NovoRapid FlexPen 100 U / ml, solution for injection in a pre-filled pen.

NovoRapid FlexPen

NovoRapid FlexPen

100 U/ml solution for injection in pre-filled pen

Insulin aspart

Read all of this leaflet carefully before you start using this medicine.

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


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

In this leaflet:

• 1. What NovoRapid is and what it is used for


• 2. Before you use NovoRapid


• 3. How to use NovoRapid


• 4. Possible side effects


• 5. How to store NovoRapid


• 6. Further information

What NovoRapid is and what it is used for

NovoRapid is a modern insulin (insulin analogue ) with a rapid-acting effect. Modern insulins are improved versions of human insulin.

NovoRapid is used to treat diabetes mellitus in adults, children and adolescents aged 2 to 17 years. NovoRapid will start to lower your blood sugar 10-20 minutes after you take it, a maximum effect occurs between 1 and 3 hours and the effect lasts for 3-5 hours. Due to this short action NovoRapid should normally be taken in combination with intermediate-acting or long-acting insulin preparations.

Before you use NovoRapid

Do not use NovoRapid

• If you are allergic (hypersensitive) to insulin aspart, or any of the other ingredients of NovoRapid (see 6 Further information)


• If you suspect hypoglycaemia (low blood sugar) is starting (see 4 Possible side effects)


• If FlexPen is dropped, damaged or crushed


• If it has not been stored correctly or if it has been frozen (see 5 How to store NovoRapid)


• If the insulin does not appear water clear and colourless.

Before using NovoRapid

• Check the label to make sure it is the right type of insulin


• Always use a new needle for each injection to prevent contamination.

Take special care with NovoRapid

• If you have trouble with your kidneys or liver, or with your adrenal, pituitary or thyroid glands


• If you are exercising more than usual or if you want to change your usual diet, as this may affect your blood sugar level


• If you are ill: carry on taking your insulin and consult your doctor


• If you are going abroad: travelling over time zones may affect your insulin needs and the timing of the injections. Consult your doctor if you are planning such travelling.

NovoRapid can be used in children instead of soluble human insulin when a rapid onset of effect is preferred. For example, when it is difficult to dose the child in relation to meals.

No clinical studies with NovoRapid have been performed in children under the age of 2 years. Therefore only use NovoRapid in children below this age, if your doctor have specifically told you to.

As with all insulin products, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin aspart dosage adjusted on an individual basis.

Using other medicines

Some medicines affect the way glucose works in your body and this may influence your insulin dose. Listed below are the most common medicines, which may affect your insulin treatment. Tell your doctor, nurse or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. In particular, you should tell your doctor if you are using any medicine as mentioned below that affect your blood sugar level.

If you take any of the below medicine your blood sugar level may fall (hypoglycaemia):

• Other medicines for the treatment of diabetes


• Monoamine oxidase inhibitors (MAOI) (used to treat depression)


• Beta-blockers (used to treat high blood pressure)


• Angiotensin converting enzyme (ACE) inhibitors (used to treat certain heart conditions or high blood pressure)


• Salicylates (used to relieve pain and lower fever)


• Anabolic steroids (such as testosterone)


• Sulphonamides (used to treat infections).

If you take any of the below medicine your blood sugar level may rise (hyperglycaemia):

• Oral contraceptives (birth control pills)


• Thiazides (used to treat high blood pressure or excessive fluid retention)


• Glucocorticoids (such as "cortisone" used to treat inflammation)


• Thyroid hormones (use to treatthyroid gland disorders)


• Sympathomimetics (such as epinephrine [adrenaline], or salbutamol, terbutaline used to treat asthma)


• Growth hormone (medicine for stimulation of skeletal and somatic growth and pronounced influence on the body’s metabolic processes)


• Danazol (medicine acting on ovulation).

Octreotide and lanreotide (used for treatment of acromegaly) may both increase or decrease your sugar level.

Beta-blockers (used to treat high blood pressure) may weaken or suppress entirely the first warning symptoms which help you to recognise a hypoglycaemia.

Taking NovoRapid with food and drink

• If you are drinking alcohol your need for insulin may change as your blood sugar level may either rise or fall. Carefull monitoring is recommended.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

• If you are pregnant, planning a pregnancy or breast-feeding please contact your doctor for advice. NovoRapid can be used during pregnancy. Your insulin dosage may need to be changed during pregnancy and after delivery. Careful control of your diabetes, particulary prevention of hypoglycaemia, is important, for the health of your baby.

