Trevaclyn - patient leaflet, side effects, dosage

kN

Laropiprant

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

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

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

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

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

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

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Hypromellose (E464)

Colloidal anhydrous silica (E551)

Sodium stearyl fumarate

Hydroxypropyl­cellulose (E463)

Microcrystalline cellulose (E460) Croscarmellose sodium

Lactose monohydrate Magnesium stearate

• 6.2 Incompati­bilities

Not applicable.

• 6.3 Shelf life

PVC/Aclar blisters: 2 years.

Aluminium/Aluminium blisters: 18 months.

• 6.4 Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from light and moisture.

• 6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

• 6.6 Special 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)

EU/1/08/458/001

EU/1/08/458/002

EU/1/08/458/003

EU/1/08/458/004

EU/1/08/458/005

EU/1/08/458/006

EU/1/08/458/007

EU/1/08/458/008

EU/1/08/458/009

EU/1/08/458/010

EU/1/08/458/011

EU/1/08/458/012

EU/1/08/458/013

EU/1/08/458/014

Date of first authorisation: 3 July 2008

10. DATE OF REVISION OF THE

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

• A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

Merck, Sharp & Dohme Ltd.

Shotton Lane

Cramlington

Northumberland NE23 3JU

United Kingdom

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription

• C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the Marketing Authorisation, is in place and functioning before and whilst the medicinal product is on the market.

Risk Management Plan (RMP)

The MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in the RMP presented in Module 1.8.2 of the Marketing Authorisation and any subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use (CHMP).

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the sa (PSUR).

In addition, an updated RMP should be submitted:

• When new information i eived that may impact on the current Safety Specification,

minimisation activities

(pharmacovigilance or risk minimisation) milestone being

uropean Medicines Agency.

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (for Alu/Alu blister)

• 1. NAME OF THE MEDICINAL PRODUCT

Trevaclyn 1,000 mg/20 mg modified-release tablets

Nicotinic acid/laropiprant

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

  
  

14 modified-release tablets

28 modified-release tablets

56 modified-release tablets

168 modified-release tablets

32 × 1modified-release tablets

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.

Read the package leaflet before use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

• 8. EXPIRY DATE

EXP

• 9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

Store in the original package in order to protect from light and moisture.

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

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

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

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (for PVC/Aclar blister)

• 1. NAME OF THE MEDICINAL PRODUCT

Trevaclyn 1,000 mg/20 mg modified-release tablets

Nicotinic acid/laropiprant

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

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

  
  
  
  

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 o 49 × 1 modified-release tablets „X _

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.

Read the package leaflet before use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

• 8. EXPIRY DATE

EXP

• 9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.

Store in the original package in order to protect from light and moisture.

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

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

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

EU/1/08/458/001 14 modified-release tablets

EU/1/08/458/002 28 modified-release tablets

EU/1/08/458/003 56 modified-release tablets

EU/1/08/458/004 84 modified-release tablets

EU/1/08/458/005 98 modified-release tablets

EU/1/08/458/0­06 168 modifi­ed-release tablets

EU/1/08/458/0­07 196 modifi­ed-release tablets

EU/1/08/458/008 49 × 1 modified-release tablets

EU/1/08/458/012 196 (2 packs of 98

Medicinal product subject to medical prescription.

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Trevaclyn

PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON

Multi-packs of 196 (2 packs of 98 modified-release tablets) – without blue box (for PVC/Aclar blister)

1. NAME OF THE MEDICINAL PRODUCT

Trevaclyn 1,000 mg/20 mg modified-release tablets

Nicotinic acid/laropiprant

2. STATEMENT OF ACTIVE SUBSTANCE(S)

• 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.

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

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

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

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

• 1. NAME OF THE MEDICINAL PRODUCT

Trevaclyn 1000 mg/20 mg modified-release tablets

Nicotinic acid/laropiprant

• 2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

Package leaflet: Information for the patient

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

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor or pharmacist.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet:

What Trevaclyn is and what it is used for

What you need to know before you take Trevaclyn

How to take Trevaclyn

Possible side effects

How to store Trevaclyn

Contents of the pack and other information

What Trevaclyn is and what it is used for

The name of your medicine is Trevaclyn. It contains two di

nicotinic acid, a lipid modifying medicine, and

laropiprant, which reduces symptoms of flushing, a common side effect of nicotinic acid.

How Trevaclyn Works

Trevaclyn is used in addition to diet

• to lower your ‘bad’ cholesterol level. It does this by lowering the levels of total cholesterol, LDL cholesterol, fatty substances called triglycerides and apo B (a part of LDL) in the blood;
• to raise levels of ‘good’ cholesterol (HDL cholesterol) and apo A-I (a part of HDL).

What should I know about cholesterol and triglycerides?

