ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Tredaptive 1000 mg/20 mg modified-release tablets.
2.
Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.
Excipient
Each modified-release tablet contains 128.4 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Modified-release tablet.
Capsule-shaped, white to off-white tablet, with “552” debossed on one side.
4.
Tredaptive is indicated for the treatment of dyslipidaemia, particularly in patients with combined
mixed dyslipidaemia (characterised by elevated levels of LDL-cholesterol and triglycerides and low
HDL-cholesterol) and in patients with primary hypercholesterolaemia (heterozygous familial and
non-familial).
Tredaptive should be used in patients in combination with HMG-CoA reductase inhibitors (statins),
when the cholesterol lowering effect of HMG-CoA reductase inhibitor monotherapy is inadequate. It
can be used as monotherapy only in patients in whom HMG-CoA reductase inhibitors are considered
inappropriate or not tolerated. Diet and other non-pharmacological treatments (e.g. exercise, weight
reduction) should be continued during therapy with Tredaptive.
Posology
The starting dose is one modified-release tablet (1000 mg nicotinic acid/20 mg laropiprant) once a
day. After four weeks, it is recommended that patients be advanced to the maintenance dose of
2000 mg/40 mg taken as two modified-release tablets (1000 mg/20 mg each) once daily. Daily doses
greater than 2000 mg/40 mg have not been studied and therefore are not recommended.
If Tredaptive is missed for less than 7 consecutive days, patients can resume therapy at the last
administered dose. If Tredaptive is missed for 7 or more consecutive days, therapy should be resumed
at the 1000 mg/20 mg dose for 1 week, before advancing to the maintenance dose of 2000 mg/40 mg.
Those patients switching from 2000 mg or more of prolonged-release nicotinic acid can initiate
Tredaptive at the 2000 mg/40 mg dose. Patients switching from less than 2000 mg of
prolonged-release nicotinic acid should initiate therapy at the starting dose of 1000 mg/20 mg and
advance to the 2000 mg/40 mg maintenance dose after four weeks. For patients switching from
immediate-release nicotinic acid to Tredaptive, therapy should be initiated at the 1000 mg/20 mg dose
and advanced to the 2000 mg/40 mg maintenance dose after four weeks.
2
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.
Use in the elderly
No dose adjustment is required for elderly patients.
Use in paediatric patients
Safety and effectiveness of Tredaptive in paediatric patients have not been established. Therefore,
treatment is not recommended in this age group.
Use in 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).
•
Hypersensitivity to the active substances or to any of the excipients.
•
Significant or unexplained hepatic dysfunction.
•
Active peptic ulcer disease.
•
Arterial bleeding.
When Tredaptive is co-administered with a statin, please refer to the Summary of Product
Characteristics for that particular medicinal product.
Hepatic effects
Switching from immediate-release (crystalline) nicotinic acid to Tredaptive has not been studied.
However, cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in
patients who have switched from immediate-release nicotinic acid to long-acting nicotinic acid at
equivalent doses. Therefore, patients switching from immediate-release nicotinic acid to Tredaptive
should be initiated at the 1000 mg/20 mg dose.
Tredaptive should be used with caution in patients who consume substantial quantities of alcohol
and/or have a past history of liver disease.
Like other lipid-lowering therapies, nicotinic acid medicinal products have been associated with
abnormal liver function tests (see section 4.8). Transaminase elevations were reversible upon
discontinuation of therapy.
Liver function tests are recommended before initiation, every 6 to 12 weeks for the first year, and
periodically (e.g. semi-annually) thereafter. Patients who develop increased transaminase levels should
3
be monitored until the abnormalities have resolved. Should an increase in alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) of ≥ 3 X ULN persist, reduction of dose or withdrawal of
Tredaptive is recommended.
Effect on skeletal muscle
Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of
lipid-altering doses (≥ 1000 mg/day) of nicotinic acid and HMG-CoA reductase inhibitors (statins)
(see section 4.8).
Physicians contemplating combined therapy with statins and Tredaptive should carefully weigh the
potential benefits and risks and should carefully monitor patients for any signs and symptoms of
muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the
dose of either medicinal product is increased. Periodic serum creatine kinase (CK) should be
considered in such situations, but there is no assurance that such monitoring will prevent the
occurrence of severe myopathy.
Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis.
•
Age > 70 years
•
Renal impairment
•
Uncontrolled hypothyroidism
•
Personal or familial history of hereditary muscular disorders
•
Previous history of muscular toxicity with a statin or fibrate
•
Alcohol abuse.
If muscle pain, weakness or cramps occur while a patient is receiving Tredaptive with a statin, their
CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be
significantly elevated (> 5 x ULN), treatment should be stopped.
Race
In an interim analysis of an ongoing clinical outcome study, an independent safety monitoring
committee identified a higher than expected incidence of myopathy in Chinese patients taking
Tredaptive and simvastatin 40 mg. Therefore, caution should be used when treating Chinese patients
with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin (particularly simvastatin
doses of 40 mg or higher). Because the risk of myopathy with statins is dose-related, the use of
Tredaptive with simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg is not recommended in Chinese
patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated
with Tredaptive co-administered with simvastatin or ezetimibe/simvastatin.
Renal dysfunction
Because nicotinic acid and its metabolites are excreted through the kidneys, Tredaptive should be used
with caution in patients with renal dysfunction.
Effect on glucose
Nicotinic acid medicinal products have been associated with increases of fasting blood glucose levels
(see section 4.8). Diabetic or potentially diabetic patients should be observed closely. Adjustment of
diet and/or hypoglycaemic therapy may be necessary.
Acute coronary syndrome
As with other nicotinic acid medicinal products, caution should be used when Tredaptive is used in
patients with unstable angina or in the acute phase of an MI, particularly when such patients are also
receiving vasoactive medicinal products such as nitrates, calcium channel blockers, or adrenergic
blocking agents.
Haematologic effects
As with other nicotinic acid medicinal products, Tredaptive (2000 mg/40 mg) was associated with
small reductions in platelet count (see section 4.8). Therefore, patients undergoing surgery should be
carefully evaluated.
4
Effect on uric acid
As with other nicotinic acid medicinal products, Tredaptive (2000 mg/40 mg) was associated with
small increases in uric acid levels (see section 4.8). Therefore, Tredaptive should be used with caution
in patients with or predisposed to gout.
Hypophosphatemia
As with other nicotinic acid medicinal products, Tredaptive was associated with small decreases in
phosphorus levels. Therefore, patients with a risk for hypophosphatemia should be closely followed.
Other information
As with other nicotinic acid medicinal products, patients with a history of jaundice, hepato-biliary
disorder or peptic ulcer should be observed closely (see sections 4.2 and 4.3).
Excipient
Tredaptive contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Drinking alcohol or hot drinks or eating spicy foods can enhance the effects of flushing and should
therefore be avoided around the time of ingestion of Tredaptive.
Nicotinic acid
Effects of nicotinic acid on other medicinal products
Antihypertensive therapy:
Nicotinic acid may potentiate the effects of ganglionic blocking agents and
vasoactive medicinal products such as nitrates, calcium channel blockers, and adrenergic receptor
blocking agents, resulting in postural hypotension.
HMG-CoA reductase inhibitors:
When simvastatin is combined with nicotinic acid, a modest increase
in AUC and C
max
of simvastatin acid (the active form of simvastatin) was observed, which may be
devoid of clinical relevance. The pharmacokinetic interaction of Tredaptive with statins has been
studied only with simvastatin (see section 4.4).
Effects of other medicinal products on nicotinic acid
Bile acid sequestrants:
Because co-administration of bile acid sequestrants may reduce the
bioavailability of acidic medicinal products such as nicotinic acid, it is recommended that Tredaptive
be administered > 1 hour before or > 4 hours after administration of a bile acid sequestrant.
Supplements containing nicotinic acid:
Vitamins or other nutritional supplements containing
(≥ 50 mg/day) of nicotinic acid (or nicotinamide) have not been studied with Tredaptive. Physicians
should consider the nicotinic acid intake from vitamins and nutritional supplements when prescribing
Tredaptive.
Medicinal product /laboratory test interactions:
In urine glucose tests, nicotinic acid may also give
false-positive reactions with cupric sulfate solution (Benedict’s reagent).
Laropiprant
Effects of laropiprant on other medicinal products
Midazolam:
Multiple doses of laropiprant 40 mg did not affect the pharmacokinetics of midazolam, a
sensitive CYP3A4 substrate. Therefore, laropiprant is not an inducer or inhibitor of CYP3A4.
However, the plasma concentration of a metabolite of midazolam, 1'-hydroxymidazolam, was
increased approximately 2-fold with multiple doses of laropiprant. Because 1'-hydroxymidazolam is
an active metabolite, the sedative effect of midazolam may be increased and caution should be used
when laropiprant is co-administered with midazolam.
5
Other medicinal products:
Co-administration of laropiprant 40 mg with midazolam increased the
AUC
0-∞
and C
max
of 1'-hydroxymidazolam, a midazolam metabolite, by 98 % and 59 %, respectively.
1'-hydroxymidazolam is metabolised predominantly by uridine diphosphate-glucuronosyltransferases
(UGT) 2B4 and 2B7. Clinical and
in vitro
studies support the conclusion that laropiprant is a mild to
moderate inhibitor of UGT2B4/UGT2B7. Very few medicinal products are known to be metabolised
predominantly by UGT2B4 or UGT2B7. Caution should be used when Tredaptive is co-administered
with medicinal products metabolised predominantly by UGT2B4 or UGT2B7, for instance zidovudine.
In interaction studies, laropiprant did not have clinically significant effects on the pharmacokinetics of
the following medicinal products: simvastatin, warfarin, oral contraceptives, rosiglitazone and digoxin.
Based on these data, laropiprant is not expected to cause interactions with substrates of CYP isozymes
3A4, 2C9, 2C8 and human P-glycoprotein (P-gp). In
in vitro
studies, laropiprant did not inhibit
CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP2E1-mediated reactions.
Clopidogrel:
In a clinical study, there was no meaningful effect of laropiprant on the inhibition of
ADP-induced platelet aggregation by clopidogrel, but there was a modest increase in the inhibition of
collagen-induced platelet aggregation by clopidogrel. This effect is unlikely to be clinically important
as laropiprant did not increase bleeding time when co-administered with clopidogrel throughout the
dosing interval.
Acetylsalicylic acid:
In a clinical study, concomitant administration of laropiprant with acetylsalicylic
acid did not have an effect on collagen-induced platelet aggregation or on bleeding time compared to
treatment with acetylsalicylic acid alone (see section 5.1).
Acetylsalicylic acid and clopidogrel:
A clinical study to evaluate the effect of laropiprant on platelet
function in patients concomitantly receiving both acetylsalicylic acid and clopidogrel was inconclusive.
Because this study did not rule out the potential for prolongation of bleeding time, patients receiving
Tredaptive concomitantly with acetylsalicylic acid and clopidogrel should be closely monitored.
Effects of other medicinal products on laropiprant
CYP3A4 Inhibitor:
Clarithromycin (a potent inhibitor of CYP3A4 and P-gp) did not have a clinically
meaningful effect on the pharmacokinetics of laropiprant. Laropiprant is not a substrate of human P-gp,
and therefore other inhibitors of CYP3A4 and/or P-gp are also not expected to have a clinically
meaningful impact on the pharmacokinetics of laropiprant.
Pregnancy
Tredaptive
There are no data from the combined use of nicotinic acid and laropiprant in pregnant women. The
combination has not been tested in reproductive toxicity studies. The potential risk for humans is
unknown. Therefore, Tredaptive should not be used during pregnancy unless clearly necessary.
Nicotinic acid
There are no adequate data from the use of high dose nicotinic acid in pregnant women. Animal
studies are insufficient with respect to reproductive toxicity (see section 5.3).
Laropiprant
There are no data from the use of laropiprant in pregnant women. Studies in animals have shown
reproductive toxicity at high doses of laropiprant (see section 5.3).
Lactation
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.
6
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.
No studies on the effects on the ability to drive and use machines have been performed. However,
when driving vehicles or operating machines, it should be taken into account that dizziness has been
reported (see section 4.8).
In clinical trials, over 2500 patients received Tredaptive alone or with an HMG-CoA reductase
inhibitor. Adverse reactions have usually been mild and transient.
Flushing
Flushing is the most common adverse reaction of Tredaptive. Flushing is most prominent in the head,
neck, and upper torso. In a pool of four active- or placebo-controlled clinical trials (N=4747, n=2548
taking Tredaptive), flushing was reported by the investigator as a possibly, probably, or definitely
treatment-related adverse reaction in 12.3 % of patients taking Tredaptive. In these studies, the
percentage of patients taking Tredaptive, nicotinic acid (pooled prolonged-release formulations) or
pooled placebo/simvastatin who discontinued due to any flushing-related symptom (redness, warmth,
itching and tingling) was 7.2 %, 16.6 %, and 0.4 %, respectively. Discontinuations due to other
specific adverse reactions among patients taking Tredaptive were infrequent (< 1 %).
Overall adverse reactions with Tredaptive
In addition to flushing, clinical adverse reactions reported by the investigators as possibly, probably,
or definitely related to Tredaptive in ≥ 1 % of patients treated with Tredaptive alone (n=947) or
co-administered with statin (n=1601) and clinically meaningful adverse reactions (< 1 %), for up to
one year are listed below.
The frequencies of adverse reactions are ranked according to the following: Very common (≥ 1/10),
Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10000 to < 1/1000), Very
rare (< 1/10000).
System organ class
Adverse reaction
Frequency
Investigations
Elevations in ALT and/or AST (consecutive,
≥ 3 X ULN), fasting glucose, uric acid (see
below)
Common
Elevations in CK (≥ 10 X ULN), total bilirubin,
reductions in phosphorus and platelet counts
(see below)
Uncommon
Nervous system disorders
Dizziness, headache, paraesthesia
Common
Gastrointestinal disorders
Diarrhoea, dyspepsia, nausea, vomiting
Common
Skin and subcutaneous tissue
disorders
Erythema, pruritus, rash, urticaria
Common
Vascular disorders
Flushing
Very
common
General disorders and
administration site conditions
Feeling hot
Common
Immune system disorders
Hypersensitivity reaction (see below)
Uncommon
7
Hypersensitivity reactions
An apparent hypersensitivity reaction has been reported (< 1 %) This is characterised by multiple
symptoms that may include: angio-oedema, pruritus, erythema, paraesthesia, loss of consciousness,
vomiting, urticaria, flushing, dyspnoea, nausea, incontinence of urine and stool, cold sweats, shivering,
chills, increased blood pressure, lip swelling, burning sensation, drug eruption, arthralgia, leg swelling,
and tachycardia.
Investigations
Marked and persistent increases of serum transaminases have been reported infrequently (see
section 4.4). In controlled clinical studies, the incidence of clinically important elevations in serum
transaminases (ALT and/or AST ≥ 3 X ULN, consecutive) was 1.0 % for patients treated with
Tredaptive with or without a statin. These elevations were generally asymptomatic and returned to
baseline after discontinuation of therapy or with continued treatment.
Clinically important elevations of CK (≥ 10 X ULN) were seen in 0.3 % of the patients treated with
Tredaptive with or without a statin (see section 4.4).
Other abnormal laboratory values reported were elevations in LDH, fasting glucose, uric acid, total
bilirubin, and amylase, and reductions in phosphorus and platelet counts (see section 4.4).
As with other nicotinic acid medicinal products, elevations in fasting glucose (a median increase of
approximately 4 mg/dL), and uric acid (mean change from baseline of +14.7 %), and reductions in
platelet counts (a mean change from baseline of -14.0 %) were reported in controlled clinical studies
with Tredaptive (2000 mg/40 mg) (see section 4.4). In diabetic patients a median increase in HbA1c of
0.2 % was observed (where modification of hypoglycaemic therapy was allowed).
Nicotinic acid-related adverse reactions
The following nicotinic acid-related adverse reactions have been seen in clinical trials or
post-marketing experience with other nicotinic acid medicinal products at unknown frequency or in
clinical trials with Tredaptive (or the nicotinic acid component of Tredaptive) in < 1 % of the patients
treated:
Cardiac disorders:
Atrial fibrillation and other cardiac arrhythmias, palpitations, tachycardia.
Nervous system disorders:
Migraine, syncope.
Eye disorders:
Cystoid macular oedema, toxic amblyopia.
Respiratory, thoracic, and mediastinal disorders:
Dyspnoea.
Gastrointestinal disorders:
Abdominal pain, mouth oedema, eructation, peptic ulcer.
Skin and subcutaneous tissue disorders:
Acanthosis nigricans, dry skin, hyperpigmentation, macular
rash, sweating (night or cold sweat), vesicular rash.
Musculoskeletal and connective tissue disorders:
Muscular weakness, myalgia.
Metabolism and nutrition disorders:
Impaired glucose tolerance, gout.
Infections and infestations
: Rhinitis.
Vascular disorders:
Hypotension, orthostatic hypotension.
General disorders and administration site conditions:
Asthaenia, chills, face oedema, generalised
oedema, pain, peripheral oedema.
Immune system disorders:
Angio-oedema, type I hypersensitivity.
Hepatobiliary disorders:
Jaundice.
Psychiatric disorders:
Anxiety, insomnia.
Tredaptive
In the event of an overdose, it is reasonable to employ the usual symptomatic and supportive
measures. Cases of overdose have been reported; the maximum dose of Tredaptive taken was
5000 mg/100 mg. All patients recovered without sequelae. The most commonly reported adverse
reactions from the subjects who received this higher dose were consistent with a high dose of nicotinic
acid and included: flushing, headache, pruritus, nausea, dizziness, vomiting, diarrhoea, epigastric and
8
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: nicotinic acid and derivatives, ATC code: C10AD52.
Tredaptive contains nicotinic acid, which at therapeutic doses is a lipid-modifying agent, and
laropiprant, a potent, selective antagonist of the prostaglandin D
2
(PGD
2
) receptor subtype 1 (DP
1
).
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 PGD
2
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 HDL
2
subfraction
to a greater extent than the HDL
3
subfraction, thereby increasing the HDL
2
:HDL
3
ratio, which is
associated with decreased cardiovascular disease risk. HDL is hypothesised to participate in the
transport of cholesterol from tissues back to the liver, to suppress vascular inflammation associated
with atherosclerosis, and to have anti-oxidative and anti-thrombotic effects.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density
lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma TG levels are
frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association
with non-lipid metabolic risk factors for coronary heart disease (CHD).
Treatment with nicotinic acid reduces the risk of death and cardiovascular events, and slows
progression or promotes regression of atherosclerotic lesions. The Coronary Drug Project, a five year
study completed in 1975, showed that nicotinic acid had a statistically significant benefit in decreasing
nonfatal, recurrent myocardial infarctions (MI) in men 30 to 64 years old with a history of MI. Though
9
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 D
2
(PGD
2
) in the
skin. Genetic and pharmacologic studies in animal models have provided evidence that PGD
2
, acting
through DP
1
, one of the two receptors for PGD
2
, plays a key role in nicotinic acid-induced flushing.
Laropiprant is a potent and selective antagonist of DP
1
. 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 A
2
receptor (TP) (although it is substantially less
potent at TP as compared to DP
1
). TP plays a role in platelet function; however, therapeutic doses of
laropiprant had no clinically relevant effect on bleeding time and collagen-induced platelet
aggregation (see section 4.5).
Clinical studies
Effect on lipids
Tredaptive was consistently efficacious across all prespecified patient subpopulations defined by race,
gender, baseline LDL-C, HDL-C and TG levels, age and diabetes status.
In a multicentre, double-blind, 24-week placebo-controlled study, patients taking Tredaptive
(2000 mg/40 mg) with or without a statin, when compared to placebo, had significantly decreased
LDL-C (-18.9 % vs. -0.5 %), TG (-21.7 % vs. 3.6 %), LDL-C:HDL-C (-28.9 % vs. 2.3 %),
non-HDL-C (-19.0 % vs. 0.8 %), apo B (-16.4 % vs. 2.5 %), TC (-9.2 % vs. -0.6 %), Lp(a) (-17.6 %
vs. 1.1 %), and TC:HDL-C (-21.2 % vs. 1.9 %) and also had significantly increased HDL-C (18.8 %
vs. -1.2 %), and apo A-I (11.2 % vs. 4.3 %) as measured by percent change from baseline. In general,
the between-group treatment effects on all lipid parameters were consistent across all patient
subgroups examined. Patients receiving Tredaptive, nicotinic acid (prolonged-released formulation),
or placebo were also taking statins (29 % atorvastatin [5-80 mg], 54 % simvastatin [10-80 mg], 17 %
other statins [2.5-180 mg] (pravastatin, fluvastatin, rosuvastatin, lovastatin)), of which 9 % were also
taking ezetimibe [10 mg]. The effect on lipids was similar whether Tredaptive was given as
monotherapy or was added to ongoing statin therapy with or without ezetimibe.
The placebo-adjusted LDL-C, HDL-C and TG responses appeared greater among women compared to
men and appeared greater among elderly patients (≥ 65 years) compared to younger patients
(< 65 years).
In a multicentre, double-blind, 12-week factorial study, Tredaptive 1000 mg/20 mg co-administered
with simvastatin, when compared with simvastatin alone or Tredaptive 1000 mg/20 mg alone, for
4 weeks, significantly lowered LDL-C (-44.2 %, -37.4 %, -8.2 % respectively), TG
(-25.8 %, -15.7 %, -18.7 % respectively), TC (-27.9 %, -25.8 %, -4.9 % respectively) and significantly
increased HDL-C (19.2 %, 4.2 %, 12.5 % respectively). Tredaptive (2000 mg/40 mg) co-administered
with simvastatin when compared with simvastatin alone or Tredaptive (2000 mg/40 mg) alone for
12 weeks, significantly lowered LDL-C (-47.9 %, -37.0 %, -17.0 % respectively), TG
(-33.3 %, -14.7 %, -21.6 % respectively), apo B (-41.0 %, -28.8 %, -17.1 % respectively), and TC
(-29.6 %, -24.9 %, -9.1 % respectively), as well as LDL-C:HDL-C (-57.1 %, -39.8 %, -31.2 %
respectively), non-HDL-C (-45.8 %, -33.4 %, -18.1 % respectively), and TC:HDL-C
(-43.0 %, -28.0 %, -24.9 % respectively), and significantly increased HDL-C (27.5 %, 6.0 %, 23.4 %
10
respectively). Further analysis showed Tredaptive (2000 mg/40 mg) co-administered with simvastatin
when compared with simvastatin alone significantly increased apo A-I (8.6 %, 2.3 % respectively) and
significantly decreased Lp(a) (-19.8 %, 0.0 % respectively
). Efficacy and safety of Tredaptive in
combination with simvastatin > 40 mg were not included in this study.
Flushing
In two large clinical trials measuring patient-reported flushing symptoms, patients taking Tredaptive
experienced less flushing than those taking nicotinic acid (prolonged-release formulations). In patients
continuing in the first study (24 weeks), the frequency of moderate or greater flushing in patients
treated with Tredaptive declined and approached that of patients receiving placebo (see Figure 1),
whereas in patients treated with nicotinic acid (prolonged-release formulation) the flushing frequency
remained constant (after Week 6).
Flushing efficacy of laropiprant has not been established past 24 weeks.
Figure 1. Average number of days per week with
moderate or greater
*
flushing symptoms across weeks 1-24
2
1
0
012345678910111213141516171819202122232425
†
Weeks on Treatment
●Tredaptive (1000 mg/20 mg to 2000 mg/40 mg at week 5)
▲Nicotinic acid (prolonged-release 1000 mg to 2000 mg at week 5)
○Placebo
*Includes patients with moderate, severe, or extreme flushing symptoms
†
Dose advancement at Week 5
In the second study (16 weeks) where acetylsalicylic acid was allowed, patients taking Tredaptive
experienced significantly fewer days per week with moderate or greater flushing compared to nicotinic
acid (prolonged-release formulation taken as a 12-week multi-step 500 mg to 2000 mg titration)
(p< 0.001).
5.2 Pharmacokinetic properties
Absorption
Nicotinic acid
Following a 2000 mg dose of nicotinic acid administered orally as two modified-release tablets of
nicotinic acid/laropiprant with food, nicotinic acid was absorbed with a median time to peak plasma
concentration (T
max
) of 4 hours, a mean area under the plasma concentration-time curve (AUC
0-last
) of
approximately 58.0 μM·hr and a mean peak plasma concentration (C
max
) of approximately 20.2 μM.
Bioavailability with or without food is at least 72 % based on the recovery of the nicotinic acid dose in
the urine. The oral bioavailability of nicotinic acid is not altered when it is taken with a high-fat meal.
11
Laropiprant
Following a 40 mg dose of laropiprant administered orally as two modified-release tablets of nicotinic
acid/laropiprant with food, laropiprant is rapidly absorbed with a median T
max
of 1 hour, a mean
AUC
0-∞
of approximately 13 μM·hr, and a mean C
max
of approximately 1.6 μM. The rate and extent of
absorption are not altered with a high-fat meal. The pharmacokinetics of laropiprant are linear,
displaying approximately dose-proportional increases in AUC and C
max
and no evidence of
time-dependent clearance.
The mean absolute bioavailability of laropiprant is approximately 71 % following a 40 mg dose when
administered as two modified-release tablets of nicotinic acid/laropiprant after an overnight fast.
Distribution
Nicotinic acid
Nicotinic acid is less than 20 % bound to serum proteins.
Laropiprant
The mean volume of distribution at steady state following a single 40 mg intravenous dose of
laropiprant to healthy subjects is approximately 70 litres. Laropiprant is highly bound (> 99 %) to
plasma proteins, and its binding is independent of concentration. Laropiprant crosses the placenta in
rats and rabbits.
Metabolism
Nicotinic acid
Nicotinic acid undergoes extensive first-pass metabolism through two pathways that are dose and
dose-rate dependent. The first pathway results in the formation of nicotinamide adenine dinucleotide
(NAD) and nicotinamide. In humans, nicotinamide is further predominantly metabolised to
N-methylnicotinamide (MNA) and to N-methyl-2-pyridone-5-carboxamide (2PY). In the second
pathway, glycine is conjugated with nicotinic acid to form nicotinuric acid (NUA). With low doses of
nicotinic acid or lower rates of absorption, the first pathway predominates. At higher doses or higher
rates of absorption, the NAD pathway is saturable, and an increasing fraction of the oral dose reaches
the bloodstream unchanged as nicotinic acid. The glycine conjugation pathway is not saturated across
the clinically relevant dose range, based on the dose-proportional increase in the plasma
concentrations of NUA from 1000 mg to 2000 mg.
In
in vitro
studies, nicotinic acid and its metabolites did not inhibit CYP1A2, CYP2B6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, or CYP3A4-mediated reactions or UGT1A1-mediated
3-glucuronidation of estradiol.
Laropiprant
Laropiprant is metabolised primarily via acyl glucuronidation, with a smaller component of oxidative
metabolism, followed by excretion of the glucuronide into faeces (via bile) and urine. Laropiprant and
its acyl glucuronide conjugate are the major circulating components in human plasma.
In vitro
studies
have shown that the acyl glucuronide conjugate of laropiprant had at least a 65-fold reduced affinity
for DP
1
as compared to laropiprant; thus, it is not expected to contribute to the overall DP
1
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.
12
Laropiprant
Laropiprant is eliminated primarily via acyl glucuronidation, followed by excretion of the glucuronide
in faeces (via bile) and urine. Following oral administration of
14
C-laropiprant in humans,
approximately 68 % of the dose was recovered in faeces (primarily as parent compound, comprising
unabsorbed active substance and/or hydrolysed glucuronic acid conjugate) and 22 % was recovered in
urine (primarily as metabolites). The majority of the dose was excreted within 96 hours. The apparent
terminal half-life (t
1/2
) following a 40 mg dose of laropiprant administered as two modified-release
tablets of nicotinic acid/laropiprant with food was approximately 17 hours. Pharmacokinetic steady
state is achieved within 2 days of once-daily dosing of laropiprant, with minimal accumulation in
AUC (approximately 1.3-fold) and C
max
(approximately 1.1-fold).
Characteristics in patients
Renal insufficiency
Tredaptive:
Use in patients with renal insufficiency has not been studied.
Nicotinic acid:
see section 4.4.
Laropiprant:
Administration of laropiprant 40 mg in non-dialysed patients with severe renal
insufficiency resulted in no clinically meaningful change in the AUC and C
max
of laropiprant,
compared to healthy control subjects. As no effect was observed in severe renal insufficiency, no
effect is expected in patients with mild and moderate renal insufficiency; however, the effects of
end-stage renal failure and dialysis on laropiprant pharmacokinetics cannot be inferred from this study.
Hepatic insufficiency
Tredaptive:
Use in patients with hepatic insufficiency has not been studied.
Nicotinic acid:
see sections 4.3 and 4.4.
Laropiprant
: Consistent with the characteristics of a medicinal product that is primarily cleared by
metabolism, moderate hepatic disease has a significant impact on laropiprant pharmacokinetics, with
an increase in AUC and C
max
of approximately 2.8- and 2.2-fold respectively.
Gender
Nicotinic acid:
No dose adjustment is necessary based on gender. Gender has no clinically meaningful
effect on pharmacokinetics of nicotinic acid (prolonged-release formulation). There is no difference in
the oral bioavailability of nicotinic acid in men and women receiving Tredaptive. Women have a
modest increase in plasma concentrations of nicotinuric acid and nicotinic acid compared to men.
Laropiprant:
No dose adjustment is necessary based on gender. Gender had no clinically meaningful
effect on the pharmacokinetics of laropiprant.
Elderly
Nicotinic acid:
There is no pharmacokinetic data in the elderly (≥ 65 years). Age has no clinically
meaningful effect on pharmacokinetics of nicotinic acid (prolonged-release formulation) based on a
composite analysis of subjects ages 18-65 years. There is no change in the oral bioavailability of
nicotinic acid with age.
Laropiprant:
No dose adjustment is necessary in the elderly. Age had no clinically meaningful effect
on the pharmacokinetics of laropiprant.
Paediatric
Tredaptive:
No studies have been performed in paediatric patients.
Race
Nicotinic acid:
No dose adjustment is necessary based on race. Race has no clinically meaningful
effect on the pharmacokinetics of nicotinic acid (prolonged-release formulation) based on
13
pharmacokinetic data including subjects of Hispanic, White, Black, and Native American racial
groups.
Laropiprant:
No dose adjustment is necessary based on race. Race had no clinically meaningful effect
on the pharmacokinetics of laropiprant based on a composite analysis of pharmacokinetic data
including subjects of White, Hispanic, Black, Asian, and Native American racial groups.
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 2000 mg/day as
determined on a mg/m
2
basis. Nicotinic acid showed no mutagenic effects in the
in vitro
assays.
No studies are available on possible effects of high dose nicotinic acid on fertility or on postnatal
development after
in utero
exposure. Nicotinic acid induced reproduction toxic effects in rats when
dosed at 1000 mg/kg/day during days 5-16 of gestation. Decreased placental and fetal weights were
observed.
Laropiprant
Ketonuria and hepatocellular centrilobular hypertrophy were observed in rats in repeated dose toxicity
studies for up to 6 months dosing. The hepatocellular centrilobular hypertrophy was consistent with
rodent specific enzyme induction. The no-observed-adverse-effect level (NOAEL) was at least
118 times the human exposure based on the AUC of the recommended daily human dose.
Increases in serum alanine aminotransferase (ALT) levels were observed in all dog studies, at systemic
exposure levels at least 14 times the human exposure based on the AUC of the recommended daily
human dose. No other effects were observed in dog studies with exposures at least 100 times the
human exposure based on the AUC of the recommended daily human dose.
Laropiprant was not carcinogenic in 2 year studies in mice and rats at the highest doses tested, which
represents at least 218 to 289 times the human exposure based on the AUC of the recommended daily
human dose.
Laropiprant was not mutagenic or clastogenic in a series of genetic toxicology studies.
No adverse effects on fertility were observed in male or female rats given laropiprant prior to mating
and throughout mating, at systemic exposure levels at least 289 times the human exposure based on
the AUC of the recommended daily human dose.
Laropiprant was not teratogenic in rats or in rabbits at systemic exposure levels at least 153 and
438 times the human exposure based on the AUC of the recommended daily human dose.
Reproduction toxicity studies showed slight treatment-related decreases in mean maternal weight gain
14
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.
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
PVC/Aclar blisters: Store in the original package in order to protect from light and moisture.
Aluminium/Aluminium blisters: 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.
15
7.
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
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.
3 July 2008
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/.
16
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
17
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Merck, Sharp & Dohme Ltd.
Shotton Lane
Cramlington
Northumberland NE23 3JU
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 6.0 (of
22 June 2009) presented in Module 1.8.1. of the Marketing Authorisation Application and any
subsequent updates, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3.1 dated 23 April 2008 of the Risk Management
Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the 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 EMEA
18
ANNEX III
LABELLING AND PACKAGE LEAFLET
19
A. LABELLING
20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (for Alu/Alu blister)
1.
Tredaptive 1000 mg/20 mg modified-release tablets
Nicotinic acid/laropiprant
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate. See the package leaflet for further information.
4.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
21
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
Tredaptive
22
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON (for PVC/Aclar blister)
1.
Tredaptive 1000 mg/20 mg modified-release tablets
Nicotinic acid/laropiprant
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate. See the package leaflet for further information.
4.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
23
9.
SPECIAL STORAGE CONDITIONS
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
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
24
PARTICULARS TO APPEAR ON THE INTERMEDIATECARTON
Multi-packs of 196 (2 packs of 98 modified-release tablets) – without blue box (for PVC/Aclar
blister)
1.
Tredaptive 1000 mg/20 mg modified-release tablets
Nicotinic acid/laropiprant
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each modified-release tablet contains 1000 mg of nicotinic acid and 20 mg of laropiprant.
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate. See the package leaflet for further information.
4.
Component of a multi-pack comprising 2 packs, each containing 98 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from light and moisture.
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
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
26
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Tredaptive 1000 mg/20 mg modified-release tablets
Nicotinic acid/laropiprant
2.
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
27
B. PACKAGE LEAFLET
28
PACKAGE LEAFLET: INFORMATION FOR THE USER
Tredaptive 1000 mg/20 mg modified-release tablets
nicotinic acid/laropiprant
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Tredaptive is and what it is used for
2.
Before you take Tredaptive
4.
Possible side effects
5.
How to store Tredaptive
6.
Further 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.
The medicine comes as a modified-release tablet. This means one or more active substances are
released slowly over a period of time.
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?
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 if you need to
improve cholesterol and fat levels in your blood (primary
hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia):
29
-
Keep this leaflet. You may need to read it again.
3.
How to take Tredaptive
•
when you cannot control your cholesterol levels with a statin (class of cholesterol-lowering
medicines working in the liver);
•
when you cannot tolerate a statin or when a statin is not recommended for you.
Tredaptive can be used by itself or with other medicines to treat cholesterol problems. You should stay
on a diet designed to lower cholesterol or other non-pharmacological treatments (e.g. exercise, weight
reduction) while you take this medicine.
2.
BEFORE YOU TAKE TREDAPTIVE
Do not take Tredaptive if
•
you are allergic (hypersensitive) to nicotinic acid, to laropiprant, or to any of the other
ingredients of Tredaptive (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.
Take special care with Tredaptive
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.
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.
30
Using other medicines
Please 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, a medicine to help prevent harmful blood clots.
•
medicines used to lower cholesterol called ‘statins’, a class of medicine that works in the liver.
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.
Taking Tredaptive with food and drink
•
Take Tredaptive with food.
•
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
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 any medicine. Your doctor will decide if
Tredaptive is right for you.
Driving and using machines
The effects of Tredaptive on the ability to drive and use machines have not been studied. However,
some people get dizzy after taking Tredaptive. If you get dizzy, you should avoid driving or operating
machines after taking Tredaptive.
Important information about some of the ingredients of Tredaptive
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 Tredaptive 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.
How to take
•
Take Tredaptive once a day, in the evening or at bedtime.
31
•
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 adverse events 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, Tredaptive can cause side effects, although not everybody gets them.
Side effects of Tredaptive are:
Very common
(affects more than 1 in 10 patients)
•
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
(affects less than 1 in 10 patients)
•
diarrhoea
•
nausea (feeling sick)
•
dizziness
•
rash
•
pruritus (itching)
•
hives
•
upset stomach or heartburn
•
getting sick (vomiting)
•
headache
•
tingling or numbness of the hands or feet.
Uncommon (affects less than 1 in 100 patients)
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
32
•
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.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE TREDAPTIVE
Keep out of the reach and sight of children.
Do not use Tredaptive after the expiry date (EXP) which is stated on the carton and the blister.
PVC/Aclar blisters: Store in the original packaging in order to protect from light and moisture.
Aluminium/Aluminium blisters: Do not store above 30°C. Store in the original packaging in order to
protect from light and moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Tredaptive contains
•
The active substances are nicotinic acid and laropiprant. Each tablet contains 1000 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.
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.
33
Marketing Authorisation
Holder
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:
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 38 693
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 38 693
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme (Middle East) Limited
Tel: +357 22866700
info_cyprus@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
Tredaptive@msd.dk
Nederland
Merck Sharp & Dohme BV
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme GmbH
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
Tredaptive@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
România
Merck Sharp & Dohme Romania S.R.L.
Tel: +4021 529 29 00
msdromania@merck.com
34
Merck Sharp & Dohme Ltd.
Manufacturer
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
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
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
medinfo_uk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel. +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website: http://www.emea.europa.eu/.
35
Source: European Medicines Agency
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