Driving and using machines

If your blood sugar is low or high your concentration and ability to react might be affected and therefore also your ability to drive or operate a machine. Bear in mind that you could endanger yourself or others. Please ask your doctor whether you can drive a car:

• If you have frequent hypoglycaemias


• If you find it hard to recognise hypoglycaemia.

NovoRapid has a rapid onset of effect therefore if hypoglycaemia occurs, you may experience it earlier after an injection when compared to soluble human insulin.

How to use NovoRapid

Dosage

Talk about your insulin dose with your doctor and nurse. Make sure you get the colour coded NovoRapid FlexPen that your doctor and nurse have told you to use and follow their advice carefully. This leaflet is a general guide. If your doctor has switched you from one type or brand of insulin to another, your dose may have to be adjusted by your doctor. Do not change your insulin unless your doctor tells you to.

Eat a meal or snack containing carbohydrates within 10 minutes of the injection to avoid hypoglycaemia.

When necessary, NovoRapid may be given soon after the meal, instead of before the meal.

Method of administration

NovoRapid is for injection under the skin (subcutaneously) or for continuous infusion in a pump system. NovoRapid may also be given directly into a vein (intravenously) by health care professionals under close supervision by a doctor. Never inject your insulin directly into a vein or muscle (intramuscular).

Always vary the sites you inject within the same region to avoid lumps (see 4 Possible side effects). The best places to give yourself an injection are: the front of your waist (abdomen), the upper arm or the front of your thighs.

You should always measure your blood glucose regularly.

For use in an infusion pump system

NovoRapid should never be mixed with any other insulin when used in a pump.

Follow the instructions and recommendations from your doctor regarding the use of NovoRapid in a pump.

Before use of NovoRapid in the pump system you must have received a comprehensive instruction in the use and information about any actions to be taken in case of illness, too high or too low blood sugar or failure of the pump system.

• Before inserting the needle, use soap and water to clean your hands and the skin where the needle is inserted so as to avoid any infection at the infusion site


• When you fill a new reservoir, be certain not to leave large air bubbles in either the syringe or the tubing


• Changing of the infusion set (tubing and needle) must be done according to the instructions in the product information supplied with the infusion set.

To get the benefit of insulin infusion, and to detect possible malfunction of the insulin pump, it is recommended that you measure your blood sugar level regularly.

What to do in case of pump system failure

You should always have alternative insulin available for injection under the skin in case of pump system failure.

If you take more insulin than you should

If you take too much insulin your blood sugar gets too low (this is called hypoglycaemia or hypo). This may also happen:

• If you eat too little or miss a meal


• If you exercise more than usual.

The warning signs of a hypo may come on suddenly and can include: cold sweat; cool pale skin; headache; rapid heart beat; feeling sick; feeling very hungry; temporary changes in vision; drowsiness; unusual tiredness and weakness; nervousness or tremor; feeling anxious; feeling confused; difficulty in concentrating.

If you feel a hypo coming on: take a high sugar snack and then measure your blood sugar.

If your blood sugar is too low: eat glucose tablets or another high sugar snack (sweets, biscuits, fruit juice), then rest.

Always carry glucose tablets, sweets, biscuits or fruit juice with you, just in case.

When symptoms of hypoglycaemia have disappeared or when blood glucose level is stabilised continue insulin treatment.

Tell relevant people you have diabetes and what may be the consequences, including the risk of passing out due to a hypo.

Tell relevant people that if you pass out (become unconscious), they must turn you on your side and get medical help straight away. They must not give you any food or drink. It could choke you.

You may recover more quickly from unconsciousness with an injection of the hormone glucagon by someone who knows how to use it. If you are given glucagon you will need glucose or a sugary snack as soon as you are conscious. If you do not respond to glucagon treatment, you will have to be treated in a hospital. Contact your doctor or an emergency ward after an injection of glucagon: you need to find the reason for your hypo to avoid getting more.

• If prolonged severe hypoglycaemia is not treated, it can cause brain damage (temporary or permanent) and even death


• If you have a hypo that makes you pass out, or a lot of hypos, talk to your doctor. The amount or timing of insulin, food or exercise may need to be adjusted.

If you forget to take your insulin

If you forget to take your insulin your blood sugar may get too high (this is called hyperglycaemia). This may also happen:

• If you repeatedly take less insulin than you need


• If you get an infection or a fever


• If you eat more than usual


• If you exercise less than usual.

