Tredaptive

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Tredaptive 1,000 mg/20 mg modified-release tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant. 
 
Excipient(s) with known effect: 
Each modified-release tablet contains 128.4 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Modified-release tablet. 
 
Capsule-shaped, white to off-white tablet, with “552” debossed on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tredaptive is indicated for the treatment of dyslipidaemia, particularly in adult patients with combined 
mixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low 
HDL-cholesterol) and in adult 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. 
 
4.2 Posology and method of administration 
 
Posology 
The starting dose is one modified-release tablet (1,000 mg nicotinic acid/20 mg laropiprant) once a 
day. After four weeks, it is recommended that patients be advanced to the maintenance dose of 
2,000 mg/40 mg taken as two modified-release tablets (1,000 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 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 
Tredaptive at the 2,000 mg/40 mg dose. Patients switching from less than 2,000 mg of 
prolonged-release nicotinic acid should initiate therapy at the starting dose of 1,000 mg/20 mg and 
advance to the 2,000 mg/40 mg maintenance dose after four weeks. For patients switching from 
immediate-release nicotinic acid to Tredaptive, therapy should be initiated at the 1,000 mg/20 mg dose 
and advanced to the 2,000 mg/40 mg maintenance dose after four weeks. 
 

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Elderly patients 
No dose adjustment is required for elderly patients. 
 
Paediatric population 
Safety and effectiveness of Tredaptive in paediatric patients under the age of 18 years 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. 
 
4.3 Contraindications 
 
• 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. 
 
4.4 Special warnings and precautions for use 
 
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 1,000 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 

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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 (≥ 1,000 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 (2,000 mg/40 mg) was associated with 
small reductions in platelet count (see section 4.8). Therefore, patients undergoing surgery should be 
carefully evaluated. 

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Effect on uric acid 
As with other nicotinic acid medicinal products, Tredaptive (2,000 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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 Cmax 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. 
 

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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 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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 

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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). 
 
4.7 Effects on ability to drive and use machines 
 
When driving vehicles or operating machines, it should be taken into account that dizziness has been 
reported (see section 4.8). 
 
4.8 Undesirable effects 
 
In clinical trials, over 5,700 patients received Tredaptive alone or with an HMG-CoA reductase 
inhibitor. 
 
Summary of the safety profile 
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=4,747, n=2,548 
taking Tredaptive), flushing was reported 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. 
 
Tabulated list of adverse reactions 
The following adverse reactions have been reported during clinical studies and/or post-marketing use 
with Tredaptive (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), Very 
rare (< 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 
disorders 

Uncommon: gout 
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 

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System organ class Adverse reaction 
Vascular disorders Very common: flushing 

Uncommon: hypotension 
Rare: orthostatic hypotension 

Respiratory, thoracic, and 
mediastinal disorders 

Uncommon: dyspnoea 

Gastrointestinal disorders Common: abdominal pain; diarrhoea; dyspepsia; nausea; vomiting  
Rare: mouth oedema; eructation; peptic ulcer 

Hepatobiliary disorders Not known: jaundice 
Skin and subcutaneous tissue 
disorders 

Common: erythema; pruritus; rash; urticaria 
Uncommon: dry skin; macular rash 
Rare: acanthosis nigricans; hyperpigmentation; sweating (night or 
cold sweat) 
Not known: vesicular or vesiculobullous rash 

Musculoskeletal and connective 
tissue disorders 

Uncommon: myalgia 
Rare: muscular weakness 

General disorders and 
administration site conditions 

Common: feeling hot 
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 (see 
below) 
Rare: elevations in total bilirubin, amylase; reductions in 
phosphorus and platelet counts (see below) 

 
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 (2,000 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). 
 
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: 
 

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Eye disorders: Cystoid macular oedema, toxic amblyopia. 
 
4.9 Overdose 
 
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 
5,000 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). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Lipid modifying agents, 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. 

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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 
(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 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). 
 

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In a multicentre, double-blind, 12-week factorial study, Tredaptive 1,000 mg/20 mg co-administered 
with simvastatin, when compared with simvastatin alone or Tredaptive 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). 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 three 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). 
 

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

Weeks on Treatment

0 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

N
um

be
r o

f D
ay

s 
pe

r W
ee

k

0

1

2

† 

 
 
●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 2,000 mg titration) 
(p< 0.001). 
 
