TREDAPTIVE^® 1000 mg/20 mg modified-release tablets.

Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.

Excipient

Each modified-release tablet contains 128.4 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

Modified-release tablet.

Capsule-shaped, white to off-white tablet, with “552” debossed on one side.

Tredaptive is indicated for the treatment of dyslipidaemia, particularly in patients with combined mixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low HDL-cholesterol) and in patients with primary hypercholesterolaemia (heterozygous familial and non-familial).

Tredaptive should be used in patients in combination with HMG-CoA reductase inhibitors (statins), when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It can be used as monotherapy only in patients in whom HMG-CoA reductase inhibitors are considered inappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Tredaptive.

Posology

The starting dose is one modified-release tablet (1000 mg nicotinic acid/20 mg laropiprant) once a day. After four weeks, it is recommended that patients be advanced to the maintenance dose of 2000 mg/40 mg taken as two modified-release tablets (1000 mg/20 mg each) once daily. Daily doses greater than 2000 mg/40 mg have not been studied and therefore are not recommended.

If Tredaptive is missed for less than 7 consecutive days, patients can resume therapy at the last administered dose. If Tredaptive is missed for 7 or more consecutive days, therapy should be resumed at the 1000 mg/20 mg dose for 1 week, before advancing to the maintenance dose of 2000 mg/40 mg.

Those patients switching from 2000 mg or more of prolonged-release nicotinic acid can initiate Tredaptive at the 2000 mg/40 mg dose. Patients switching from less than 2000 mg of prolonged-release nicotinic acid should initiate therapy at the starting dose of 1000 mg/20 mg and advance to the 2000 mg/40 mg maintenance dose after four weeks. For patients switching from immediate-release nicotinic acid to Tredaptive, therapy should be initiated at the 1000 mg/20 mg dose and advanced to the 2000 mg/40 mg maintenance dose after four weeks.

Elderly patients

No dose adjustment is required for elderly patients.

Paediatric population

Safety and effectiveness of Tredaptive in paediatric patients have not been established. No data are available.

Patients with hepatic or renal insufficiency

Use of Tredaptive in patients with hepatic or renal insufficiency has not been studied. Like other nicotinic acid medicinal products, Tredaptive is contraindicated in patients with significant or unexplained hepatic dysfunction. It should be used with caution in patients with renal insufficiency, because nicotinic acid and its metabolites are primarily excreted by the kidneys (see sections 4.3, 4.4 and 5.2).

Concomitant therapy

Acetylsalicylic acid provides no additional reduction of flushing beyond that achieved by Tredaptive. Therefore, treatment with acetylsalicylic acid to alleviate flushing symptoms is not necessary (see section 5.1).

Because co-administration of bile acid sequestrants may reduce the bioavailability of acidic medicinal products such as nicotinic acid, it is recommended that Tredaptive be administered > 1 hour before or > 4 hours after administration of a bile acid sequestrant (see section 4.5).

Method of administration

The tablets should be taken whole, with food, in the evening or at bedtime. To preserve the modified-release properties, the tablets must not be split, broken, crushed, or chewed before swallowing. To reduce the possibility of flushing, drinking alcohol or hot drinks or eating spicy foods should be avoided at the time of ingestion of the medicinal product.

• Hypersensitivity to the active substances or to any of the excipients.

• Significant or unexplained hepatic dysfunction.

• Active peptic ulcer disease.

• Arterial bleeding.

When Tredaptive is co-administered with a statin, please refer to the Summary of Product Characteristics for that particular medicinal product.

Hepatic effects

Switching from immediate-release (crystalline) nicotinic acid to Tredaptive has not been studied. However, cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have switched from immediate-release nicotinic acid to long-acting nicotinic acid at equivalent doses. Therefore, patients switching from immediate-release nicotinic acid to Tredaptive should be initiated at the 1000 mg/20 mg dose.

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

Like other lipid-lowering therapies, nicotinic acid medicinal products have been associated with abnormal liver function tests (see section 4.8). Transaminase elevations were reversible upon discontinuation of therapy.

Liver function tests are recommended before initiation, every 6 to 12 weeks for the first year, and periodically (e.g. semi-annually) thereafter. Patients who develop increased transaminase levels should be monitored until the abnormalities have resolved. Should an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of 3 X ULN persist, reduction of dose or withdrawal of Tredaptive is recommended.

Effect on skeletal muscle

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of lipid-altering doses ( 1000 mg/day) of nicotinic acid and HMG-CoA reductase inhibitors (statins) (see section 4.8).

Physicians contemplating combined therapy with statins and Tredaptive 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. Periodic serum creatine kinase (CK) should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.

Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis.

• Age > 70 years

• Renal impairment

• Uncontrolled hypothyroidism

• Personal or familial history of hereditary muscular disorders

• Previous history of muscular toxicity with a statin or fibrate

• Alcohol abuse.