The warning signs appear gradually. They include: increased urination; feeling thirsty; losing your appetite; feeling sick (nausea or vomiting); feeling drowsy or tired; flushed, dry skin; dry mouth and a fruity (acetone) smell of the breath.

If you get any of these signs: test your blood sugar level, test your urine for ketones if you can, then seek medical advice immediately.

These may be signs of a very serious condition called diabetic ketoacidosis. If you do not treat it, this could lead to diabetic coma and eventually death.

If you stop taking your insulin

This could lead to severe hyperglycaemia (very high blood sugar) and ketoacidosis (build-up of acid in the blood because the body is breaking down fat instead of sugar).

Do not stop taking your insulin without speaking to a doctor, who will tell you what needs to be done.

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

How to handle NovoRapid FlexPen

NovoRapid FlexPen is a pre-filled disposable pen containing insulin aspart.

Read carefully the NovoRapid FlexPen instruction for use included in this package leaflet. You must use the pen as described in the Instructions for Use

Possible side effects

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

Side effects may occur with certain frequencies, which are defined as follows:

• Very common: affects more than 1 user in 10


• Common: affects 1 to 10 users in 100


• Uncommon: affects 1 to 10 users in 1,000


• Rare: affects 1 to 10 users in 10,000


• Very rare: affects less than 1 user in 10,000


• Not known: frequency cannot be estimated from the available data.

Uncommon side effects

Signs of allergy. Reactions (pain, redness, hives, inflammation, swelling and itching) at the injection site may occur (local allergic reactions). These usually disappear after a few weeks of taking your insulin. If they do not disappear, see your doctor.

Seek medical advice immediately:

• If signs of allergy spread to other parts of your body, or


• If you suddenly feel unwell, and you: start sweating; start being sick (vomiting); have difficulty in breathing; have a rapid heart beat; feel dizzy.

Vision problems. When you first start your insulin treatment, it may disturb your vision, but the disturbance is usually temporary.

Changes at the injection site (lipodystrophy). If you inject yourself too often at the same site, fatty tissue under the skin at this site may shrink (lipoatrophy) or thicken (lipohypertrophy). Changing the site with each injection may help to prevent such skin changes. If you notice your skin pitting or thickening at the injection site, tell your doctor or nurse because these reactions can become more severe, or they may change the absorption of your insulin if you inject in such a site.

Swollen joints. When you start taking insulin, water retention may cause swelling around your ankles and other joints. Normally this soon disappears.

Diabetic retinopathy. If you have diabetic retinopathy and your blood glucose level improve very fast, the retinopathy may get worse. Ask your doctor about this.

Common side effects

Low blood sugar (hypoglycaemia).

Rare side effects

Painful neuropathy. If your blood glucose level improve very fast, you may get nerve related pain, this is called acute painful neuropathy and is usually transient.

Very rare side effects

Serious allergic reaction to NovoRapid or one of its ingredients (called a systemic allergic reaction). See also the warning in 2 Before using NovoRapid.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.

How to store NovoRapid

Keep out of the reach and sight of children.

Do not use NovoRapid after the expiry date which is stated on the FlexPen label and carton, after EXP. The expiry date refers to the last day of that month.

NovoRapid FlexPen that is not being used is to be stored in the refrigerator at 2°C - 8°C, away from the cooling element. Do not freeze.

NovoRapid FlexPen that is being used or carried as a spare is not to be kept in the refrigerator. You can carry it with you and keep it at room temperature (below 30°C) for up to 4 weeks.

Always keep the cap on your FlexPen when you are not using it in order to protect it from light.

NovoRapid must be protected from excessive heat and light.

Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What NovoRapid contains

• The active substance is insulin aspart. Each ml contains 100 U of insulin aspart. Each pre-filled pen contains 300 U of insulin aspart in 3 ml solution for injection


• The other ingredients are: glycerol, phenol, metacresol, zinc chloride, disodium phosphate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.

What NovoRapid looks like and contents of the pack

NovoRapid comes as a clear, colourless, aqueous solution.

Pack sizes of 1, 5 and 10 pre-filled pens of 3 ml. Not all packs may be marketed.

