Normalip

Hypercholesterolaemia

Normalip is indicated as an adjunct to diet for reduction of elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and triglycerides in adults, adolescents and children aged 10 years or older with primary hypercholesterolaemia including familial hypercholesterolaemia (heterozygous variant) or combined (mixed) hyperlipidaemia (corresponding to Types IIa and IIb of the Fredrickson classification) when response to diet and other nonpharmacological measures is inadequate.

Normalip is also indicated to reduce total-C and LDL-C in adults with homozygous familial hypercholesterolaemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Prevention of cardiovascular disease

Prevention of cardiovascular events in adult patients estimated to have a high risk for a first cardiovascular event , as an adjunct to correction of other risk factors.

Posology

The patient should be placed on a standard cholesterol-lowering diet before receiving Normalip and should continue on this diet during treatment with Normalip.

The dose should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response.

The usual starting dose is 10 mg once a day. Adjustment of dose should be made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.

Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia

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

Heterozygous familial hypercholesterolaemia

Patients should be started with Normalip 10 mg daily. Doses should be individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant may be combined with 40 mg Normalip once daily.

Homozygous familial hypercholesterolaemia

Only limited data are available.

The dose of Normalip in patients with homozygous familial hypercholesterolemia is 10 to 80 mg daily. Normalip should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) in these patients or if such treatments are unavailable.

Prevention of cardiovascular disease

In the primary prevention trials the dose was 10 mg/day. Higher doses may be necessary in order to attain (LDL-) cholesterol levels according to current guidelines.

Renal impairment

No adjustment of dose is required.

Hepatic impairment

Normalip should be used with caution in patients with hepatic impairment. Normalip is contraindicated in patients with active liver disease.

Use in the elderly

Efficacy and safety in patients older than 70 using recommended doses are similar to those seen in the general population.

Paediatric use

Hypercholesterolaemia:

Paediatric use should only be carried out by physicians experienced in the treatment of paediatric hyperlipidaemia and patients should be re-evaluated on a regular basis to assess progress.

For patients aged 10 years and above, the recommended starting dose of Normalip is 10 mg per day with titration up to 20 mg per day. Titration should be conducted according to the individual response and tolerability in paediatric patients. Safety information for paediatric patients treated with doses above 20 mg, corresponding to about 0.5 mg/kg, is limited.

There is limited experience in children between 6-10 years of age. Normalip is not indicated in the treatment of patients below the age of 10 years.

Other pharmaceutical forms/strengths may be more appropriate for this population.

Method of administration

Normalip is for oral administration. Each daily dose of Normalip is given all at once and may be given at any time of day with or without food.

Normalip is contraindicated in patients:

− With hypersensitivity to the active substance or to any of the excipients of this medicinal product.

− With active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal.

− During pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures.

Liver effects

Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. Patients who develop increased transaminase levels should be monitored until the abnormality(ies) resolve. Should an increase in transaminases of greater than 3 times the upper limit of normal (ULN) persist, reduction of dose or withdrawal of Normalip is recommended.

Normalip should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease.

Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)

In a post-hoc analysis of stroke subtypes in patients without coronary heart disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there was a higher incidence of hemorrhagic stroke in patients initiated on Normalip 80 mg compared to placebo. The increased risk was particularly noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry. For patients with prior hemorrhagic stroke or lacunar infarct, the balance of risks and benefits of Normalip 80 mg is uncertain, and the potential risk of hemorrhagic stroke should be carefully considered before initiating treatment .

Skeletal muscle effects

Normalip, like other HMG-CoA reductase inhibitors, may in rare occasions affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, a potentially life-threatening condition characterised by markedly elevated creatine kinase (CK) levels (> 10 times ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.

Before the treatment

Normalip should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. A CK level should be measured before starting statin treatment in the following situations:

− Renal impairment

− Hypothyroidism

− Personal or familial history of hereditary muscular disorders

− Previous history of muscular toxicity with a statin or fibrate

− Previous history of liver disease and/or where substantial quantities of alcohol are consumed

− In elderly (age > 70 years), the necessity of such measurement should be considered, according to the presence of other predisposing factors for rhabdomyolysis

− Situations where an increase in plasma levels may occur, such as interactions and special populations including genetic subpopulations

In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.

If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment should not be started.

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 times ULN), levels should be remeasured within 5 to 7 days later to confirm the results.

Whilst on treatment

− Patients must be asked to promptly report muscle pain, cramps, or weakness especially if accompanied by malaise or fever.

