PELZONT 1000mg / 20mg modified release tablets medication leaflet

Pelzont 1,000 mg/20 mg modified-release tablets.

Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant.

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

For the full list of excipients, see section 6.1.

Modified-release tablet.

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

Pelzont is indicated for the treatment of dyslipidaemia, particularly in adult patients with combinedmixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low

HDL-cholesterol) and in adult patients with primary hypercholesterolaemia (heterozygous familial andnon-familial).

Pelzont should be used in patients in combination with HMG-CoA reductase inhibitors (statins), whenthe cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It can beused as monotherapy only in patients in whom HMG-CoA reductase inhibitors are consideredinappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weightreduction) should be continued during therapy with Pelzont.

The starting dose is one modified-release tablet (1,000 mg nicotinic acid/20 mg laropiprant) once aday. After four weeks, it is recommended that patients be advanced to the maintenance dose of2,000 mg/40 mg taken as two modified-release tablets (1,000 mg/20 mg each) once daily. Daily dosesgreater than 2,000 mg/40 mg have not been studied and therefore are not recommended.

If Pelzont is missed for less than 7 consecutive days, patients can resume therapy at the lastadministered dose. If Pelzont is missed for 7 or more consecutive days, therapy should be resumed atthe 1,000 mg/20 mg dose for 1 week, before advancing to the maintenance dose of 2,000 mg/40 mg.

Those patients switching from 2,000 mg or more of prolonged-release nicotinic acid can initiate

Pelzont at the 2,000 mg/40 mg dose. Patients switching from less than 2,000 mg of prolonged-releasenicotinic acid should initiate therapy at the starting dose of 1,000 mg/20 mg and advance to the2,000 mg/40 mg maintenance dose after four weeks. For patients switching from immediate-releasenicotinic acid to Pelzont, therapy should be initiated at the 1,000 mg/20 mg dose and advanced to the2,000 mg/40 mg maintenance dose after four weeks.

No dose adjustment is required for elderly patients.

Safety and effectiveness of Pelzont in paediatric patients under the age of 18 years have not beenestablished. No data are available.

Patients with hepatic or renal insufficiency

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

Concomitant therapy

Acetylsalicylic acid provides no additional reduction of flushing beyond that achieved by Pelzont.

Therefore, treatment with acetylsalicylic acid to alleviate flushing symptoms is not necessary (seesection 5.1).

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

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

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

* Significant or unexplained hepatic dysfunction.

* Active peptic ulcer disease.

* Arterial bleeding.

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

Switching from immediate-release (crystalline) nicotinic acid to Pelzont has not been studied.

However, cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred inpatients who have switched from immediate-release nicotinic acid to long-acting nicotinic acid atequivalent doses. Therefore, patients switching from immediate-release nicotinic acid to Pelzontshould be initiated at the 1,000 mg/20 mg dose.

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

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

Liver function tests are recommended before initiation, every 6 to 12 weeks for the first year, andperiodically (e.g. semi-annually) thereafter. Patients who develop increased transaminase levels shouldbe 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

Pelzont is recommended.

Effect on skeletal muscle

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration oflipid-altering doses (≥ 1,000 mg/day) of nicotinic acid and HMG-CoA reductase inhibitors (statins)(see section 4.8).

Physicians contemplating combined therapy with statins and Pelzont should carefully weigh thepotential benefits and risks and should carefully monitor patients for any signs and symptoms ofmuscle pain, tenderness, or weakness, particularly during the initial months of therapy and when thedose of either medicinal product is increased. Periodic serum creatine kinase (CK) should beconsidered in such situations, but there is no assurance that such monitoring will prevent theoccurrence 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 Pelzont with a statin, their CKlevels should be measured. If these levels are found, in the absence of strenuous exercise, to besignificantly elevated (> 5 x ULN), treatment should be stopped.