A multicenter, randomized, double-blind, placebo-controlled 32-week study to assess the effects of 
withdrawal of laropiprant showed that dyslipidaemic patients in whom laropiprant was withdrawn 
after 20 weeks on Tredaptive experienced significantly more flushing than patients who continued 

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12 

taking Tredaptive 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 
Tredaptive for the duration of the study decreased. 
 

 
Figure 2 

Percentage of Patients with Moderate or  
Greater Flushing Symptoms Across Weeks 1-32 

 
● Tredaptive 
▲ Tredaptive  nicotinic acid (laropiprant withdrawn at Week 21)  
○ Placebo 

 
Paediatric population 
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 
(see section 4.2 for information on paediatric use). 
 
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). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Nicotinic acid 
Following a 2,000 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 (Tmax) of 4 hours, a mean area under the plasma concentration-time curve (AUC0-last) of 
approximately 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 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 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 of 
absorption 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 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. 
 

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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 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-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 (t1/2) 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 Cmax (approximately 1.1-fold). 
 

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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 Cmax 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 Cmax 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 population 
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. 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). (See 
section 4.4). 
 
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. 
 

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5.3 Preclinical safety data 
 
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 2,000 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. 
 

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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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Hypromellose (E464) 
Colloidal anhydrous silica (E551) 
Sodium stearyl fumarate 
Hydroxypropylcellulose (E463) 
Microcrystalline cellulose (E460) 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
PVC/Aclar blisters: 2 years. 
Aluminium/Aluminium blisters: 18 months. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C.  
Store in the original package in order to protect from light and moisture. 
 
6.5 Nature and contents of container 
 
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. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 

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7. MARKETING AUTHORISATION HOLDER 
 
Merck Sharp & Dohme Ltd. 
Hertford Road, Hoddesdon 
Hertfordshire EN11 9BU 
United Kingdom 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/459/001 
EU/1/08/459/002 
EU/1/08/459/003 
EU/1/08/459/004 
EU/1/08/459/005 
EU/1/08/459/006 
EU/1/08/459/007 
EU/1/08/459/008 
EU/1/08/459/009 
EU/1/08/459/010 
EU/1/08/459/011 
EU/1/08/459/012 
EU/1/08/459/013 
EU/1/08/459/014 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 3 July 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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ANNEX II 
 
A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Merck, Sharp & Dohme Ltd. 
Shotton Lane 
Cramlington 
Northumberland NE23 3JU 
United Kingdom 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
Pharmacovigilance system 
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the 
Marketing Authorisation, is in place and functioning before and whilst the medicinal product is on the 
market. 
 
Risk Management Plan (RMP) 
The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as 
agreed in the RMP presented in Module 1.8.2 of the Marketing Authorisation and any subsequent 
updates of the RMP agreed by the Committee for Medicinal Products for Human Use (CHMP). 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted: 
• When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities 
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached 
• At the request of the European Medicines Agency. 

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20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (for Alu/Alu blister) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tredaptive 1,000 mg/20 mg modified-release tablets 
Nicotinic acid/laropiprant 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 modified-release tablets 
28 modified-release tablets 
56 modified-release tablets 
168 modified-release tablets 
32 x 1 modified-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C.   
Store in the original package in order to protect from light and moisture. 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Sharp & Dohme Ltd. 
Hertford Road, Hoddesdon 
Hertfordshire EN11 9BU 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/459/009 14 modified-release tablets 
EU/1/08/459/010 28 modified-release tablets 
EU/1/08/459/011 56 modified-release tablets 
EU/1/08/459/013 168 modified-release tablets 
EU/1/08/459/014 32 x 1 modified-release tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (for PVC/Aclar blister) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tredaptive 1,000 mg/20 mg modified-release tablets 
Nicotinic acid/laropiprant 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 modified-release tablets 
28 modified-release tablets 
56 modified-release tablets 
84 modified-release tablets 
98 modified-release tablets 
168 modified-release tablets 
196 modified-release tablets 
Multi-pack containing 196 (2 packs of 98) modified-release tablets 
49 x 1 modified-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 