If muscle pain, weakness or cramps occur while a patient is receiving Tredaptive 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.

Race

In an interim analysis of an ongoing clinical outcome study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking Tredaptive and simvastatin 40 mg. Therefore, caution should be used when treating Chinese patients with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin (particularly simvastatin doses of 40 mg or higher). Because the risk of myopathy with statins is dose-related, the use of Tredaptive with simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin.

Renal dysfunction

Because nicotinic acid and its metabolites are excreted through the kidneys, Tredaptive should be used with caution in patients with renal dysfunction.

Effect on glucose

Nicotinic acid medicinal products have been associated with increases of fasting blood glucose levels (see section 4.8). Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycaemic therapy may be necessary.

Acute coronary syndrome

As with other nicotinic acid medicinal products, caution should be used when Tredaptive is used in patients with unstable angina or in the acute phase of an MI, particularly when such patients are also receiving vasoactive medicinal products such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Haematologic effects

As with other nicotinic acid medicinal products, Tredaptive (2000 mg/40 mg) was associated with small reductions in platelet count (see section 4.8). Therefore, patients undergoing surgery should be carefully evaluated.

Effect on uric acid

As with other nicotinic acid medicinal products, Tredaptive (2000 mg/40 mg) was associated with small increases in uric acid levels (see section 4.8). Therefore, Tredaptive should be used with caution in patients with or predisposed to gout.

Hypophosphatemia

As with other nicotinic acid medicinal products, Tredaptive was associated with small decreases in phosphorus levels. Therefore, patients with a risk for hypophosphatemia should be closely followed.

Other information

As with other nicotinic acid medicinal products, patients with a history of jaundice, hepato-biliary disorder or peptic ulcer should be observed closely (see sections 4.2 and 4.3).

Excipient

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

Drinking alcohol or hot drinks or eating spicy foods can enhance the effects of flushing and should therefore be avoided around the time of ingestion of Tredaptive.

Nicotinic acid

Effects of nicotinic acid on other medicinal products

Antihypertensive therapy: Nicotinic acid may potentiate the effects of ganglionic blocking agents and vasoactive medicinal products such as nitrates, calcium channel blockers, and adrenergic receptor blocking agents, resulting in postural hypotension.

HMG-CoA reductase inhibitors: When simvastatin is combined with nicotinic acid, a modest increase in AUC and C_max of simvastatin acid (the active form of simvastatin) was observed, which may be devoid of clinical relevance. The pharmacokinetic interaction of Tredaptive with statins has been studied only with simvastatin (see section 4.4).

Effects of other medicinal products on nicotinic acid

Bile acid sequestrants: Because co-administration of bile acid sequestrants may reduce the bioavailability of acidic medicinal products such as nicotinic acid, it is recommended that Tredaptive be administered > 1 hour before or > 4 hours after administration of a bile acid sequestrant.

Supplements containing nicotinic acid: Vitamins or other nutritional supplements containing ( 50 mg/day) of nicotinic acid (or nicotinamide) have not been studied with Tredaptive. Physicians should consider the nicotinic acid intake from vitamins and nutritional supplements when prescribing Tredaptive.

Medicinal product /laboratory test interactions: In urine glucose tests, nicotinic acid may also give false-positive reactions with cupric sulfate solution (Benedict's reagent).

Laropiprant

Effects of laropiprant on other medicinal products

Midazolam: Multiple doses of laropiprant 40 mg did not affect the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Therefore, laropiprant is not an inducer or inhibitor of CYP3A4. However, the plasma concentration of a metabolite of midazolam, 1'-hydroxymidazolam, was increased approximately 2-fold with multiple doses of laropiprant. Because 1'-hydroxymidazolam is an active metabolite, the sedative effect of midazolam may be increased and caution should be used when laropiprant is co-administered with midazolam.

Other medicinal products: Co-administration of laropiprant 40 mg with midazolam increased the AUC_0- and C_max of 1'-hydroxymidazolam, a midazolam metabolite, by 98 % and 59 %, respectively. 1'-hydroxymidazolam is metabolised predominantly by uridine diphosphate-glucuronosyltransferases (UGT) 2B4 and 2B7. Clinical and in vitro studies support the conclusion that laropiprant is a mild to moderate inhibitor of UGT2B4/UGT2B7. Very few medicinal products are known to be metabolised predominantly by UGT2B4 or UGT2B7. Caution should be used when Tredaptive is co-administered with medicinal products metabolised predominantly by UGT2B4 or UGT2B7, for instance zidovudine.

In interaction studies, laropiprant did not have clinically significant effects on the pharmacokinetics of the following medicinal products: simvastatin, warfarin, oral contraceptives, rosiglitazone and digoxin. Based on these data, laropiprant is not expected to cause interactions with substrates of CYP isozymes 3A4, 2C9, 2C8 and human P-glycoprotein (P-gp). In in vitro studies, laropiprant did not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP2E1-mediated reactions.