Marketing authorisation holder

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Manufacturer

The manufacturer can be identified by the batch number printed on the slip of the carton and on the label:

• If the second and third characters are W5, S6, P5, K7, R7 or ZF

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

is the manufacturer

• If the second and third characters are H7 or T6

Novo Nordisk Production SAS

45 Avenue d’Orléans F-28002 Chartres

France

is the manufacturer.

Now turn over for information on how to use your FlexPen.

This leaflet was last approved in 04/2009

NovoRapid,
FlexPen,
NovoTwist
and NovoFine,
are trademarks owned by Novo Nordisk A/S

© 2002/2009

Novo Nordisk A/S

NOVORAPID solution for injection in a pre-filled pen. FlexPen. INSTRUCTIONS FOR USE

Please read the following instructions carefully before using your NovoRapid FlexPen.

Your FlexPen is a unique dial-a-dose insulin pen. You can select doses from 1 to 60 units in increments of 1 unit. FlexPen is designed to be used with NovoFine or NovoTwist disposable needles up to a length of 8 mm. As a precautionary measure, always carry a spare insulin delivery device in case your FlexPen is lost or damaged.

The colour of the pen in the illustrations differs from your FlexPen.

Maintenance

Your FlexPen is designed to work accurately and safely. It must be handled with care.

If it is dropped or crushed, there is a risk of damage and leakage of insulin.

You can clean the exterior of your FlexPen by wiping it with a medicinal swab. Do not soak
it, wash or lubricate it as it may damage the pen.

Do not refill your FlexPen.

Preparing your NovoRapid FlexPen

Check the label to make sure that your FlexPen contains the correct type of insulin.

• 
  A. Pull off the cap.
  
  Disinfect the rubber membrane with a medicinal swab.

• 
  B. Remove the protective tab from a new disposable needle.
  
  Screw the needle straight and tightly onto your FlexPen

• 
  C. Pull off the big outer needle cap and keep it for later.

• 
  D. Pull off the inner needle cap and dispose of it.

• Always use a new needle for each injection to prevent contamination.


• Be careful not to bend or damage the needle before use.


• To reduce the risk of unexpected needle sticks, never put the inner needle cap back on when you have removed it from the needle.

Checking the insulin flow

Prior to each injection small amounts of air may collect in the cartridge during normal use. To avoid injection of air and ensure proper dosing:

• 
  E Turn the dose selector to select 2 units.

• 
  F. Hold your FlexPen with the needle pointing upwards and tap the cartridge gently with your finger a few times to make any air bubbles collect at the top of the cartridge.

• 
  G. Keeping the needle upwards, press the push-button all the way in. The dose selector returns to 0.
  
  A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than six times.
  
  If a drop of insulin still does not appear, the pen is defective, and you must use a new one.

Selecting your dose

Check that the dose selector is set at 0.

• 
  H. Turn the dose selector to select the number of units you need to inject.
  
  The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer. When turning the dose selector be careful not to push the push-button as insulin will come out.
  
  
  You cannot select a dose larger than the number of units left in the cartridge.

• Do not use the residual scale to measure your dose of insulin.

Making the injection

Insert the needle into your skin. Use the injection technique shown by your doctor or nurse.

• 
  I Inject the dose by pressing the push-button all the way in until 0 lines up with the pointer. Be careful only to push the push-button when injecting.
  
  
  Turning the dose selector will not inject insulin.

• 
  J Keep the push-button fully depressed after the injection until the needle has been withdrawn from the skin.
  
  The needle must remain under the skin for at least six seconds. This will ensure that the full dose has been injected.

• 
  K Lead the needle into the big outer needle cap without touching the big outer needle cap. When the needle is covered, carefully push the big outer needle cap completely on and then unscrew the needle.
  
  
  Dispose of it carefully and put the cap back on.

• Always remove the needle after each injection and store your FlexPen without the needle attached. Otherwise, the liquid may leak out which can cause inaccurate dosing.


• Caregivers should be most careful when handling used needles to avoid needle sticks.


• Dispose of the used FlexPen carefully without the needle attached.


• Do not share your FlexPen with anyone else.

8-9670-01-005-2

Dexalocal

Dexalocal may be available in the countries listed below.

