 2- 5 fold), a dose adjustment of Coleflux may be necessary. For certain moderate CYP3A4 inhibitors e.g. diltiazem, a maximum dose of 20 mg Coleflux is recommended.

Coleflux is a substrate of the Breast Cancer Resistant Protein (BCRP) efflux transporter. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of Coleflux and an increased risk of myopathy; therefore, a dose adjustment of Coleflux should be considered depending on the prescribed dose. Co-administration of elbasvir and grazoprevir with Coleflux has not been studied; however, the dose of Coleflux should not exceed 20 mg daily in patients receiving concomitant medicinal products containing elbasvir or grazoprevir .

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone.

In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on Coleflux 40 mg/day with or without ezetimibe 10 mg, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (>1 g/day) of niacin (nicotinic acid). Therefore, physicians contemplating combined therapy with Coleflux and lipid-modifying doses (> 1 g/day) of niacin (nicotinic acid) or products containing 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 when the dose of either medicinal product is increased.

In addition, in this trial, the incidence of myopathy was approximately 0.24 % for Chinese patients on Coleflux 40 mg or ezetimibe/Coleflux 10/40 mg compared with 1.24 % for Chinese patients on Coleflux 40 mg or ezetimibe/Coleflux 10/40 mg coadministered with modified-release nicotinic acid/laropiprant 2000 mg/40 mg. While the only Asian population assessed in this clinical trial was Chinese, because the incidence of myopathy is higher in Chinese than in non-Chinese patients, coadministration of Coleflux with lipid-modifying doses (>1 g/day) of niacin (nicotinic acid) is not recommended in Asian patients.

Acipimox is structurally related to niacin. Although acipimox was not studied, the risk for muscle related toxic effects may be similar to niacin.

Hepatic effects

In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received Coleflux. When Coleflux was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels.

It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, Coleflux should be discontinued. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy (see above Myopathy/Rhabdomyolysis).

There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Coleflux. If serious liver injury with clinical symptoms and /or hyperbilirubinaemia or jaundice occurs during treatment with Coleflux, promptly interrupt therapy. If an alternate etiology is not found, do not restart Coleflux.

The product should be used with caution in patients who consume substantial quantities of alcohol.

As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with Coleflux. These changes appeared soon after initiation of therapy with Coleflux, were often transient, were not accompanied by any symptoms and interruption of treatment was not required.

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 > 30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Interstitial lung disease

Cases of interstitial lung disease have been reported with some statins, including Coleflux, especially with long term therapy. 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.

Paediatric population

Safety and effectiveness of Coleflux in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been evaluated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with Coleflux had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls.. Adolescent females should be counselled on appropriate contraceptive methods while on Coleflux therapy. In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Coleflux has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls.

Excipients

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Coleflux has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences.

The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively. For HPS, only serious adverse events were recorded as well as myalgia increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on Coleflux were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”.

In HPS involving 20,536 patients treated with 40 mg/day of Coleflux (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients treated with Coleflux 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to adverse reactions were comparable (4.8 % in patients treated with Coleflux 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was <0.1 % in patients treated with Coleflux 40 mg. Elevated transaminases (>3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Coleflux 40 mg compared with 0.09 % (n = 9) of patients treated with placebo.

The frequencies of adverse events are ranked according to the following:

Very common (> 1/10), Common (> 1/100 to < 1/10), Uncommon (> 1/1000 to < 1/100), Rare (> 1/10,000 to < 1/1000), Very Rare (< 1/10,000), Not known (cannot be estimated from the available data).

* There have been rare post-marketing reports of cognitive impairment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including Coleflux. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

** In a clinical trial, myopathy occurred commonly in patients treated with Coleflux 80 mg/day compared to patients treated with 20 mg/day (1.0% vs 0.02%, respectively).

*** An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise.

**** Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Coleflux.

***** There have been very rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, during or after treatment with some statins. IMNM is clinically characterized by: persistent proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

The following additional adverse events have been reported with some statins:

- Sleep disturbances, including nightmares

- Sexual dysfunction

- Diabetes mellitus: 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).

Paediatric population

In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with Coleflux was generally similar to that of the group treated with placebo.

The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment.

Reporting of suspected adverse 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 the Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

To date, a few cases of overdose have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted.