In an interim analysis of an ongoing clinical outcome study, an independent safety monitoringcommittee identified a higher than expected incidence of myopathy in Chinese patients taking Pelzontand simvastatin 40 mg. Therefore, caution should be used when treating Chinese patients with Pelzontco-administered with simvastatin or ezetimibe/simvastatin (particularly simvastatin doses of 40 mg orhigher). Because the risk of myopathy with statins is dose-related, the use of Pelzont with simvastatin80 mg or ezetimibe/simvastatin 10/80 mg is not recommended in Chinese patients. It is unknownwhether there is an increased risk of myopathy in other Asian patients treated with Pelzontco-administered with simvastatin or ezetimibe/simvastatin.

Because nicotinic acid and its metabolites are excreted through the kidneys, Pelzont should be usedwith 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 ofdiet and/or hypoglycaemic therapy may be necessary.

Acute coronary syndrome

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

Haematologic effects

As with other nicotinic acid medicinal products, Pelzont (2,000 mg/40 mg) was associated with smallreductions in platelet count (see section 4.8). Therefore, patients undergoing surgery should becarefully evaluated.

Effect on uric acid

As with other nicotinic acid medicinal products, Pelzont (2,000 mg/40 mg) was associated with smallincreases in uric acid levels (see section 4.8). Therefore, Pelzont should be used with caution inpatients with or predisposed to gout.

Hypophosphatemia

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

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

Excipient

Pelzont contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapplactase 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 shouldtherefore be avoided around the time of ingestion of Pelzont.

Nicotinic acid

Effects of nicotinic acid on other medicinal products

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

HMG-CoA reductase inhibitors: When simvastatin is combined with nicotinic acid, a modest increasein AUC and Cmax of simvastatin acid (the active form of simvastatin) was observed, which may bedevoid of clinical relevance. The pharmacokinetic interaction of Pelzont with statins has been studiedonly 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 thebioavailability of acidic medicinal products such as nicotinic acid, it is recommended that Pelzont beadministered > 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 Pelzont. Physiciansshould consider the nicotinic acid intake from vitamins and nutritional supplements when prescribing

Pelzont.

Medicinal product /laboratory test interactions: In urine glucose tests, nicotinic acid may also givefalse-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, asensitive CYP3A4 substrate. Therefore, laropiprant is not an inducer or inhibitor of CYP3A4.

However, the plasma concentration of a metabolite of midazolam, 1'-hydroxymidazolam, wasincreased approximately 2-fold with multiple doses of laropiprant. Because 1'-hydroxymidazolam isan active metabolite, the sedative effect of midazolam may be increased and caution should be usedwhen laropiprant is co-administered with midazolam.

Other medicinal products: Co-administration of laropiprant 40 mg with midazolam increased the

AUC0-∞ and Cmax 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 tomoderate inhibitor of UGT2B4/UGT2B7. Very few medicinal products are known to be metabolisedpredominantly by UGT2B4 or UGT2B7. Caution should be used when Pelzont is co-administeredwith medicinal products metabolised predominantly by UGT2B4 or UGT2B7, for instance zidovudine.

In interaction studies, laropiprant did not have clinically significant effects on the pharmacokinetics ofthe 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 isozymes3A4, 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 ofcollagen-induced platelet aggregation by clopidogrel. This effect is unlikely to be clinically importantas laropiprant did not increase bleeding time when co-administered with clopidogrel throughout thedosing interval.

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

Acetylsalicylic acid and clopidogrel: In a clinical study in dyslipidaemic patients receiving bothacetylsalicylic 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 Pelzont concomitantly withacetylsalicylic 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 thanusual to stop bleeding and that they should report any unusual bleeding (site or duration) to theirphysician.

Effects of other medicinal products on laropiprant

CYP3A4 Inhibitor: Clarithromycin (a potent inhibitor of CYP3A4 and P-gp) did not have a clinicallymeaningful 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 clinicallymeaningful impact on the pharmacokinetics of laropiprant.

Pelzont

There are no data from the combined use of nicotinic acid and laropiprant in pregnant women. Thecombination has not been tested in reproductive toxicity studies. The potential risk for humans isunknown. Therefore, Pelzont 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 inanimals 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 shownfoetal developmental toxicity at high doses of laropiprant (see section 5.3).