Cholesterol is one of several fats found in your blood. Your total cholesterol is made up mainly of ‘bad’ (LDL) and ‘good’ (HDL) cholesterol.

LDL cholesterol is often called ‘bad’ cholesterol because it can build up in the walls of your arteries and form plaque. Over time, this plaque build-up can lead to a clogging of your arteries. This clogging can slow or block blood flow to vital organs such as the heart and brain. When the blood flow is blocked, the result can be a heart attack or stroke.

HDL cholesterol is often called ‘good’ cholesterol because it helps keep the ‘bad’ cholesterol from building up in the arteries and because it protects against heart disease.

Triglycerides are another fat in your blood. They may raise your risk of having heart problems.

In most people, at first there are no signs of cholesterol problems. Your doctor can measure your cholesterol with a simple blood test. Visit your doctor regularly to keep track of your cholesterol and discuss your goals with your doctor.

Trevaclyn is used in addition to diet and exercise in adult patients with primary hypercholeste­rolaemia or mixed dyslipidaemia :

• when you cannot control your cholesterol levels with a statin alone (class of cholesterol-lowering

medicines working in the liver);

• when you cannot tolerate a statin or when a statin is not recommended for you.

Patients with combined mixed dyslipidaemia have high blood levels of ‘bad’ LDL cholesterol and triglycerides (a type of fat), and low levels of ‘good’ HDL cholesterol. Primary hypercholeste­rolaemia is when the levels of cholesterol in the blood are high. Primary means that the hypercholeste­rolaemia does not have any identifiable cause.

2. What you need to know before you take TrevaclynDo not take Trevaclyn if you are allergic to nicotinic acid, to laropiprant, or to any of the other ingredients of this medicine (listed in section 6).

• you currently have liver problems.
• you have an ulcer in your stomach.
• you have arterial bleeding.

Do not take Trevaclyn if any of the above apply to you. If you are not sure, tal pharmacist before taking Trevaclyn.

Warnings and precautions

Tell your doctor about all of your medical conditions. Check with your doctor or pharmacist before and while taking your medicine if:

• you have any allergies.
• you have ever had liver disease, jaundice (a liver disorder causing yellowing of the skin and whites of the eyes), or hepatobiliary (liver and bile duct) disease.
• you have kidney problems.
• you have thyroid problems.
• you drink large amounts of alcohol.
• you or close family members have a hereditary muscle disorder, or you have ever had muscle problems during treatment with cholesterol-lowering medicines called “statins” or fibrates.
• you have unexplained muscle pain, muscle tenderness, or muscle weakness. If you have these symptoms talk to your doctor immediately.
• you have high blood sugar or diabetes.
• you have heart problems.

you are going to hav you have gout.

you have low levels

you are over 70 years old.

you are taking simvastatin (a statin) or a medicine containing simvastatin and are Chinese.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Trevaclyn.

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 Trevaclyn to check how well your liver is working.
• Your doctor may also want you to periodically have blood tests after you start taking Trevaclyn, to check how well your liver is working and for other side effects.

Children and adolescents

Trevaclyn has not been studied in children and adolescents who are under 18 years of age. Therefore,

Trevaclyn should not be used in children and adolescents under 18 years of age.

Other medicines and Trevaclyn

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, vitamins, and herbal supplements.

In particular, tell your doctor or pharmacist if you are taking any of the following:

• medicines used to lower blood pressure.
• medicines used to lower cholesterol called ‘bile acid sequestrants’, such as colestyramine.
• zidovudine, a medicine used for HIV.
• midazolam, a medicine to make you sleepy before some medical procedures.
• vitamins or supplements that contain nicotinic acid.
• clopidogrel and acetylsalicylic acid (ASA), medicines to help prevent harmful blood clots.
• medicines used to lower cholesterol called ‘statins’.

Also tell your doctor if you are taking simvastatin (a statin) or a medicine containing simvastatin and are Chinese.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Trevaclyn.

near the time you take your dose of Trevaclyn.

It is important to follow the advice given in section 3

How to take Trevaclyn

.

Pregnancy and breast-feeding

Trevaclyn is not recommended in pregnancy unless clearl

Talk with your doctor before taking Trevaclyn if:

You are pregnant or plan to become pregnant. It is not known if Trevaclyn will harm your unborn baby.

You are breast-feeding or plan to breast-feed. It is not known if Trevaclyn will pass into your breast milk. However, nicotinic acid a component of Trevaclyn does pass into breast milk.

Ask your doctor or pharmacist for advice before taking this medicine. Your doctor will decide if Trevaclyn is right for you.

Driving and using machines

Some people get dizzy after taking Trevaclyn. If you get dizzy, you should avoid driving or operating machines after taking Trevaclyn.