Pharmacotherapeutic group: Lipid modifiying agents, plain, HMG-CoA reductase inhibitors, ATC-Code: C10A A01

Mechanism of action

After oral ingestion, Coleflux, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3-hydroxy - 3-methylglutaryl-CoA reductase). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol.

Coleflux has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Coleflux may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Coleflux. In addition, Coleflux moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced.

Clinical efficacy and safety

High risk of coronary heart disease (CHD) or existing coronary heart disease

In the Heart Protection Study (HPS), the effects of therapy with Coleflux were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Coleflux 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33%) had LDL-C levels below 116 mg/dL; 5,063 patients (25%) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42%) had levels greater than 135 mg/dL.

Treatment with Coleflux 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9%] for Coleflux-treated patients versus 1507 [14.7%] for patients given placebo; p = 0.0003), due to an 18% reduction in coronary death rate (587 [5.7%] versus 707 [6.9%]; p = 0.0005; absolute risk reduction of 1.2%). The reduction in non-vascular deaths did not reach statistical significance.

Coleflux also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27% (p < 0.0001). Coleflux reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30% (p < 0.0001) and 16% (p = 0.006), respectively. Coleflux reduced the risk of stroke by 25% (p < 0.0001), attributable to a 30% reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Coleflux reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21% (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion.

In the Scandinavian Coleflux Survival Study (4S), the effect of therapy with Coleflux on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicentre, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Coleflux 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Coleflux reduced the risk of death by 30% (absolute risk reduction of 3.3%). The risk of CHD death was reduced by 42% (absolute risk reduction of 3.5%). Coleflux also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34%. Furthermore Coleflux significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischemic attacks) by 28%. There was no statistically significant difference between groups in non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) evaluated the effect of treatment with Coleflux 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; Coleflux 20 mg (n = 1553; 25.7 %) vs. Coleflux 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Coleflux 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %.

Primary hypercholesterolaemia and combined hyperlipidaemia

In studies comparing the efficacy and safety of Coleflux 10, 20, 40 and 80 mg daily in patients with hypercholesterolaemia, the mean reductions of LDL-C were 30, 38, 41 and 47%, respectively. In studies of patients with combined (mixed) hyperlipidaemia on Coleflux 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33% (placebo: 2%), respectively, and mean increases in HDL-C were 13 and 16% (placebo: 3%), respectively.

Paediatric population

In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (HeFH) were randomized to Coleflux or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level > 189 mg/dL. The dosage of Coleflux (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received Coleflux 40 mg or placebo.

Coleflux significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study.

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Coleflux 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group.

After 24 weeks of Coleflux treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8-week intervals), Coleflux decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of Coleflux on cardiovascular events in children with HeFH are unknown.

The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of Coleflux therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

Coleflux is an inactive lactone, which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow.

The pharmacokinetic properties have been evaluated in adults. Pharmacokinetic data in children and adolescents are not available.

Absorption

In man Coleflux is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of Coleflux was found to be less than 5% of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of Coleflux. Concomitant food intake does not affect the absorption.

The pharmacokinetics of single and multiple doses of Coleflux showed that no accumulation of medicinal product occurred after multiple dosing.

Distribution

The protein binding of Coleflux and its active metabolite is >95%.

Elimination

Coleflux is a substrate of CYP3A4. The major metabolites of Coleflux present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive Coleflux to man, 13% of the radioactivity was excreted in the urine and 60% in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3% of the IV dose was excreted in urine as inhibitors.

Coleflux acid is taken up actively into the hepatocytes by the transporter OATP1B1.

Coleflux is a substrate of the efflux transporter BCRP.

Special populations

SLCO1B1 polymorphism

Carriers of the SLCO1B1 gene c.521T>C allele have lower OATP1B1 activity. The mean exposure (AUC) of the main active metabolite, Coleflux acid is 120% in heterozygote carriers (CT) of the C allele and 221% in homozygote (CC) carriers relative to that of patients who have the most common genotype (TT). The C allele has a frequency of 18% in the European population. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Coleflux acid, which may lead to an increased risk of rhabdomyolysis.

Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, Coleflux produced no foetal malformations, and had no effects on fertility, reproductive function or neonatal development.

Not applicable.

No special requirements for disposal.