− If such symptoms occur whilst a patient is receiving treatment with Normalip, their CK levels should be measured. If these levels are found to be significantly elevated (> 5 times ULN), treatment should be stopped.

− If muscular symptoms are severe and cause daily discomfort, even if the CK levels are elevated to ≤ 5 x ULN, treatment discontinuation should be considered.

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

− Normalip must be discontinued if clinically significant elevation of CK levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.

Concomitant treatment with other medicinal products

Risk of rhabdomyolysis is increased when Normalip is administered concomitantly with certain medicinal products that may increase the plasma concentration of Normalip such as potent inhibitors of CYP3A4 or transport proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc). The risk of myopathy may also be increased with the concomitant use of gemfibrozil and other fibric acid derivates, erythromycin, niacin and ezetimibe. If possible, alternative (non-interacting) therapies should be considered instead of these medicinal products.

In cases where co-administration of these medicinal products with Normalip is necessary, the benefit and the risk of concurrent treatment should be carefully considered. When patients are receiving medicinal products that increase the plasma concentration of Normalip, a lower maximum dose of Normalip is recommended. In addition, in the case of potent CYP3A4 inhibitors, a lower starting dose of Normalip should be considered and appropriate clinical monitoring of these patients is recommended.

The concurrent use of Normalip and fusidic acid is not recommended, therefore, temporary suspension of Normalip may be considered during fusidic acid therapy.

Interstitial lung disease

Exceptional cases of interstitial lung disease have been reported with some statins, 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 use

Developmental safety in the paediatric population has not been established.

Diabetes Mellitus

Some evidence suggests that statins as a class raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI>30kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Excipients

Normalip contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Normalip has negligible influence on the ability to drive and use machines.

In the Normalip placebo-controlled clinical trial database of 16,066 (8755 Normalip vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2% of patients on Normalip discontinued due to adverse reactions compared to 4.0% of the patients on placebo.

Based on data from clinical studies and extensive post-marketing experience, the following table presents the adverse reaction profile for Normalip.

Estimated frequencies of reactions are ranked according to the following convention:

common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000).

Infections and infestations:

Common: nasopharyngitis.

Blood and lymphatic system disorders

Rare: thrombocytopenia.

Immune system disorders

Common: allergic reactions.

Very rare: anaphylaxis.

Metabolism and nutrition disorders

Common: hyperglycaemia.

Uncommon: hypoglycaemia, weight gain, anorexia.

Psychiatric disorders

Uncommon: nightmare, insomnia.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.

Rare: peripheral neuropathy.

Eye disorders

Uncommon: vision blurred.

Rare: visual disturbance.

Ear and labyrinth disorders

Uncommon: tinnitus

Very rare: hearing loss.

Respiratory, thoracic and mediastinal disorders:

Common: pharyngolaryngeal pain, epistaxis.

Gastrointestinal disorders

Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.

Uncommon: vomiting, abdominal pain upper and lower, eructation, pancreatitis.

Hepatobiliary disorders

Uncommon: hepatitis.

Rare: cholestasis.

Very rare: hepatic failure.

Skin and subcutaneous tissue disorders

Uncommon: urticaria, skin rash, pruritus, alopecia.

Rare: angioneurotic oedema, dermatitis bullous including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, back pain.

Uncommon: neck pain, muscle fatigue.

Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes complicated by rupture.

Reproductive system and breast disorders

Very rare: gynecomastia.

General disorders and administration site conditions

Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.

Investigations

Common: liver function test abnormal, blood creatine kinase increased.

Uncommon: white blood cells urine positive.

As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving Normalip. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (> 3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on Normalip. These elevations were dose related and were reversible in all patients.

Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on Normalip, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% Normalip-treated patients.

Class Effects

− Sexual dysfunction.

− Depression.

− Exceptional cases of interstitial lung disease, especially with long-term therapy

− 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

The clinical safety database includes safety data for 249 paediatric patients who received Normalip, among which 7 patients were < 6 years old, 14 patients were in the age range of 6 to 9, and 228 patients were in the age range of 10 to 17.

Nervous system disorders

Common: headache.

Gastrointestinal disorders

Common: abdominal pain.

Investigations

Common: alanine aminotransferase increased, blood creatine phosphokinase increased.

Based on the data available, frequency, type and severity of adverse reactions in children are expected to be the same as in adults. There is currently limited experience with respect to long-term safety in the paediatric population.

Specific treatment is not available for Normalip overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive Normalip binding to plasma proteins, haemodialysis is not expected to significantly enhance Normalip clearance.

Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase inhibitors, ATC code: C10AA05

Normalip is a selective, competitive inhibitor of HMG-CoA reductase, the rate- limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl- coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through the receptor with high affinity to LDL (LDL receptor).

Normalip lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.

Normalip reduces LDL production and the number of LDL particles. Normalip produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Normalip is effective in reducing LDL-C in patients with homozygous familial hypercholesterolaemia, a population that has not usually responded to lipid-lowering medicinal products.

Normalip has been shown to reduce concentrations of total-C (30% - 46%), LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% - 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a dose response study. These results are consistent in patients with heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, and mixed hyperlipidaemia, including patients with noninsulin-dependent diabetes mellitus.

Reductions in total-C, LDL-C, and apolipoprotein B have been proven to reduce risk for cardiovascular events and cardiovascular mortality.

Homozygous familial hypercholesterolaemia

In a multicenter 8 week open-label compassionate-use study with an optional extension phase of variable length, 335 patients were enrolled, 89 of which were identified as homozygous familial hypercholesterolaemia patients. From these 89 patients, the mean percent reduction in LDL-C was approximately 20%. Normalip was administered at doses up to 80 mg/day.

Atherosclerosis

In the Reversing Atherosclerosis with Aggressive Lipid-Lowering Study (REVERSAL), the effect of intensive lipid lowering with Normalip 80 mg and standard degree of lipid lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease. In this randomised, double- blind, multicenter, controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the Normalip group (n=253), there was no progression of atherosclerosis.

The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the Normalip group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin the effects of Normalip were statistically significant (p=0.02). The effect of intensive lipid lowering on cardiovascular endpoints (e. g. need for revascularisation, non fatal myocardial infarction, coronary death) was not investigated in this study.

In the Normalip group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8 (78.9 mg/dl ± 30) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/l ± 0.7 (110 mg/dl ± 26) from baseline 3.89 mmol/l ± 0.7 (150 mg/dl ± 26) (p<0.0001). Normalip also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and mean apolipoprotein B by 39.1% (pravastatin: - 22.0%, p<0.0001). Normalip increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the Normalip group compared to a 5.2% reduction in the pravastatin group (p<0.0001).

Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.

The safety and tolerability profiles of the two treatment groups were comparable.

The effect of intensive lipid lowering on major cardiovascular endpoints was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.

Acute coronary syndrome

In the MIRACL study, Normalip 80 mg has been evaluated in 3,086 patients (Normalip n=1,538; placebo n=1,548) with an acute coronary syndrome (non Q-wave MI or unstable angina).

Prevention of cardiovascular disease

The effect of Normalip on fatal and non-fatal coronary heart disease was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA). Patients were hypertensive, 40- 79 years of age, with no previous myocardial infarction or treatment for angina, and with TC levels ≤ 6.5 mmol/l (251 mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors: male gender, age > 55 years, smoking, diabetes, history of CHD in a first-degree relative, TC:HDL-C > 6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific ECG abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a first cardiovascular event.

Patients were treated with anti-hypertensive therapy (either amlodipine or atenolol- based regimen) and either Normalip 10 mg daily (n=5,168) or placebo (n=5,137).

The absolute and relative risk reduction effect of Normalip was as follows:

¹ Based on difference in crude events rates occurring over a median follow-up of 3.3 years.

CHD = coronary heart disease; MI = myocardial infarction.

Total mortality and cardiovascular mortality were not significantly reduced (185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of Normalip was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs. 30 and 17 vs. 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus non-fatal MI) was significantly reduced by Normalip in patients treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).

The effect of Normalip on fatal and non-fatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the Collaborative Normalip Diabetes Study (CARDS) in patients with type 2 diabetes, 40-75 years of age, without prior history of cardiovascular disease, and with LDL-C ≤ 4.14 mmol/l (160 mg/dl) and TG ≤ 6.78 mmol/l (600 mg/dl). All patients had at least 1 of the following risk factors: hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.

Patients were treated with either Normalip 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.

The absolute and relative risk reduction effect of Normalip was as follows:

¹ Based on difference in crude events rates occurring over a median follow-up of 3.9 years.

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; CHD = coronary heart disease; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.

There was no evidence of a difference in the treatment effect by patient's gender, age, or baseline LDL-C level. A favourable trend was observed regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the Normalip group, p=0.0592).

Recurrent stroke

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, the effect of Normalip 80 mg daily or placebo on stroke was evaluated in 4731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of coronary heart disease (CHD). Patients were 60% male, 21- 92 years of age (average age 63 years), and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with Normalip and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.

Normalip 80 mg reduced the risk of the primary endpoint of fatal or non-fatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2365) for Normalip versus 8.9% (211/2366) for placebo.