Pelzont

No studies in lactating animals have been conducted with Pelzont. A decision on whether tocontinue/discontinue breast-feeding or to continue/discontinue therapy should be made taking intoaccount the benefit of breast-feeding to the child and the benefit of Pelzont 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 shownexcretion of laropiprant in milk.

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

When driving vehicles or operating machines, it should be taken into account that dizziness has beenreported (see section 4.8).

In clinical trials, over 5,700 patients received Pelzont alone or with an HMG-CoA reductase inhibitor.

Flushing is the most common adverse reaction of Pelzont. Flushing is most prominent in the head,neck, and upper torso. In a pool of four active- or placebo-controlled clinical trials (N=4,747, n=2,548taking Pelzont), flushing was reported in 12.3 % of patients taking Pelzont. In these studies, thepercentage of patients taking Pelzont, nicotinic acid (pooled prolonged-release formulations) or pooledplacebo/simvastatin who discontinued due to any flushing-related symptom (redness, warmth, itchingand tingling) was 7.2 %, 16.6 %, and 0.4 %, respectively.

The following adverse reactions have been reported during clinical studies and/or post-marketing usewith Pelzont (with or without a statin).

The frequencies of adverse reactions are ranked according to the following: Very common (≥ 1/10),

Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Veryrare (< 1/10,000), Not known (cannot be estimated from the available data).

System organ class Adverse reaction

Infections and infestations Rare: rhinitis

Immune system disorders Uncommon: hypersensitivity reaction (see below)

Rare: angio-oedema; type I hypersensitivity

Not known: anaphylactic shock

Metabolism and nutrition Uncommon: goutdisorders Rare: impaired glucose tolerance

Psychiatric disorders Uncommon: insomnia

Rare: anxiety

Nervous system disorders Common: headache; paraesthesia

Uncommon: dizziness

Rare: migraine; syncope

Cardiac disorders Uncommon: palpitations

Rare: atrial fibrillation and other cardiac arrhythmias; tachycardia

System organ class Adverse reaction

Vascular disorders Very common: flushing

Uncommon: hypotension

Rare: orthostatic hypotension

Respiratory, thoracic, and Uncommon: dyspnoeamediastinal disorders

Gastrointestinal disorders Common: abdominal pain; diarrhoea; dyspepsia; nausea; vomiting

Rare: mouth oedema; eructation; peptic ulcer

Hepatobiliary disorders Not known: jaundice

Skin and subcutaneous tissue Common: erythema; pruritus; rash; urticariadisorders Uncommon: dry skin; macular rash

Rare: acanthosis nigricans; hyperpigmentation; sweating (night orcold sweat)

Not known: vesicular or vesiculobullous rash

Musculoskeletal and connective Uncommon: myalgiatissue disorders Rare: muscular weakness

General disorders and Common: feeling hotadministration site conditions Uncommon: chills; pain; peripheral oedema

Rare: asthaenia; face oedema; generalised oedema

Investigations Common: elevations in ALT and/or AST (consecutive,≥ 3 X ULN), fasting glucose (see below)

Uncommon: elevations in CK (≥ 10 X ULN), LDH, uric acid (seebelow)

Rare: elevations in total bilirubin, amylase; reductions inphosphorus and platelet counts (see below)

An apparent hypersensitivity reaction has been reported (< 1 %). This is characterised by multiplesymptoms 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.

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

Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.3 % of the patients treated with

Pelzont with or without a statin (see section 4.4).

Other abnormal laboratory values reported were elevations in LDH, fasting glucose, uric acid, totalbilirubin, 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 ofapproximately 4 mg/dL), and uric acid (mean change from baseline of +14.7 %), and reductions inplatelet counts (a mean change from baseline of -14.0 %) were reported in controlled clinical studieswith Pelzont (2,000 mg/40 mg) (see section 4.4). In diabetic patients a median increase in HbA1c of0.2 % was observed (where modification of hypoglycaemic therapy was allowed).

Additional adverse reactions reported with other nicotinic acid medical products

Additional adverse reactions that have been reported with other nicotinic acid medicinal products(with or without a statin) in post-marketing use or in clinical trials include the following:

Eye disorders: Cystoid macular oedema, toxic amblyopia.