Clopidogrel: In a clinical study, there was no meaningful effect of laropiprant on the inhibition of ADP-induced platelet aggregation by clopidogrel, but there was a modest increase in the inhibition of collagen-induced platelet aggregation by clopidogrel. This effect is unlikely to be clinically important as laropiprant did not increase bleeding time when co-administered with clopidogrel throughout the dosing interval.

Acetylsalicylic acid: In a clinical study, concomitant administration of laropiprant with acetylsalicylic acid did not have an effect on collagen-induced platelet aggregation or on bleeding time compared to treatment with acetylsalicylic acid alone (see section 5.1).

Acetylsalicylic acid and clopidogrel: In a clinical study in dyslipidaemic patients receiving both acetylsalicylic acid (81 mg) and clopidogrel (75 mg), laropiprant induced transient (4 hours post-dose) inhibition of platelet function in vivo (as evaluated by bleeding time and platelet aggregation studies), but had little effect across the dosing interval. Patients receiving Tredaptive concomitantly with acetylsalicylic acid and clopidogrel should be closely monitored as recommended in the Summary of Product Characteristics for those medicinal products and should be told that it might take longer than usual to stop bleeding and that they should report any unusual bleeding (site or duration) to their physician.

Effects of other medicinal products on laropiprant

CYP3A4 Inhibitor: Clarithromycin (a potent inhibitor of CYP3A4 and P-gp) did not have a clinically meaningful effect on the pharmacokinetics of laropiprant. Laropiprant is not a substrate of human P-gp, and therefore other inhibitors of CYP3A4 and/or P-gp are also not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.

Pregnancy

Tredaptive

There are no data from the combined use of nicotinic acid and laropiprant in pregnant women. The combination has not been tested in reproductive toxicity studies. The potential risk for humans is unknown. Therefore, Tredaptive should not be used during pregnancy unless clearly necessary.

Nicotinic acid

There are no adequate data from the use of high dose nicotinic acid in pregnant women. Studies in animals have shown foetal developmental toxicity at high doses of nicotinic acid (see section 5.3).

Laropiprant

There are no data from the use of laropiprant in pregnant women. Studies in animals have shown foetal developmental toxicity at high doses of laropiprant (see section 5.3).

Breast-feeding

Tredaptive

No studies in lactating animals have been conducted with Tredaptive. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of Tredaptive to the woman.

Nicotinic acid

Nicotinic acid is excreted in human breast milk.

Laropiprant

It is unknown whether laropiprant is excreted in human breast milk. Animal studies have shown excretion of laropiprant in milk.

Fertility

Animal studies are insufficient with respect to impairment on fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported (see section 4.8).

In clinical trials, over 2500 patients received Tredaptive alone or with an HMG-CoA reductase inhibitor. Adverse reactions have usually been mild and transient.

Flushing

Flushing is the most common adverse reaction of Tredaptive. Flushing is most prominent in the head, neck, and upper torso. In a pool of four active- or placebo-controlled clinical trials (N=4747, n=2548 taking Tredaptive), flushing was reported by the investigator as a possibly, probably, or definitely treatment-related adverse reaction in 12.3 % of patients taking Tredaptive. In these studies, the percentage of patients taking Tredaptive, nicotinic acid (pooled prolonged-release formulations) or pooled placebo/simvastatin who discontinued due to any flushing-related symptom (redness, warmth, itching and tingling) was 7.2 %, 16.6 %, and 0.4 %, respectively. Discontinuations due to other specific adverse reactions among patients taking Tredaptive were infrequent (< 1 %).

Overall adverse reactions with Tredaptive

In addition to flushing, clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to Tredaptive in 1 % of patients treated with Tredaptive alone (n=947) or co-administered with statin (n=1601) and clinically meaningful adverse reactions (< 1 %), for up to one year are listed below.

The frequencies of adverse reactions are ranked according to the following: Very common ( 1/10), Common ( 1/100 to < 1/10), Uncommon ( 1/1000 to < 1/100), Rare ( 1/10000 to < 1/1000), Very rare (< 1/10000).

Hypersensitivity reactions

An apparent hypersensitivity reaction has been reported (< 1 %). This is characterised by multiple symptoms that may include: angio-oedema, pruritus, erythema, paraesthesia, loss of consciousness, vomiting, urticaria, flushing, dyspnoea, nausea, incontinence of urine and stool, cold sweats, shivering, chills, increased blood pressure, lip swelling, burning sensation, drug eruption, arthralgia, leg swelling, and tachycardia.