Ingredient matches for Dexalocal

Budesonide

Budesonide is reported as an ingredient of Dexalocal in the following countries:

• Greece

Dexamethasone

Dexamethasone is reported as an ingredient of Dexalocal in the following countries:

• Bahrain


• Cyprus


• Dominican Republic


• Guatemala


• Jordan


• Kuwait


• Lebanon


• Oman


• Qatar


• Switzerland


• United Arab Emirates


• Yemen

Framycetin

Framycetin sulfate (a derivative of Framycetin) is reported as an ingredient of Dexalocal in the following countries:

• Oman

International Drug Name Search

Nurofen for Children Orange Singles

1. Name Of The Medicinal Product

Nurofen for Children Orange Singles

2. Qualitative And Quantitative Composition

Ibuprofen 100mg/ 5ml (equivalent to 2.0% w/v)

For excipients, see 6.1.

3. Pharmaceutical Form

Oral suspension

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of rheumatic or muscular pain, headache, dental pain, feverishness, or symptoms of colds and influenza.

4.2 Posology And Method Of Administration

For pain and fever: The daily dosage of Nurofen For Children Strawberry Singles is 20-30 mg/kg bodyweight in divided doses. This can be achieved as follows:

Infants 3 - 6 months weighing more than 5kg: One 2.5ml dose may be taken 3 times in 24 hours.

Infants 6 - 12 months: One 2.5ml spoonful may be taken 3 to 4 times in 24 hours.

Children 1 - 3 years: One 5ml spoonful may be taken 3 times in 24 hours.

Children 4 - 6 years: 7.5ml ( 5ml + 2.5ml spoonful ) may be taken 3 times in 24 hours.

Children 7 - 9 years: Two 5ml spoonfuls may be taken 3 times in 24 hours.

Doses should be given approximately every 6 to 8 hours, (or with a minimum of 4 hours between each dose if required).

Not suitable for children under 3 months of age.

If the fever is not reduced, consult your doctor.

For oral administration.

For short term use only. If the child's (aged over 6months) symptoms persist for more than 3 days, consult your doctor.

For children under 6 months medical advice should be sought after 24 hours use (3 doses) if the symptoms persist.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the constituents in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe hepatic failure, renal failure or heart failure (see section 4.4).

Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.

Other NSAIDs:

The use of ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease - increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see section 4.3 and 4.8).

Hepatic:

Hepatic dysfunction (see section 4.3 and 4.8).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility

There is limited evidence that drugs which inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will state:

Read the leaflet carefully before use.

Do not take if you or your child is:

• under 3 months old

• have (or have had two or more episodes of ) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Speak to your doctor or pharmacist before giving this product if baby or child:

• have or had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

If symptoms persist or worsen, consult your doctor.

Adults intending to take this product should take note of the above warnings.

Speak to your doctor or pharmacist before taking if; you are pregnant; you are trying to get pregnant; you are elderly; you are a smoker.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should not be used in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4)

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs.

Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4)

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Children under 9 years are unlikely to become pregnant or breast feed.

Whilst no teratogenic effects have been demonstrated in animal experiments, the use of ibuprofen should, if possible, be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (see section 4.3).

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of:

(a) Non-specific allergic reactions and anaphylaxis;

(b) Respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea;

(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis. Exacerbation of ulcerative colitis and Crohn's disease (See section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Dermatological:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).

Cardiovascular and Cerebrovascular

Oedema, hypertension and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses (2400mg daily)) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintainance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the consumer.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid

Sodium citrate

Sodium chloride

Sodium saccharin

Domiphen bromide

Purified water

Polysorbate 80

Maltitol syrup

Xanthan gum

Orange flavour

Glycerin.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

The suspension is packed in laminated sachets consisting of:

1. Polyethylene (contact material)/ 12 micron aluminium/ paper or

2. Polyethylene (contact material)/ 12 micron aluminium/ polyester or

3. Polyethylene (contact material) 15 micron aluminium/ paper

Pack sizes of 2,3,4,5, 8,10,12,15,16,18,20 sachets in a cardboard carton.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 4AQ

8. Marketing Authorisation Number(S)

PL 00063/0669

9. Date Of First Authorisation/Renewal Of The Authorisation

12 April 2002

10. Date Of Revision Of The Text

16/08/2011

Niaspan Prolonged-Release Tablets Starter Pack

1. Name Of The Medicinal Product

Niaspan Prolonged-Release Tablets- Starter Pack

2. Qualitative And Quantitative Composition

Starter Pack contains 7 tablets each:

Prolonged-Release Tablets containing 375 mg nicotinic acid

Prolonged-Release Tablets containing 500 mg nicotinic acid

Prolonged-Release Tablets containing 750 mg nicotinic acid

For excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release tablets

White to off-white capsule-shaped tablets. Each tablet is embossed with the tablet strength on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

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. Niaspan 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. Niaspan can be used as monotherapy only in patients who do not tolerate HMG-CoA reductase inhibitors. Diet and other non-pharmacological treatments (e.g. exercise, weight reduction) should be continued during therapy with Niaspan.