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9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from light and moisture.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Sharp & Dohme Ltd. 
Hertford Road, Hoddesdon 
Hertfordshire EN11 9BU 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/459/001 14 modified-release tablets 
EU/1/08/459/002 28 modified-release tablets 
EU/1/08/459/003 56 modified-release tablets 
EU/1/08/459/004 84 modified-release tablets 
EU/1/08/459/005 98 modified-release tablets 
EU/1/08/459/006 168 modified-release tablets 
EU/1/08/459/007 196 modified-release tablets 
EU/1/08/459/008 49 x 1 modified-release tablets 
EU/1/08/459/012 196 (2 packs of 98) modified-release tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Tredaptive 

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PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON 
 
Multi-packs of 196 (2 packs of 98 modified-release tablets) – without blue box  (for PVC/Aclar 
blister) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tredaptive 1,000 mg/20 mg modified-release tablets 
Nicotinic acid/laropiprant 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each modified-release tablet contains 1,000 mg of nicotinic acid and 20 mg of laropiprant. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
98 modified-release tablets. Component of a multi-pack, can’t be sold separately.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from light and moisture.  
 
 

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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Merck Sharp & Dohme Ltd. 
Hertford Road, Hoddesdon 
Hertfordshire EN11 9BU 
United Kingdom 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/459/012 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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28 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tredaptive 1000 mg/20 mg modified-release tablets 
Nicotinic acid/laropiprant 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
MSD 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 

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29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

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Package leaflet: Information for the patient 
 

Tredaptive 1,000 mg/20 mg modified-release tablets 
nicotinic acid/laropiprant 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. 
 
What is in this leaflet: 
1. What Tredaptive is and what it is used for 
2. What you need to know before you take Tredaptive 
3. How to take Tredaptive 
4. Possible side effects 
5. How to store Tredaptive  
6. Contents of the pack and other information 
 
 
1. What Tredaptive is and what it is used for 
 
The name of your medicine is Tredaptive. It contains two different active substances: 
• nicotinic acid, a lipid modifying medicine, and  
• laropiprant, which reduces symptoms of flushing, a common side effect of nicotinic acid. 
 
How Tredaptive Works 
Tredaptive is used in addition to diet  
• to lower your ‘bad’ cholesterol level. It does this by lowering the levels of total cholesterol, 

LDL cholesterol, fatty substances called triglycerides and apo B (a part of LDL) in the blood;  
• to raise levels of ‘good’ cholesterol (HDL cholesterol) and apo A-I (a part of HDL). 
 
What should I know about cholesterol and triglycerides? 
Cholesterol is one of several fats found in your blood. Your total cholesterol is made up mainly of 
‘bad’ (LDL) and ‘good’ (HDL) cholesterol. 
 
LDL cholesterol is often called ‘bad’ cholesterol because it can build up in the walls of your arteries 
and form plaque. Over time, this plaque build-up can lead to a clogging of your arteries. This clogging 
can slow or block blood flow to vital organs such as the heart and brain. When the blood flow is 
blocked, the result can be a heart attack or stroke. 
 
HDL cholesterol is often called ‘good’ cholesterol because it helps keep the ‘bad’ cholesterol from 
building up in the arteries and because it protects against heart disease. 
 
Triglycerides are another fat in your blood. They may raise your risk of having heart problems. 
 
In most people, at first there are no signs of cholesterol problems. Your doctor can measure your 
cholesterol with a simple blood test. Visit your doctor regularly to keep track of your cholesterol and 
discuss your goals with your doctor. 
 
Tredaptive is used in addition to diet and exercise in adult patients with primary 
hypercholesterolaemia  or mixed dyslipidaemia: 
• when you cannot control your cholesterol levels with a statin alone (class of cholesterol-lowering 

medicines working in the liver); 

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• when you cannot tolerate a statin or when a statin is not recommended for you. 
 
Patients with combined mixed dyslipidaemia have high blood levels of ‘bad’ LDL cholesterol and 
triglycerides (a type of fat), and low levels of ‘good’ HDL cholesterol. Primary hypercholesterolaemia 
is when the levels of cholesterol in the blood are high. Primary means that the hypercholesterolaemia 
does not have any identifiable cause. 
 