Investigations

Marked and persistent increases of serum transaminases have been reported infrequently (see section 4.4). In controlled clinical studies, the incidence of clinically important elevations in serum transaminases (ALT and/or AST 3 X ULN, consecutive) was 1.0 % for patients treated with Tredaptive with or without a statin. These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment.

Clinically important elevations of CK ( 10 X ULN) were seen in 0.3 % of the patients treated with Tredaptive with or without a statin (see section 4.4).

Other abnormal laboratory values reported were elevations in LDH, fasting glucose, uric acid, total bilirubin, and amylase, and reductions in phosphorus and platelet counts (see section 4.4).

As with other nicotinic acid medicinal products, elevations in fasting glucose (a median increase of approximately 4 mg/dL), and uric acid (mean change from baseline of +14.7 %), and reductions in platelet counts (a mean change from baseline of -14.0 %) were reported in controlled clinical studies with Tredaptive (2000 mg/40 mg) (see section 4.4). In diabetic patients a median increase in HbA1c of 0.2 % was observed (where modification of hypoglycaemic therapy was allowed).

Post-marketing Experience and Other Clinical Trial Experience

Additional adverse reactions that have been reported in post-marketing use with Tredaptive or other nicotinic acid medicinal products (with or without a statin) at unknown frequency or in clinical trials with Tredaptive (< 1 % of patients ) or other nicotinic acid medicinal products (with or without a statin) include the following:

Infections and infestations: Rhinitis.

Immune system disorders: Anaphylactic shock, angio-oedema, type I hypersensitivity.

Metabolism and nutrition disorders: Impaired glucose tolerance, gout.

Psychiatric disorders: Anxiety, insomnia.

Nervous system disorders: Migraine, syncope.

Eye disorders: Cystoid macular oedema, toxic amblyopia.

Cardiac disorders: Atrial fibrillation and other cardiac arrhythmias, palpitations, tachycardia.

Vascular disorders: Hypotension, orthostatic hypotension.

Respiratory, thoracic, and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Abdominal pain, mouth oedema, eructation, peptic ulcer.

Hepatobiliary disorders: Jaundice.

Skin and subcutaneous tissue disorders: Acanthosis nigricans, dry skin, hyperpigmentation, macular rash, sweating (night or cold sweat), vesicular or vesiculobullous rash.

Musculoskeletal and connective tissue disorders: Muscular weakness, myalgia.

General disorders and administration site conditions: Asthaenia, chills, face oedema, generalised oedema, pain, peripheral oedema.

Tredaptive

In the event of an overdose, it is reasonable to employ the usual symptomatic and supportive measures. Cases of overdose have been reported; the maximum dose of Tredaptive taken was 5000 mg/100 mg. All patients recovered without sequelae. The most commonly reported adverse reactions from the subjects who received this higher dose were consistent with a high dose of nicotinic acid and included: flushing, headache, pruritus, nausea, dizziness, vomiting, diarrhoea, epigastric and abdominal pain/discomfort, and back pain. Laboratory abnormalities included increased amylase and lipase, decreased haematocrit and occult blood in the stool.

Nicotinic acid

For an overdose of nicotinic acid, supportive measures should be employed.

Laropiprant

During controlled clinical trials in healthy subjects, single doses of up to 900 mg laropiprant and multiple doses up to 450 mg once daily for 10 days were generally well tolerated. There is no experience with doses of laropiprant above 900 mg in humans. Prolongation of collagen-induced platelet aggregation was observed in subjects taking multiple doses of 300 mg or greater (see section 5.1).

Pharmacotherapeutic group: nicotinic acid and derivatives, ATC code: C10AD52.

Tredaptive contains nicotinic acid, which at therapeutic doses is a lipid-modifying agent, and laropiprant, a potent, selective antagonist of the prostaglandin D₂ (PGD₂) receptor subtype 1 (DP₁). Nicotinic acid lowers the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B, the major LDL protein), triglycerides (TG), and lipoprotein(a) (Lp(a), a modified LDL particle) and elevates the levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I, the major protein component of HDL). Laropiprant suppresses PGD₂ mediated flushing associated with administration of nicotinic acid. Laropiprant has no effect on lipid levels nor does it interfere with the effects of nicotinic acid on lipids.

Nicotinic acid

Mechanism of action

The mechanisms by which nicotinic acid modifies the plasma lipid profile are not fully understood. Nicotinic acid inhibits release of free fatty acids (FFA) from adipose tissue, which may contribute to the reduced plasma LDL-C, TC, VLDL-C, apo B, TG, and Lp(a), as well as elevated HDL-C, and apo A-I, all of which are associated with lower cardiovascular risk. Additional explanations that do not invoke plasma FFA reduction as the central driver of lipid profile modification include nicotinic acid-mediated inhibition of de novo lipogenesis or esterification of fatty acids into TG in the liver.