4.2 Posology And Method Of Administration

Niaspan Prolonged-Release Tablets Starter Pack is only a starter pack presentation for initial dose titration.

Niaspan should be taken at bedtime, after a low-fat snack (e.g. an apple, low fat yoghurt, slice of bread) and doses should be individualised according to the patient's response.

Initial dose

Therapy with Niaspan must be initiated with a low dose and increased gradually. The recommended dose escalation schedule is shown below in Table 1:

Table 1: Dose escalation schedule

	Week(s)	Dosage		Daily nicotinic acid dose
↑	1	Niaspan 375mg	1 tablet at bedtime	375mg	↑
INITIAL TITRATION SCHEDULE	2	Niaspan 500mg	1 tablet at bedtime	500mg	TITRATION STARTER PACK
	3	Niaspan 750mg	1 tablet at bedtime	750mg
	4-7	Niaspan 500mg	2 tablets at bedtime	1000mg
		Niaspan 750mg	2 tablets at bedtime	1500mg
		Niaspan 1000mg	2 tablets at bedtime	2000mg

Maintenance dose

The recommended maintenance dose is 1000mg (two 500mg tablets) to 2000mg (two 1000mg tablets) once daily at bedtime depending on the patient's response and tolerance. If the response to 1000mg daily is inadequate, the dose may be increased to 1500mg daily and subsequently to 2000mg daily.

The daily dosage of Niaspan should not be increased by more than 500mg in any four-week period after the initial titration to 1000mg. The maximum dose is 2000mg per day.

The different Niaspan tablet strengths have different bioavailability and are therefore not interchangeable.

Niaspan must not be replaced with other nicotinic acid preparations, see section 4.4.

In patients previously treated with other nicotinic acid products, Niaspan treatment must be initiated with the recommended Niaspan dose escalation schedule. The maintenance dose should subsequently be individualised according to the patient's response.

If Niaspan therapy is discontinued for an extended period, re-institution of therapy must include a dose escalation.

Niaspan tablets must not be broken, crushed or chewed before swallowing.

Renal impairment

No studies have been performed in patients with impaired renal function, Niaspan must be used with caution in patients with renal disease.

Hepatic impairment

No studies have been performed in patients with impaired hepatic function. Niaspan must be used with caution in patients with a history of liver disease and who consume substantial quantities of alcohol, see section 4.4. Niaspan is contraindicated in patients with significant hepatic dysfunction, see section 4.3.

Elderly

No dose adjustment is necessary.

Children

The safety and efficacy of nicotinic acid therapy in children and adolescents has not been established. Use in children and adolescents is not recommended.

4.3 Contraindications

Niaspan is contraindicated in patients with

- hypersensitivity to nicotinic acid or to any of the excipients, see section 6.1,

- significant hepatic dysfunction,

- active peptic ulcer disease,

- arterial bleeding.

4.4 Special Warnings And Precautions For Use

Niaspan must not be replaced with other nicotinic acid preparations. When switching from other nicotinic acid preparations to Niaspan, therapy with Niaspan must be initiated with the recommended dose escalation schedule, see section 4.2.

Liver

Nicotinic acid preparations have been associated with abnormal liver tests. Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred in patients who have taken long-acting nicotinic acid products in place of immediate-release nicotinic acid. Since the pharmacokinetics of Niaspan are different to other nicotinic acid preparations, Niaspan must not be replaced with other preparations. The prescribing information of the HMG-CoA reductase inhibitor should also be consulted for warnings and precautions for use.

Caution is advised when Niaspan is used in patients who consume substantial quantities of alcohol and/or have a past history of liver disease.

Elevated liver transaminases have been observed with Niaspan therapy. However, transaminase elevations were reversible upon discontinuation of Niaspan.

Liver tests including AST and ALT must be performed periodically in all patients during therapy with Niaspan and prior to treatment in case of history and/or symptoms of hepatic dysfunction (e.g. jaundice, nausea, fever, and/or malaise). If the transaminase levels show evidence of progression, particularly if they rise to three times the upper limit of normal, the drug must be discontinued.