In a post-hoc analysis, Normalip 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02) compared to placebo.

− The risk of hemorrhagic stroke was increased in patients who entered the study with prior hemorrhagic stroke (7/45 for Normalip versus 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was similar between groups (3/45 for Normalip versus 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).

− The risk of hemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for Normalip versus 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for Normalip versus 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive Normalip 80 mg/day.

All cause mortality was 15.6% (7/45) for Normalip versus 10.4% (5/48) in the subgroup of patients with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for Normalip versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.

Paediatric Population

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 6-17 years old

An 8-week, open-label study to evaluate pharmacokinetics, pharmacodynamics, and safety and tolerability of Normalip was conducted in children and adolescents with genetically confirmed heterozygous familial hypercholesterolemia and baseline LDL-C > 4 mmol/L. A total of 39 children and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15 children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24 children, 10 to 17 years of age and at Tanner Stage > 2.

The initial dose of Normalip was 5 mg daily of a chewable tablet in Cohort A and 10 mg daily of a tablet formulation in Cohort B. The Normalip dose was permitted to be doubled if a subject had not attained target LDL-C of < 3.35 mmol/L at Week 4 and if Normalip was well tolerated.

Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2 among all subjects. For subjects whose dose was doubled, additional decreases were observed as early as 2 weeks, at the first assessment, after dose escalation. The mean percent decreases in lipid parameters were similar for both cohorts, regardless of whether subjects remained at their initial dose or doubled their initial dose. At Week 8, on average, the percent change from baseline in LDL-C and TC was approximately 40% and 30%, respectively, over the range of exposures.

Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 10-17 years old

In a double-blind, placebo controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (FH) or severe hypercholesterolaemia were randomised to Normalip (n=140) or placebo (n=47) for 26 weeks and then all received Normalip for 26 weeks.).

Absorption

Normalip is rapidly absorbed after oral administration; maximum plasma concentrations (C_max) occur within 1 to 2 hours. Extent of absorption increases in proportion to Normalip dose. After oral administration, Normalip film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of Normalip is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism

Distribution

Mean volume of distribution of Normalip is approximately 381 l. Normalip is > 98% bound to plasma proteins.

Biotransformation

Normalip is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Normalip. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

Excretion

Normalip is eliminated primarily in bile following hepatic and/or extrahepatic metabolism. However, Normalip does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life of Normalip in humans is approximately 14 hours. The half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of active metabolites.

Special populations

Elderly: Plasma concentrations of Normalip and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.

Paediatric: In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage > 2 (N=24) paediatric patients (ages 6-17 years) with heterozygous familial hypercholesterolemia and baseline LDL-C > 4 mmol/L were treated with 5 or 10 mg of chewable or 10 or 20 mg of film-coated Normalip tablets once daily, respectively. Body weight was the only significant covariate in Normalip population PK model.

Apparent oral clearance of Normalip in paediatric subjects appeared similar to adults when scaled allometrically by body weight. Consistent decreases in LDL-C and TC were observed over the range of Normalip and o-hydroxyNormalip exposures.

Gender: Concentrations of Normalip and its active metabolites in women differ from those in men (Women: approx. 20% higher for C_max and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.

Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of Normalip and its active metabolites.

Hepatic insufficiency: Plasma concentrations of Normalip and its active metabolites are markedly increased (approx. 16-fold in C_max and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Child-Pugh B).

SLCO1B1 polymorphism: Hepatic uptake of all HMG-CoA reductase inhibitors including Normalip, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of Normalip, which may lead to an increased risk of rhabdomyolysis. Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher Normalip exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of Normalip is also possible in these patients. Possible consequences for the efficacy are unknown.

Normalip was negative for mutagenic and clastogenic potential in a battery of 4 in vitro tests and 1 in vivo assay. Normalip was not found to be carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC_0-24h reached in humans at the highest recommended dose) showed hepatocellular adenomas in males and hepatocellular carcinomas in females.

There is evidence from animal experimental studies that HMG-CoA reductase inhibitors may affect the development of embryos or fetuses. In rats, rabbits and dogs Normalip had no effect on fertility and was not teratogenic, however, at maternally toxic doses fetal toxicity was observed in rats and rabbits. The development of the rat offspring was delayed and post-natal survival reduced during exposure of the dams to high doses of Normalip. In rats, there is evidence of placental transfer. In rats, plasma concentrations of Normalip are similar to those in milk. It is not known whether Normalip or its metabolites are excreted in human milk.

Not applicable.

No special requirements