Pelzont

In the event of an overdose, it is reasonable to employ the usual symptomatic and supportivemeasures. Cases of overdose have been reported; the maximum dose of Pelzont taken was5,000 mg/100 mg. All patients recovered without sequelae. The most commonly reported adversereactions from the subjects who received this higher dose were consistent with a high dose of nicotinicacid and included: flushing, headache, pruritus, nausea, dizziness, vomiting, diarrhoea, epigastric andabdominal pain/discomfort, and back pain. Laboratory abnormalities included increased amylase andlipase, 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 andmultiple doses up to 450 mg once daily for 10 days were generally well tolerated. There is noexperience with doses of laropiprant above 900 mg in humans. Prolongation of collagen-inducedplatelet aggregation was observed in subjects taking multiple doses of 300 mg or greater (seesection 5.1).

Pharmacotherapeutic group: Lipid modifying agents, nicotinic acid and derivatives, ATC code:

C10AD52.

Pelzont 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 acidlowers the levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very lowdensity 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 ofhigh-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I, the major proteincomponent of HDL). Laropiprant suppresses PGD2 mediated flushing associated with administrationof nicotinic acid. Laropiprant has no effect on lipid levels nor does it interfere with the effects ofnicotinic acid on lipids.

Nicotinic acid

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 tothe 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 notinvoke plasma FFA reduction as the central driver of lipid profile modification include nicotinicacid-mediated inhibition of de novo lipogenesis or esterification of fatty acids into TG in the liver.

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

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

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

Laropiprant

Nicotinic acid-induced flushing is mediated primarily by release of prostaglandin D2 (PGD2) in theskin. Genetic and pharmacologic studies in animal models have provided evidence that PGD2, actingthrough 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 theproduction of prostaglandins.

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 areduction in nicotinic acid-induced vasodilatation (assessed by measurements of skin blood flow). Inhealthy subjects receiving Pelzont, pretreatment with acetylsalicylic acid 325 mg had no additionalbeneficial effects in reducing nicotinic acid-induced flushing symptoms compared to Pelzont alone(see section 4.8).

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

Clinical studies

Effect on lipids

Pelzont 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 Pelzont(2,000 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 patientsubgroups examined. Patients receiving Pelzont, nicotinic acid (prolonged-released formulation), orplacebo 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 alsotaking ezetimibe [10 mg]. The effect on lipids was similar whether Pelzont was given as monotherapyor 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 tomen and appeared greater among elderly patients (≥ 65 years) compared to younger patients(< 65 years).

In a multicentre, double-blind, 12-week factorial study, Pelzont 1,000 mg/20 mg co-administered withsimvastatin, when compared with simvastatin alone or Pelzont 1,000 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). Pelzont (2000 mg/40 mg) co-administered with simvastatin whencompared with simvastatin alone or Pelzont (2000 mg/40 mg) alone for 12 weeks, significantlylowered 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

Pelzont (2000 mg/40 mg) co-administered with simvastatin when compared with simvastatin alonesignificantly increased apo A-I (8.6 %, 2.3 % respectively) and significantly decreased Lp(a) (-19.8 %,0.0 % respectively ). Efficacy and safety of Pelzont in combination with simvastatin > 40 mg were notincluded in this study.

Flushing

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

Figure 1. Average number of days per week withmoderate or greater* flushing symptoms across weeks 1-240 1 2 3 4 5† 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Weeks on Treatment●Pelzont (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 Pelzontexperienced significantly fewer days per week with moderate or greater flushing compared to nicotinicacid (prolonged-release formulation taken as a 12-week multi-step 500 mg to 2,000 mg titration)(p< 0.001).

A multicenter, randomized, double-blind, placebo-controlled 32-week study to assess the effects ofwithdrawal of laropiprant showed that dyslipidaemic patients in whom laropiprant was withdrawnafter 20 weeks on Pelzont experienced significantly more flushing than patients who continued taking

Number of Days per Week

Pelzont in terms of number of days per week with moderate or greater flushing, p< 0.001, Figure 2.

The incidence and frequency of moderate or greater flushing in patients treated with Pelzont for theduration of the study decreased.