Skeletal muscle

Reports of rhabdomyolysis in patients on combined therapy with Niaspan and HMG-CoA reductase inhibitors have been received from spontaneous reporting. Physicians contemplating combined therapy with HMG-CoA reductase inhibitors and Niaspan should carefully weigh the potential benefits and risks and should carefully monitor patients for any symptoms of rhabdomyolysis e.g. muscle pain, tenderness or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations.

A CPK level should be measured before starting such a combination in patients with pre-disposing factors for rhabdomyolysis, as follows:

• renal impairment

• hypothyroidism

• alcohol abuse

• age > 70 years

• personal or family history of hereditary muscular disorders

• previous history of muscular toxicity with fibrate or HMG-CoA reductase inhibitor

Muscle damage must be considered in any patient presenting with diffuse myalgia, muscle tenderness and/or marked increase in muscle CK levels (>5 x ULN); under these conditions treatment must be discontinued.

The prescribing information of the HMG-CoA reductase inhibitors should be consulted.

Glucose Intolerance

Diabetic or potentially diabetic patients should be observed closely since there may be a dose-related increase in glucose intolerance. Adjustment of diet and/or oral antidiabetics and/or insulin therapy may become necessary.

Unstable angina and acute myocardial infarction

Caution is advised when Niaspan is used in patients with unstable angina or in the acute phase of myocardial infarction, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers, or adrenergic blocking agents.

Uric acid

Elevated uric acid levels have occurred with Niaspan therapy. Monitoring of patients predisposed to gout is recommended.

Coagulation

Niaspan may affect platelet count and prothrombin time, see section 4.5. Patients undergoing surgery should be carefully evaluated. Caution is also advised when Niaspan is administered concomitantly with anti-coagulants; patients receiving anti-coagulants must be monitored closely for prothrombin time and platelet count.

Hypophosphataemia

Niaspan has been associated with reductions in phosphorous levels. Although these reductions were transient, monitoring of phosphorous levels is recommended in patients at risk of hypophosphataemia.

Other

Patients with a history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niaspan therapy.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant alcohol or hot drinks may increase undesirable flushing and pruritus and should be avoided around the time of Niaspan ingestion.

Niaspan has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000mg). In addition, Niaspan has been associated with small but statistically significant increases in prothrombin time (mean of approximately +4%). When Niaspan is administered concomitantly with anti-coagulants, prothrombin time and platelet counts must be monitored closely.

Nicotinic acid may potentiate the blood-pressure lowering effect of ganglionic blocking agents e.g. transdermal nicotine or vasoactive drugs such as nitrates, calcium channel blockers or adrenergic blocking agents.

Bile acid sequestrants bind to other orally administered medicinal products and should be taken separately, see also prescribing information of the concerned product.

Nicotinic acid may produce false elevations in some fluorometric determinations of plasma or urinary catecholamines. Nicotinic acid may also give false-positive reactions with cupric sulphate solution (Benedict's reagent) in urine glucose tests.

Combination of nicotinic acid with HMG-CoA reductase inhibitors may increase the risk for myopathy and rhabdomyolysis, see also section 4.4. The prescribing information of the HMG-CoA reductase inhibitor should also be consulted.

4.6 Pregnancy And Lactation

Pregnancy

It is not known whether nicotinic acid at doses typically used for lipid disorders can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity. Animal studies are incomplete, see section 5.3.

Niaspan should not be prescribed to pregnant women unless strictly necessary.

Lactation

Nicotinic acid has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with Niaspan in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Niaspan has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Flush

In the placebo-controlled clinical trials, flushing episodes (i.e. warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events for Niaspan (reported by 88% of patients). In these studies fewer than 6% of Niaspan patients discontinued due to flushing.

In comparisons of immediate-release (IR) nicotinic acid and Niaspan, although the number of patients who flushed was similar, fewer flushing episodes were reported by patients who received Niaspan. Following four weeks of maintenance therapy with Niaspan at daily doses of 1500mg, the frequency of flushing over the four week period averaged 1.88 events per patient.

Flushing reactions generally occur during early treatment and the dose titration phase. They are thought to be mediated by the release of prostaglandin D2 and tolerance to flushing usually develops over the course of several weeks.

Spontaneous reports suggest that in rare cases, flushing may be more severe and accompanied by symptoms of dizziness, tachycardia, palpitations, dyspnoea, sweating, chills and/or oedema which in rare cases may lead to syncope. Medical treatment should be administered as necessary.