Pharmacodynamic effects

Nicotinic acid causes a relative shift in the distribution of LDL subclasses from small, dense (most atherogenic) LDL particles to larger LDL particles. Nicotinic acid also elevates the HDL₂ subfraction to a greater extent than the HDL₃ subfraction, thereby increasing the HDL₂:HDL₃ ratio, which is associated with decreased cardiovascular disease risk. HDL is hypothesised to participate in the transport of cholesterol from tissues back to the liver, to suppress vascular inflammation associated with atherosclerosis, and to have anti-oxidative and anti-thrombotic effects.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma TG levels are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD).

Treatment with nicotinic acid reduces the risk of death and cardiovascular events, and slows progression or promotes regression of atherosclerotic lesions. The Coronary Drug Project, a five year study completed in 1975, showed that nicotinic acid had a statistically significant benefit in decreasing nonfatal, recurrent myocardial infarctions (MI) in men 30 to 64 years old with a history of MI. Though total mortality was similar in the two groups at five years, in a fifteen-year cumulative follow-up there were 11 % fewer deaths in the nicotinic acid group compared to the placebo cohort.

Laropiprant

Mechanism of action

Nicotinic acid-induced flushing is mediated primarily by release of prostaglandin D₂ (PGD₂) in the skin. Genetic and pharmacologic studies in animal models have provided evidence that PGD₂, acting through DP₁, one of the two receptors for PGD₂, plays a key role in nicotinic acid-induced flushing. Laropiprant is a potent and selective antagonist of DP₁. Laropiprant is not expected to inhibit the production of prostaglandins.

Pharmacodynamic effects

Laropiprant has been shown to be effective in reducing flushing symptoms induced by nicotinic acid. The reduction in flushing symptoms (assessed by patient questionnaires) was correlated with a reduction in nicotinic acid-induced vasodilatation (assessed by measurements of skin blood flow). In healthy subjects receiving Tredaptive, pretreatment with acetylsalicylic acid 325 mg had no additional beneficial effects in reducing nicotinic acid-induced flushing symptoms compared to Tredaptive alone (see section 4.8).

Laropiprant also has affinity for the thromboxane A₂ receptor (TP) (although it is substantially less potent at TP as compared to DP₁). TP plays a role in platelet function; however, therapeutic doses of laropiprant had no clinically relevant effect on bleeding time and collagen-induced platelet aggregation (see section 4.5).

Clinical studies

Effect on lipids

Tredaptive was consistently efficacious across all prespecified patient subpopulations defined by race, gender, baseline LDL-C, HDL-C and TG levels, age and diabetes status.

In a multicentre, double-blind, 24-week placebo-controlled study, patients taking Tredaptive (2000 mg/40 mg) with or without a statin, when compared to placebo, had significantly decreased LDL-C (-18.9 % vs. -0.5 %), TG (-21.7 % vs. 3.6 %), LDL-C:HDL-C (-28.9 % vs. 2.3 %), non-HDL-C (-19.0 % vs. 0.8 %), apo B (-16.4 % vs. 2.5 %), TC (-9.2 % vs. -0.6 %), Lp(a) (-17.6 % vs. 1.1 %), and TC:HDL-C (-21.2 % vs. 1.9 %) and also had significantly increased HDL-C (18.8 % vs. -1.2 %), and apo A-I (11.2 % vs. 4.3 %) as measured by percent change from baseline. In general, the between-group treatment effects on all lipid parameters were consistent across all patient subgroups examined. Patients receiving Tredaptive, nicotinic acid (prolonged-released formulation), or placebo were also taking statins (29 % atorvastatin [5-80 mg], 54 % simvastatin [10-80 mg], 17 % other statins [2.5-180 mg] (pravastatin, fluvastatin, rosuvastatin, lovastatin)), of which 9 % were also taking ezetimibe [10 mg]. The effect on lipids was similar whether Tredaptive was given as monotherapy or was added to ongoing statin therapy with or without ezetimibe.

The placebo-adjusted LDL-C, HDL-C and TG responses appeared greater among women compared to men and appeared greater among elderly patients ( 65 years) compared to younger patients (< 65 years).