 
2. What you need to know before you take Tredaptive 
 
Do not take Tredaptive if 
• you are allergic to nicotinic acid, to laropiprant, or to any of the other ingredients of this 

medicine (listed in section 6). 
• you currently have liver problems. 
• you have an ulcer in your stomach. 
• you have arterial bleeding. 
 
Do not take Tredaptive if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Tredaptive. 
 
Warnings and precautions 
Tell your doctor about all of your medical conditions. Check with your doctor or pharmacist before 
and while taking your medicine if: 
• you have any allergies. 
• you have ever had liver disease, jaundice (a liver disorder causing yellowing of the skin and 

whites of the eyes), or hepatobiliary (liver and bile duct) disease. 
• you have kidney problems. 
• you have thyroid problems. 
• you drink large amounts of alcohol. 
• you or close family members have a hereditary muscle disorder, or you have ever had muscle 

problems during treatment with cholesterol-lowering medicines called “statins” or fibrates. 
• you have unexplained muscle pain, muscle tenderness, or muscle weakness. If you have these 

symptoms talk to your doctor immediately. 
• you have high blood sugar or diabetes. 
• you have heart problems. 
• you are going to have an operation. 
• you have gout. 
• you have low levels of phosphorus. 
• you are over 70 years old. 
• you are taking simvastatin (a statin) or a medicine containing simvastatin and are Chinese. 
 
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking 
Tredaptive. 
 
Blood tests and monitoring 
• See your doctor regularly to check your LDL (bad) and HDL (good) cholesterol levels and your 

triglyceride level. 
• Your doctor should do a blood test before you start taking Tredaptive to check how well your 

liver is working. 
• Your doctor may also want you to periodically have blood tests after you start taking 

Tredaptive, to check how well your liver is working and for other side effects. 
 
Children and adolescents 
Tredaptive has not been studied in children and adolescents who are under 18 years of age. Therefore, 
Tredaptive should not be used in children and adolescents under 18 years of age. 
 

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Other medicines and Tredaptive 
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This 
includes medicines obtained without a prescription, vitamins, and herbal supplements. 
 
In particular, tell your doctor or pharmacist if you are taking any of the following: 
• medicines used to lower blood pressure. 
• medicines used to lower cholesterol called ‘bile acid sequestrants’, such as colestyramine. 
• zidovudine, a medicine used for HIV. 
• midazolam, a medicine to make you sleepy before some medical procedures. 
• vitamins or supplements that contain nicotinic acid. 
• clopidogrel and acetylsalicylic acid (ASA), medicines to help prevent harmful blood clots. 
• medicines used to lower cholesterol called ‘statins’. 
 
Also tell your doctor if you are taking simvastatin (a statin) or a medicine containing simvastatin and 
are Chinese. 
 
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking 
Tredaptive. 
 
Tredaptive with food, drink and alcohol 
• To lower your chance of flushing, avoid drinking alcohol or hot drinks or eating spicy foods 

near the time you take your dose of Tredaptive. 
• It is important to follow the advice given in section 3 How to take Tredaptive. 
 
Pregnancy and breast-feeding 
Tredaptive is not recommended in pregnancy unless clearly necessary.  
Talk with your doctor before taking Tredaptive if: 
• You are pregnant or plan to become pregnant. It is not known if Tredaptive will harm your 

unborn baby. 
• You are breast-feeding or plan to breast-feed. It is not known if Tredaptive will pass into your 

breast milk. However, nicotinic acid a component of Tredaptive does pass into breast milk. 
 
Ask your doctor or pharmacist for advice before taking this medicine. Your doctor will decide if 
Tredaptive is right for you. 
 
Driving and using machines 
Some people get dizzy after taking Tredaptive. If you get dizzy, you should avoid driving or operating 
machines after taking Tredaptive. 
 
Tredaptive contains lactose 
Tredaptive contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Tredaptive 
 
Always take this medicine exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
How much to take 
• You should start by taking one tablet a day.  
• After 4 weeks, your doctor may raise your dose to two tablets a day. 
• If you are switching from a medicine containing 2,000 mg or more of a prolonged-release 

nicotinic acid, your doctor can start you with two tablets of Tredaptive a day. If you are 
switching from a medicine with less than 2,000 mg of prolonged-nicotinic acid, you should start 
by taking one tablet of Tredaptive a day. After 4 weeks, your doctor may raise your dose of 

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Tredaptive to two tablets a day. 
 