Figure 2

Percentage of Patients with Moderate or

Greater Flushing Symptoms Across Weeks 1-32● Pelzont▲ Pelzont  nicotinic acid (laropiprant withdrawn at Week 21)○ Placebo

The European Medicines Agency has waived the obligation to submit the results of studies with

Pelzont in all subsets of the paediatric population in homozygous familial hypercholesterolaemia (seesection 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Pelzont in paediatric patients from 7-18 years old in heterozygous familial hypercholesterolaemia (seesection 4.2 for information on paediatric use).

Nicotinic acid

Following a 2,000 mg dose of nicotinic acid administered orally as two modified-release tablets ofnicotinic acid/laropiprant with food, nicotinic acid was absorbed with a median time to peak plasmaconcentration (Tmax) of 4 hours, a mean area under the plasma concentration-time curve (AUC0-last) ofapproximately 58.0 μM·hr and a mean peak plasma concentration (Cmax) of approximately 20.2 μM.

Bioavailability with or without food is at least 72 % based on the recovery of the nicotinic acid dose inthe 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 nicotinicacid/laropiprant with food, laropiprant is rapidly absorbed with a median Tmax of 1 hour, a mean

AUC0-∞ of approximately 13 μM·hr, and a mean Cmax of approximately 1.6 μM. The rate and extent ofabsorption are not altered with a high-fat meal. The pharmacokinetics of laropiprant are linear,displaying approximately dose-proportional increases in AUC and Cmax and no evidence oftime-dependent clearance.

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

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 oflaropiprant to healthy subjects is approximately 70 litres. Laropiprant is highly bound (> 99 %) toplasma proteins, and its binding is independent of concentration. Laropiprant crosses the placenta inrats and rabbits.

Nicotinic acid

Nicotinic acid undergoes extensive first-pass metabolism through two pathways that are dose anddose-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 secondpathway, glycine is conjugated with nicotinic acid to form nicotinuric acid (NUA). With low doses ofnicotinic acid or lower rates of absorption, the first pathway predominates. At higher doses or higherrates of absorption, the NAD pathway is saturable, and an increasing fraction of the oral dose reachesthe bloodstream unchanged as nicotinic acid. The glycine conjugation pathway is not saturated acrossthe clinically relevant dose range, based on the dose-proportional increase in the plasmaconcentrations of NUA from 1,000 mg to 2,000 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-mediated3-glucuronidation of estradiol.

Laropiprant

Laropiprant is metabolised primarily via acyl glucuronidation, with a smaller component of oxidativemetabolism, followed by excretion of the glucuronide into faeces (via bile) and urine. Laropiprant andits acyl glucuronide conjugate are the major circulating components in human plasma. In vitro studieshave shown that the acyl glucuronide conjugate of laropiprant had at least a 65-fold reduced affinityfor DP1 as compared to laropiprant; thus, it is not expected to contribute to the overall DP1 activity oflaropiprant. The major component (73 % of radioactivity) in faeces is laropiprant (comprisingunabsorbed active substance and/or hydrolysed glucuronic acid conjugate). In urine, the primarycomponent is the acyl glucuronide conjugate (64 % of radioactivity) with smaller contributions fromthe parent compound (5 %). The oxidative metabolism of laropiprant is catalysed primarily by

CYP3A4, whereas several UGT isoforms (1A1, 1A3, 1A9 and 2B7) catalysed the acylglucuronidation.

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 glucuronidein 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, comprisingunabsorbed active substance and/or hydrolysed glucuronic acid conjugate) and 22 % was recovered inurine (primarily as metabolites). The majority of the dose was excreted within 96 hours. The apparentterminal half-life (t1/2) following a 40 mg dose of laropiprant administered as two modified-releasetablets of nicotinic acid/laropiprant with food was approximately 17 hours. Pharmacokinetic steadystate is achieved within 2 days of once-daily dosing of laropiprant, with minimal accumulation in

AUC (approximately 1.3-fold) and Cmax (approximately 1.1-fold).