Trevaclyn contains lactose

Trevaclyn 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 Trevaclyn

Always take this medicine exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

How much to take

• You should start by taking one tablet a day.
• After 4 weeks, your doctor may raise your dose to two tablets a day.
• If you are switching from a medicine containing 2,000 mg or more of a prolonged-release

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

Trevaclyn to two tablets a day.

How to take

• Take Trevaclyn once a day, in the evening or at bedtime.
• Take Trevaclyn 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 Trevaclyn. 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 Trevaclyn does not reduce your flushing more than taking Trevaclyn 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.
• In the event of an overdose, the following side effects were reported: flushing, headache, pruritus (itching), nausea, dizziness, vomiting, diarrho pain/discomfort, and back pain.
• If you take more than you should, talk to a doctor or pharmacist straight a
• 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 Trevaclyn for 7 or more days in a row, talk to your doctor before restarting Trevaclyn.

If you stop taking Trevaclyn

Do not stop taking Trevaclyn without talking to your doctor. Your cholesterol problem may return.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects of Trevaclyn are:

Very common (may affect more than 1 in 10 people)

• flushing (which usually includes redness of the skin, feeling warm, itching, or tingling, particularly in the head, neck, chest and upper back). If flushing occurs, symptoms are generally most noticeable at first and usually lessen over time.

Common (may affect up to 1 in 10 people)

• headache
• tingling or numbness of the hands or feet
• abdominal pain
• diarrhoea
• upset stomach or heartburn
• nausea (feeling sick)
• getting sick (vomiting)
• pruritus (itching)
• rash
• hives

Uncommon (may affect up to 1 in 100 people)

• gout
• sleeplessness
• dizziness
• palpitation (feeling your heartbeat)
• low blood pressure
• shortness of breath
• dry skin
• rash with flat, red spots
• muscle pain or tenderness
• chills
• pain
• swelling of the fingers, toes or ankles

In addition, one or more of the following symptoms have been reported as part of an allergic reaction to Trevaclyn.

• swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (angioedema, which may require treatment right away)
• fainting
• shortness of breath
• loss of control over urine and stool
• cold sweats
• shivering
• chills
• increased blood pressure
• swelling of the lips
• burning sensation
• whole body rash
• joint pain
• swelling of the legs
• rapid heart rate.

Rare (may affect up to 1 in 1000

• runny nose
• decreased glucose (sugar) t
• anxiety
• migraine
• fainting
• rapid or irregular heartbeat
• dizziness upon standing
• belching
• stomach ulcer
• skin disorder with dark velvety plaques called acanthosis nigricans
• patches of darkened skin
• sweating
• muscle weakness

weakness

generalised swelling

Not known: frequency cannot be estimated from the available data

Additionally, the following were reported during post-marketing experience with Trevaclyn and/or other nicotinic acid products (alone and/or with certain other cholesterol-lowering medicines).

• a sudden serious allergic reaction (anaphylactic shock). Symptoms included fainting, shortness of breath, wheezing or trouble breathing, swelling of the face, lips, tongue, itching or hives on the skin. This condition requires immediate medical attention.
• eye disorders called toxic amblyopia and cystoid macular oedema which may lead to blurred, decreased, or lost vision
• yellowing of the skin and/or eyes (jaundice)
• blistering rash

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How to store Trevaclyn

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the blister after EXP.

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

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other informationWhat Trevaclyn containsh tablet contains 1000 mg nicotinic

• The active substances are nicotinic acid and laropipr 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 Trevaclyn 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 × 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 × 1 modified-release tablets in perforated unit dose blister.

Not all pack sizes may be marketed.

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

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique/Belgi­e/Belgien

MSD Belgium BVBA/SPRL

Tél/Tel: 0800 38 693 (+32 (0)27766211)

Efcnrapua

MepK fflapn u floyM Etnrapua EOOfl

Ten.: +359 2 819 3737

Česká republika

Merck Sharp & Dohme s.r.o.

Tel.: +420 233 010 111

Luxembourg/Lu­xemburg

MSD Belgium BVBA/SPRL

Tel/Tel: 0800 38 693 (+32 (0)27766211)

Magyarorszag

MSD Pharma Hungary Kft.

Tel.: +36 1 888 53 00

Malta

Merck Sharp & Dohme Cyprus Limited

Tel: +8007 4433 (+356 99917558)

Ireland

Merck Sharp and Dohme Ireland (Human Health)

Limited

Tel: +353 (0)1 2998700

island

Vistor hf.

Simi: +354 535 7000

Slovenija

Merck Sharp & Dohme, inovativna zdravila d.o.o.

Tel: + 386 1 5204201

Slovenská republika

Merck Sharp & Dohme, s. r. o. Tel.: +421 2 58282010

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