How to take 
• Take Tredaptive once a day, in the evening or at bedtime. 
• Take Tredaptive with food. 
• Swallow each tablet whole. In order for your medicine to work as intended, do not split, break, 

crush, or chew the tablet before you swallow it. 
• Avoid drinking alcohol or hot drinks or eating spicy foods near the time you take your dose of 

Tredaptive. This will lower your chance of flushing (redness of the skin, feeling warm, itching, 
or tingling, particularly in your head, neck, chest and upper back). 

• Taking aspirin before you take Tredaptive does not reduce your flushing more than taking 
Tredaptive alone. Therefore, taking aspirin to reduce flushing symptoms is not necessary. If you 
take aspirin for any other reason, continue to follow your doctor's advice.  

 
If you take more Tredaptive than you should 
• In the event of an overdose, the following side effects were reported: 

flushing, headache, pruritus (itching), nausea, dizziness, vomiting, diarrhoea, abdominal 
pain/discomfort, and back pain. 

• If you take more than you should, talk to a doctor or pharmacist straight away. 
 
If you forget to take Tredaptive 
• If you miss a dose, do not take an extra dose. Continue with your usual dose the next evening or 

at bedtime. However, if you do not take Tredaptive for 7 or more days in a row, talk to your 
doctor before restarting Tredaptive. 

 
If you stop taking Tredaptive 
Do not stop taking Tredaptive without talking to your doctor. Your cholesterol problem may return. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Side effects of Tredaptive are: 
 
Very common (may affect more than 1 in 10 people) 
• flushing (which usually includes redness of the skin, feeling warm, itching, or tingling, 

particularly in the head, neck, chest and upper back). If flushing occurs, symptoms are generally 
most noticeable at first and usually lessen over time. 

 
Common (may affect up to 1 in 10 people) 
• headache 
• tingling or numbness of the hands or feet 
• abdominal pain 
• diarrhoea 
• upset stomach or heartburn 
• nausea (feeling sick) 
• getting sick (vomiting) 
• pruritus (itching) 
• rash 
• hives 
 
Uncommon  (may affect up to 1 in 100 people) 
• gout 

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• sleeplessness 
• dizziness 
• palpitation (feeling your heartbeat) 
• low blood pressure 
• shortness of breath 
• dry skin 
• rash with flat, red spots 
• muscle pain or tenderness 
• chills 
• pain 
• swelling of the fingers, toes or ankles 
 
In addition, one or more of the following symptoms have been reported as part of an allergic reaction 
to Tredaptive.  
• swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or 

swallowing (angioedema, which may require treatment right away) 
• fainting 
• shortness of breath 
• loss of control over urine and stool 
• cold sweats 
• shivering 
• chills 
• increased blood pressure 
• swelling of the lips 
• burning sensation 
• whole body rash 
• joint pain 
• swelling of the legs 
• rapid heart rate. 
 
Rare (may affect up to 1 in 1000 people) 
• runny nose 
• decreased glucose (sugar) tolerance 
• anxiety 
• migraine 
• fainting 
• rapid or irregular heartbeat 
• dizziness upon standing 
• belching 
• stomach ulcer 
• skin disorder with dark velvety plaques called acanthosis nigricans 
• patches of darkened skin 
• sweating 
• muscle weakness 
• weakness 
• generalised swelling 
 
Not known: frequency cannot be estimated from the available data  
Additionally, the following were reported during post-marketing experience with Tredaptive and/or 
other nicotinic acid products (alone and/or with certain other cholesterol-lowering medicines):  
• a sudden serious allergic reaction (anaphylactic shock). Symptoms included fainting, shortness 

of breath, wheezing or trouble breathing, swelling of the face, lips, tongue, itching or hives on 
the skin. This condition requires immediate medical attention.  

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• eye disorders called toxic amblyopia and cystoid macular oedema which may lead to blurred, 
decreased, or lost vision 

• yellowing of the skin and/or eyes (jaundice) 
• blistering rash 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 
 
 
5. How to store Tredaptive 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the blister after EXP. 
 
Do not store above 30°C. Store in the original packaging in order to protect from light and moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Tredaptive contains 
• The active substances are nicotinic acid and laropiprant. Each tablet contains 1,000 mg nicotinic 

acid and 20 mg laropiprant. 
• The other ingredients are: hypromellose (E464), colloidal anhydrous silica (E551), sodium 

stearyl fumarate, hydroxypropylcellulose (E463), microcrystalline cellulose (E460), 
croscarmellose sodium, lactose monohydrate, and magnesium stearate. 