In a multicentre, double-blind, 12-week factorial study, Tredaptive 1000 mg/20 mg co-administered with simvastatin, when compared with simvastatin alone or Tredaptive 1000 mg/20 mg alone, for 4 weeks, significantly lowered LDL-C (-44.2 %, -37.4 %, -8.2 % respectively), TG (-25.8 %, -15.7 %, -18.7 % respectively), TC (-27.9 %, -25.8 %, -4.9 % respectively) and significantly increased HDL-C (19.2 %, 4.2 %, 12.5 % respectively). Tredaptive (2000 mg/40 mg) co-administered with simvastatin when compared with simvastatin alone or Tredaptive (2000 mg/40 mg) alone for 12 weeks, significantly lowered LDL-C (-47.9 %, -37.0 %, -17.0 % respectively), TG (-33.3 %, -14.7 %, -21.6 % respectively), apo B (-41.0 %, -28.8 %, -17.1 % respectively), and TC (-29.6 %, -24.9 %, -9.1 % respectively), as well as LDL-C:HDL-C (-57.1 %, -39.8 %, -31.2 % respectively), non-HDL-C (-45.8 %, -33.4 %, -18.1 % respectively), and TC:HDL-C (-43.0 %, -28.0 %, -24.9 % respectively), and significantly increased HDL-C (27.5 %, 6.0 %, 23.4 % respectively). Further analysis showed Tredaptive (2000 mg/40 mg) co-administered with simvastatin when compared with simvastatin alone significantly increased apo A-I (8.6 %, 2.3 % respectively) and significantly decreased Lp(a) (-19.8 %, 0.0 % respectively ). Efficacy and safety of Tredaptive in combination with simvastatin > 40 mg were not included in this study.

Flushing

In two large clinical trials measuring patient-reported flushing symptoms, patients taking Tredaptive experienced less flushing than those taking nicotinic acid (prolonged-release formulations). In patients continuing in the first study (24 weeks), the frequency of moderate or greater flushing in patients treated with Tredaptive declined and approached that of patients receiving placebo (see Figure 1), whereas in patients treated with nicotinic acid (prolonged-release formulation) the flushing frequency remained constant (after Week 6).

Flushing efficacy of laropiprant has not been established past 24 weeks.

Figure 1. Average number of days per week with Moderate or greater* flushing symptoms across weeks 1-24

●Tredaptive (1000 mg/20 mg to 2000 mg/40 mg at week 5)

▲Nicotinic acid (prolonged-release 1000 mg to 2000 mg at week 5)

○Placebo

*Includes patients with moderate, severe, or extreme flushing symptoms

^†Dose advancement at Week 5

In the second study (16 weeks) where acetylsalicylic acid was allowed, patients taking Tredaptive experienced significantly fewer days per week with moderate or greater flushing compared to nicotinic acid (prolonged-release formulation taken as a 12-week multi-step 500 mg to 2000 mg titration) (p< 0.001).

The European Medicines Agency has waived the obligation to submit the results of studies with Tredaptive in all subsets of the paediatric population in homozygous familial hypercholesterolaemia and in paediatric patients less than 7 years old in heterozygous familial hypercholesterolaemia.

The European Medicines Agency has deferred the obligation to submit the results of studies with Tredaptive in paediatric patients from 7-18 years old in heterozygous familial hypercholesterolaemia (see section 4.2 for information on paediatric use).

Absorption

Nicotinic acid

Following a 2000 mg dose of nicotinic acid administered orally as two modified-release tablets of nicotinic acid/laropiprant with food, nicotinic acid was absorbed with a median time to peak plasma concentration (T_max) of 4 hours, a mean area under the plasma concentration-time curve (AUC_0-last) of approximately 58.0 μM·hr and a mean peak plasma concentration (C_max) of approximately 20.2 μM. Bioavailability with or without food is at least 72 % based on the recovery of the nicotinic acid dose in the urine. The oral bioavailability of nicotinic acid is not altered when it is taken with a high-fat meal.

Laropiprant

Following a 40 mg dose of laropiprant administered orally as two modified-release tablets of nicotinic acid/laropiprant with food, laropiprant is rapidly absorbed with a median T_max of 1 hour, a mean AUC_0- of approximately 13 μM·hr, and a mean C_max of approximately 1.6 μM. The rate and extent of absorption are not altered with a high-fat meal. The pharmacokinetics of laropiprant are linear, displaying approximately dose-proportional increases in AUC and C_max and no evidence of time-dependent clearance.

The mean absolute bioavailability of laropiprant is approximately 71 % following a 40 mg dose when administered as two modified-release tablets of nicotinic acid/laropiprant after an overnight fast.

Distribution

Nicotinic acid

Nicotinic acid is less than 20 % bound to serum proteins.

Laropiprant

The mean volume of distribution at steady state following a single 40 mg intravenous dose of laropiprant to healthy subjects is approximately 70 litres. Laropiprant is highly bound (> 99 %) to plasma proteins, and its binding is independent of concentration. Laropiprant crosses the placenta in rats and rabbits.

Biotransformation

Nicotinic acid

Nicotinic acid undergoes extensive first-pass metabolism through two pathways that are dose and dose-rate dependent. The first pathway results in the formation of nicotinamide adenine dinucleotide (NAD) and nicotinamide. In humans, nicotinamide is further predominantly metabolised to N-methylnicotinamide (MNA) and to N-methyl-2-pyridone-5-carboxamide (2PY). In the second pathway, glycine is conjugated with nicotinic acid to form nicotinuric acid (NUA). With low doses of nicotinic acid or lower rates of absorption, the first pathway predominates. At higher doses or higher rates of absorption, the NAD pathway is saturable, and an increasing fraction of the oral dose reaches the bloodstream unchanged as nicotinic acid. The glycine conjugation pathway is not saturated across the clinically relevant dose range, based on the dose-proportional increase in the plasma concentrations of NUA from 1000 mg to 2000 mg.