Pelzont: 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 renalinsufficiency resulted in no clinically meaningful change in the AUC and Cmax of laropiprant,compared to healthy control subjects. As no effect was observed in severe renal insufficiency, noeffect is expected in patients with mild and moderate renal insufficiency; however, the effects ofend-stage renal failure and dialysis on laropiprant pharmacokinetics cannot be inferred from this study.

Pelzont: 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 bymetabolism, moderate hepatic disease has a significant impact on laropiprant pharmacokinetics, withan increase in AUC and Cmax of approximately 2.8- and 2.2-fold respectively.

Nicotinic acid: No dose adjustment is necessary based on gender. Gender has no clinically meaningfuleffect on pharmacokinetics of nicotinic acid (prolonged-release formulation). There is no difference inthe oral bioavailability of nicotinic acid in men and women receiving Pelzont. Women have a modestincrease 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 meaningfuleffect on the pharmacokinetics of laropiprant.

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

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

Pelzont: No studies have been performed in paediatric patients.

Nicotinic acid: No dose adjustment is necessary based on race. Race has no clinically meaningfuleffect on the pharmacokinetics of nicotinic acid (prolonged-release formulation) based onpharmacokinetic data including subjects of Hispanic, White, Black, and Native American racialgroups. Caution should be used when treating Chinese patients with Pelzont co-administered withsimvastatin or ezetimibe/simvastatin (particularly simvastatin doses of 40 mg or higher). (Seesection 4.4).

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

Pelzont

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

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

Nicotinic acid

Degeneration in the stomach and hepatocyte vacuolation were observed in rats following 6 months ofdosing at systemic exposure values at least 179 times the human exposure based on the AUC of therecommended daily human dose. Retinopathy and/or corneal lesions were observed in dogs following6 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 inthis study received approximately 9 to 13 times a human nicotinic acid dose of 2,000 mg/day asdetermined 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 toexposure levels approximately 391 times the human AUC of nicotinic acid based on the AUC of therecommended daily human dose.

Nicotinic acid was not teratogenic in rats and rabbits up to exposure levels approximately 253 and104 times the human AUC of nicotinic acid at the recommended daily human dose, respectively. Inrats, foetotoxic effects (significantly decreased foetal body weights associated with a decrease in thenumber of ossified sacrocaudal vertebrae and an increased incidence of foetuses with sites ofincomplete ossification) were noted in the absence of any signs of maternal toxicity at exposure levelsapproximately 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 maternaltoxicity at exposure levels approximately 629 times the human AUC of nicotinic acid at therecommended daily human dose.

Laropiprant

Ketonuria and hepatocellular centrilobular hypertrophy were observed in rats in repeated dose toxicitystudies for up to 6 months dosing. The hepatocellular centrilobular hypertrophy was consistent withrodent specific enzyme induction. The no-observed-adverse-effect level (NOAEL) was at least118 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 systemicexposure levels at least 14 times the human exposure based on the AUC of the recommended dailyhuman dose. No other effects were observed in dog studies with exposures at least 100 times thehuman 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, whichrepresents at least 218 to 289 times the human exposure based on the AUC of the recommended dailyhuman 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 matingand throughout mating, at systemic exposure levels at least 289 times the human exposure based onthe AUC of the recommended daily human dose.

Laropiprant was not teratogenic in rats or in rabbits at systemic exposure levels at least 153 and438 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 gainand foetal body weight, slight increases in pup mortality, and increased incidence of supernumeraryrib and incomplete ossification of the sternebra in the foetus were observed in rats at systemicexposure levels at least 513 times the human exposure based on the AUC of the recommended dailyhuman 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-releasetablets. 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 doseblister.

Aluminium/Aluminium blister with push-through lidding containing 7 modified-release tablets. Packsizes of 14, 28, 56, 168 modified-release tablets and 32 x 1 modified-release tablets in a perforatedunit 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/1/08/460/001

EU/1/08/460/002

EU/1/08/460/003

EU/1/08/460/004

EU/1/08/460/005

EU/1/08/460/006

EU/1/08/460/007

EU/1/08/460/008

EU/1/08/460/009

EU/1/08/460/010

EU/1/08/460/011

EU/1/08/460/012

EU/1/08/460/013

EU/1/08/460/014

Date of first authorisation: 3 July 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.