 
The medicine comes as a modified-release tablet. This means one or more active substances are 
released slowly over a period of time. 
 
What Tredaptive looks like and contents of the pack 
Each modified-release tablet is a capsule-shaped, white to off-white tablet, with “552” debossed on 
one side. 
 
Opaque PVC/Aclar blister with push-through aluminium lidding in 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 perforated unit dose blister. 
 
Aluminium/Aluminium blister with push-through lidding in pack sizes of 14, 28, 56, 
168 modified-release tablets and 32 x 1 modified-release tablets in perforated unit dose blister. 
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder Manufacturer 
Merck Sharp & Dohme Ltd. Merck Sharp & Dohme Ltd. 
Hertford Road, Hoddesdon Shotton Lane, Cramlington 
Hertfordshire EN11 9BU Northumberland NE23 3 JU 
United Kingdom United Kingdom 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

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Belgique/België/Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32 (0)27766211) 
dpoc_belux@merck.com 
 

Luxembourg/Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel: 0800 38 693 (+32 (0)27766211) 
dpoc_belux@merck.com 
 

България 
Мерк Шарп и Доум България ЕООД 
Тел.: +359 2 819 3737 
info-msdbg@merck.com 
 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: +36 1 888 53 00 
hungary_msd@merck.com 
 

Česká republika 
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
msd_cr@merck.com 
 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: +8007 4433 (+356 99917558) 
malta_info@merck.com 
 

Danmark 
MSD Danmark ApS 
Tlf: +45 4482 4000 
dkmail@merck.com 
 

Nederland  
Merck Sharp & Dohme BV 
Tel: 0800 99 99 000 (+31 23 5153153) 
medicalinfo.nl@merck.com 
 

Deutschland 
MSD SHARP & DOHME GMBH 
Tel: 0800 673 673 673; (+49 (0) 89 4561 2612) 
e-mail@msd.de 
 

Norge 
MSD (Norge) AS 
Tlf: +47 32 20 73 00 
msdnorge@msd.no 
 

Eesti 
Merck Sharp & Dohme OÜ 
Tel: +372 6144 200 
msdeesti@merck.com 
 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com 
 

Eλλάδα 
BIANEΞ Α.Ε 
Τηλ: +3 0210 80091 11 
Mailbox@vianex.gr 
 

Polska 
MSD Polska Sp. z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 
 

España 
Merck Sharp & Dohme de España, S.A. 
Tel: +34 91 321 06 00 
msd_info@merck.com 
 

Portugal 
Merck Sharp & Dohme, Lda 
Tel: +351 21 4465808 
clic@merck.com 
 

France 
MSD France 
Tél: + 33 (0) 1 80 46 40 40 
 

România 
Merck Sharp & Dohme Romania S.R.L. 
Tel: +4021 529 29 00 
msdromania@merck.com 
 

Ireland 
Merck Sharp and Dohme Ireland (Human Health) 
Limited 
Tel: +353 (0)1 2998700 
medinfo_ireland@merck.com 
 

Slovenija 
Merck Sharp & Dohme, inovativna zdravila d.o.o.  
Tel: + 386 1 5204201 
msd_slovenia@merck.com 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel.: +421 2 58282010 
msd_sk@merck.com 
 

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Ιtalia 
MSD Italia S.r.l. 
Tel: +39 06 361911 
medicalinformation.it@merck.com 
 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: +358 (0) 9 804650 
info@msd.fi 
 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 80000 673 (+357 22866700) 
cyprus_info@merck.com 
 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: +46 77 5700488 
medicinskinfo@merck.com 
 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: +371 67364 224 
msd_lv@merck.com 
 

United Kingdom 
Merck Sharp and Dohme Limited 
Tel: +44 (0) 1992 467272 
medicalinformationuk@merck.com 
 

Lietuva 
UAB Merck Sharp & Dohme 
Tel. +370 5 278 02 47 
msd_lietuva@merck.com 
 

 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET