Merck to Launch TREDAPTIVE (ER niacin/laropiprant) in International Markets Later This Year

WHITEHOUSE STATION, N.J.--(Business Wire)--
Merck & Co., Inc. will begin launching TREDAPTIVE (ER niacin/laropiprant) in
international markets including Mexico, the UK and Germany by the third quarter
this year. TREDAPTIVE is a lipid-modifying therapy for patients with mixed
dyslipidemia and primary hypercholesterolemia.

TREDAPTIVE, also known by the trademark of CORDAPTIVE in some places, is now
approved in 39 countries outside the U.S. In the U.S., it remains
investigational.

"Merck is pleased that we are now able to supply TREDAPTIVE in approved markets
and continue our long-standing commitment to help address unmet medical needs in
cardiovascular care," said Luciano Rossetti, MD, senior vice president and
franchise head, Atherosclerosis and Cardiovascular, Merck Research Laboratories.

About Merck

Merck & Co., Inc. (Whitehouse Station, N.J., U.S.A.), which operates in many
countries as Merck Sharp & Dohme or MSD, is a global research-driven
pharmaceutical company dedicated to putting patients first. Established in 1891,
the Company currently discovers, develops, manufactures and markets vaccines and
medicines to address unmet medical needs. The Company devotes extensive efforts
to increase access to medicines through far-reaching programs that not only
donate its medicines but help deliver them to the people who need them. Merck
also publishes unbiased health information as a not-for-profit service. For more
information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined
in the Private Securities Litigation Reform Act of 1995. These statements are
based on management's current expectations and involve risks and uncertainties,
which may cause results to differ materially from those set forth in the
statements. The forward-looking statements may include statements regarding
product development, product potential or financial performance. No
forward-looking statement can be guaranteed and actual results may differ
materially from those projected. Merck undertakes no obligation to publicly
update any forward-looking statement, whether as a result of new information,
future events, or otherwise. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that affect Merck's
business, particularly those mentioned in the risk factors and cautionary
statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and
in any risk factors or cautionary statements contained in the Company's periodic
reports on Form 10-Q or current reports on Form 8-K, which the Company
incorporates by reference.

1.NAME OF THE MEDICINAL PRODUCT

Tredaptive 1000 mg/20 mg modified-release tablets.

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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.PHARMACEUTICAL FORM

Modified-release tablet.

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

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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.

4.2Posology and method of administration

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.

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,
alcohol or hot drinks 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).

4.3Contraindications

* Hypersensitivity to the active substances or to any of the excipients.
* Significant or unexplained hepatic dysfunction.
* Active peptic ulcer disease.
* Arterial bleeding.

4.4Special 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 1000 mg/20 mg dose.

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

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

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

Effect on skeletal muscle

Rare cases of 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.

Renal dysfunction

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

Effect on glucose

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

Acute coronary syndrome

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

Haematologic effects

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

Effect on uric acid

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

Hypophosphatemia

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

Further

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.

4.5Interaction with other medicinal products and other forms of interaction

Simultaneous use of alcohol or hot drinks 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.

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. The clinical significance of these observations is unknown.

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).

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.

4.6Pregnancy 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. 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.

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.

4.7Effects on ability to drive and use machines

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).

4.8Undesirable effects

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=2548), 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 (≥ 1/1,000 to < 1/100),
Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000).

System organ class Adverse reaction Frequency
Investigations elevations in ALT and/or AST (consecutive, Common
≥ 3 X ULN), fasting glucose, uric acid (see below)
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

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.

4.9Overdose

Tredaptive

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

Nicotinic acid

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

Laropiprant

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

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic 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 D2 (PGD2) receptor subtype 1 (DP1). Nicotinic acid lowers the
levels of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC),
very low density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B, the
major LDL protein), triglycerides (TG), and lipoprotein(a) (Lp(a), a modified
LDL particle) and elevates the levels of high-density lipoprotein cholesterol
(HDL-C) and apolipoprotein A-I (apo A-I, the major protein component of HDL).
Laropiprant suppresses PGD2 mediated flushing associated with administration of
nicotinic acid. Laropiprant has no effect on lipid levels nor does it interfere
with the effects of nicotinic acid on lipids.

Nicotinic acid

Mechanism of action

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

Pharmacodynamic effects

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

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

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

Laropiprant

Mechanism of action

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

Pharmacodynamic effects

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

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

Clinical studies

Effect on lipids

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

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

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

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

Flushing

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

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

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).

5.2Pharmacokinetic 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 (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.

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 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).

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

Tredaptive: No studies have been performed in paediatric patients.

Race

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

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

5.3Preclinical 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/m2 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 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

6.1List of excipients

Hypromellose (E464)
Colloidal anhydrous silica (E551)
Sodium stearyl fumarate
Hydroxypropylcellulose (E463)
Microcrystalline cellulose (E460)
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years.

6.4Special 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.

6.5Nature 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 or 196
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 or 56 modified-release tablets.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.DATE OF REVISION OF THE TEXT

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

TREDAPTIVE and CORDAPTIVE are trademarks of Merck & Co., Inc., Whitehouse
Station, NJ, USA

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or
Investors:
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