In in vitro studies, nicotinic acid and its metabolites did not inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4-mediated reactions or UGT1A1-mediated 3-glucuronidation of estradiol.

Laropiprant

Laropiprant is metabolised primarily via acyl glucuronidation, with a smaller component of oxidative metabolism, followed by excretion of the glucuronide into faeces (via bile) and urine. Laropiprant and its acyl glucuronide conjugate are the major circulating components in human plasma. In vitro studies have shown that the acyl glucuronide conjugate of laropiprant had at least a 65-fold reduced affinity for DP₁ as compared to laropiprant; thus, it is not expected to contribute to the overall DP₁ activity of laropiprant. The major component (73 % of radioactivity) in faeces is laropiprant (comprising unabsorbed active substance and/or hydrolysed glucuronic acid conjugate). In urine, the primary component is the acyl glucuronide conjugate (64 % of radioactivity) with smaller contributions from the parent compound (5 %). The oxidative metabolism of laropiprant is catalysed primarily by CYP3A4, whereas several UGT isoforms (1A1, 1A3, 1A9 and 2B7) catalysed the acyl glucuronidation.

Elimination

Nicotinic acid

Nicotinic acid is predominantly excreted in the urine as metabolites.

Laropiprant

Laropiprant is eliminated primarily via acyl glucuronidation, followed by excretion of the glucuronide in faeces (via bile) and urine. Following oral administration of ¹⁴C-laropiprant in humans, approximately 68 % of the dose was recovered in faeces (primarily as parent compound, comprising unabsorbed active substance and/or hydrolysed glucuronic acid conjugate) and 22 % was recovered in urine (primarily as metabolites). The majority of the dose was excreted within 96 hours. The apparent terminal half-life (t_1/2) following a 40 mg dose of laropiprant administered as two modified-release tablets of nicotinic acid/laropiprant with food was approximately 17 hours. Pharmacokinetic steady state is achieved within 2 days of once-daily dosing of laropiprant, with minimal accumulation in AUC (approximately 1.3-fold) and C_max (approximately 1.1-fold).

Characteristics in patients

Renal insufficiency

Tredaptive: Use in patients with renal insufficiency has not been studied.

Nicotinic acid: see section 4.4.

Laropiprant: Administration of laropiprant 40 mg in non-dialysed patients with severe renal insufficiency resulted in no clinically meaningful change in the AUC and C_max of laropiprant, compared to healthy control subjects. As no effect was observed in severe renal insufficiency, no effect is expected in patients with mild and moderate renal insufficiency; however, the effects of end-stage renal failure and dialysis on laropiprant pharmacokinetics cannot be inferred from this study.

Hepatic insufficiency

Tredaptive: Use in patients with hepatic insufficiency has not been studied.

Nicotinic acid: see sections 4.3 and 4.4.

Laropiprant: Consistent with the characteristics of a medicinal product that is primarily cleared by metabolism, moderate hepatic disease has a significant impact on laropiprant pharmacokinetics, with an increase in AUC and C_max of approximately 2.8- and 2.2-fold respectively.

Gender

Nicotinic acid: No dose adjustment is necessary based on gender. Gender has no clinically meaningful effect on pharmacokinetics of nicotinic acid (prolonged-release formulation). There is no difference in the oral bioavailability of nicotinic acid in men and women receiving Tredaptive. Women have a modest increase in plasma concentrations of nicotinuric acid and nicotinic acid compared to men.

Laropiprant: No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of laropiprant.

Elderly

Nicotinic acid: There is no pharmacokinetic data in the elderly ( 65 years). Age has no clinically meaningful effect on pharmacokinetics of nicotinic acid (prolonged-release formulation) based on a composite analysis of subjects ages 18-65 years. There is no change in the oral bioavailability of nicotinic acid with age.

Laropiprant: No dose adjustment is necessary in the elderly. Age had no clinically meaningful effect on the pharmacokinetics of laropiprant.

Paediatric

Tredaptive: No studies have been performed in paediatric patients.

Race

Nicotinic acid: No dose adjustment is necessary based on race. Race has no clinically meaningful effect on the pharmacokinetics of nicotinic acid (prolonged-release formulation) based on pharmacokinetic data including subjects of Hispanic, White, Black, and Native American racial groups.

Laropiprant: No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of laropiprant based on a composite analysis of pharmacokinetic data including subjects of White, Hispanic, Black, Asian, and Native American racial groups.

Tredaptive

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to human use.

The safety of concomitant administration of nicotinic acid and laropiprant was assessed in dogs and rats. Toxicologic findings in these co-administration studies were consistent with those seen with nicotinic acid and laropiprant administered individually.

Nicotinic acid

Degeneration in the stomach and hepatocyte vacuolation were observed in rats following 6 months of dosing at systemic exposure values at least 179 times the human exposure based on the AUC of the recommended daily human dose. Retinopathy and/or corneal lesions were observed in dogs following 6 months of dosing at systemic exposure values at least 240 times the human exposure based on the AUC of the recommended daily human dose.

Nicotinic acid was not carcinogenic in mice when administered for the duration of their life. Mice in this study received approximately 9 to 13 times a human nicotinic acid dose of 2000 mg/day as determined on a mg/m² basis. Nicotinic acid showed no mutagenic effects in the in vitro assays.

No nicotinic acid-related adverse effects on fertility were observed in male and female rats up to exposure levels approximately 391 times the human AUC of nicotinic acid based on the AUC of the recommended daily human dose.

Nicotinic acid was not teratogenic in rats and rabbits up to exposure levels approximately 253 and 104 times the human AUC of nicotinic acid at the recommended daily human dose, respectively. In rats, foetotoxic effects (significantly decreased foetal body weights associated with a decrease in the number of ossified sacrocaudal vertebrae and an increased incidence of foetuses with sites of incomplete ossification) were noted in the absence of any signs of maternal toxicity at exposure levels approximately 959 times the human AUC of nicotinic acid at the recommended daily human dose. Similar treatment-related changes were observed in rabbit foetuses but in the presence of maternal toxicity at exposure levels approximately 629 times the human AUC of nicotinic acid at the recommended daily human dose.

Laropiprant

Ketonuria and hepatocellular centrilobular hypertrophy were observed in rats in repeated dose toxicity studies for up to 6 months dosing. The hepatocellular centrilobular hypertrophy was consistent with rodent specific enzyme induction. The no-observed-adverse-effect level (NOAEL) was at least 118 times the human exposure based on the AUC of the recommended daily human dose.

Increases in serum alanine aminotransferase (ALT) levels were observed in all dog studies, at systemic exposure levels at least 14 times the human exposure based on the AUC of the recommended daily human dose. No other effects were observed in dog studies with exposures at least 100 times the human exposure based on the AUC of the recommended daily human dose.

Laropiprant was not carcinogenic in 2 year studies in mice and rats at the highest doses tested, which represents at least 218 to 289 times the human exposure based on the AUC of the recommended daily human dose.

Laropiprant was not mutagenic or clastogenic in a series of genetic toxicology studies.

No adverse effects on fertility were observed in male or female rats given laropiprant prior to mating and throughout mating, at systemic exposure levels at least 289 times the human exposure based on the AUC of the recommended daily human dose.

Laropiprant was not teratogenic in rats or in rabbits at systemic exposure levels at least 153 and 438 times the human exposure based on the AUC of the recommended daily human dose. Reproduction toxicity studies showed slight treatment-related decreases in mean maternal weight gain and foetal body weight, slight increases in pup mortality, and increased incidence of supernumerary rib and incomplete ossification of the sternebra in the foetus were observed in rats at systemic exposure levels at least 513 times the human exposure based on the AUC of the recommended daily human dose.

Hypromellose (E464)

Colloidal anhydrous silica (E551)

Sodium stearyl fumarate

Hydroxypropylcellulose (E463)

Microcrystalline cellulose (E460)

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Not applicable.

PVC/Aclar blisters: 2 years.

Aluminium/Aluminium blisters: 18 months.

Do not store above 30°C. Store in the original package in order to protect from light and moisture.

Opaque PVC/Aclar blister with push-through aluminium lidding containing 14 modified-release tablets. Pack sizes of 14, 28, 56, 84, 98, 168, 196 modified-release tablets, multi-packs containing 196 (2 packs of 98) modified-release tablets and 49 x 1 modified-release tablets in a perforated unit dose blister.

Aluminium/Aluminium blister with push-through lidding containing 7 modified-release tablets. Pack sizes of 14, 28, 56, 168 modified-release tablets and 32 x 1 modified-release tablets in a perforated unit dose blister.

Not all pack sizes may be marketed.

No special requirements.

Merck Sharp & Dohme Ltd.

Hertford Road, Hoddesdon

Hertfordshire EN11 9BU

United Kingdom

EU/1/08/459/002: Blister (Aclar/PVC)-28 tablets

EU/1/08/459/003: Blister (Aclar/PVC)-56 tablets

3 July 2008

25 August 2011

Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

© Merck Sharp & Dohme Limited 2011. All rights reserved.

SPC.TRE.11.UK.3483-WS-0123