Hypersensitivity reactions

Hypersensitivity reactions have been reported very rarely. These may be characterised by symptoms such as generalised exanthema, flush, urticaria, vesiculobullous rash, angioedema, laryngospasm, dyspnoea, hypotension, and circulatory collapse. Medical treatment should be administered as necessary.

The following adverse reactions have been observed in clinical studies or in routine patient management, in patients receiving the recommended daily maintenance doses (1000, 1500, and 2000mg) of Niaspan. They are presented by system organ class and frequency grouping (very common >1/10; common >1/100, <1/10; uncommon >1/1,000, <1/100; rare >1/10,000, <1/1,000; very rare <1/10,000, including isolated reports). In general, the incidence of adverse reactions was higher in women compared to men. (Please refer to Table 2 below).

Table 2: Adverse reactions

Organ Class	Very common >1/10	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000, including isolated reports
Immune system disorders					Hypersensitivity
Metabolism and nutrition disorders				Glucose tolerance decreased	Anorexia, gout
Psychiatric disorders				Insomnia, nervousness
Nervous system disorders			Headache, dizziness	Syncope, paraesthesia	Migraine
Eye disorders				Visual impairment	Amblyopia, cystoid macular oedema
Cardiac disorders			Tachycardia, palpitations		Atrial fibrillation, arrhythmia
Vascular disorders	Flushing			Hypotension, orthostatic hypotension	Collapse
Respiratory, thoracic and mediastinal disorders			Dyspnoea	Rhinitis
Gastrointestinal disorders		Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia		Flatulence, eructation	Peptic ulcers
Hepatobiliary disorders					Jaundice
Skin and subcutaneous tissue disorders		Pruritus, rash	Hyperhidrosis, rash generalised, urticaria, dry skin	Face oedema, dermatitis bullous, rash maculopapular	Skin hyperpigmentation, acanthosis nigricans
Musculoskeletal, connective tissue and bone disorders				Muscle spasms, myalgia, myopathy, myasthenia
General disorders and administration site conditions			Pain, asthenia, chills, oedema peripheral	Chest pain
Investigations			Aspartate aminotransferase increased; alanine aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, blood amylase increased, blood glucose increased, blood uric acid increased, platelet count decreased, prothrombin time prolonged, blood phosphorus decreased, blood creatinine phospokinase increased

Adverse reactions from postmarketing experience:

The following adverse reactions have been reported in postmarketing experience with nicotinic acid prolonged release. Adverse reactions are presented by system organ class.

Nervous system disorders: Burning sensation

Eye disorders: Blurred vision

Hepatobiliary disorders: Hepatitis

Skin and subcutaneous tissue disorders: Skin discolouration, skin burning sensation, erythema

General disorders and administration site conditions: Feeling hot

4.9 Overdose

Information on acute overdose with Niaspan in humans is limited. The signs and symptoms of an acute overdose are anticipated to be those of excessive pharmacological effect: severe flushing, nausea/vomiting, diarrhoea, dyspepsia, dizziness, syncope, hypotension, potential cardiac arrhythmias and clinical laboratory abnormalities including elevations in liver function tests. The patient should be carefully observed and given supportive treatment. Insufficient information is available on the dialysis potential of nicotinic acid.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: nicotinic acid, ATC code: C10AD02

Nicotinic acid is a water-soluble B-complex vitamin which is a naturally occurring constituent of foods. The human body is not entirely dependent on dietary sources of nicotinic acid, since it may also be synthesised from tryptophan.

The mechanism of action by which nicotinic acid modify lipid profiles is not fully elucidated. However, it is recognised that nicotinic acid inhibits the release of free fatty acids from adipose tissue resulting in less free fatty acids being presented to the liver. Since fewer fatty acids are being transported to the liver, fewer are esterified to triglycerides and then incorporated into VLDL. This may lead to a decrease in LDL generation. By increasing lipoprotein lipase activity, nicotinic acid may increase the rate of chylomicron triglycerides removal from plasma. Thus, nicotinic acid decreases the rate of hepatic synthesis of VLDL and subsequently LDL. It does not appear to affect faecal excretion of fats, sterols, or bile acids.

At the recommended maintenance dose, Niaspan (but not nicotinamide) resulted in a clinical reduction in total cholesterol to HDL ratio [-17, to -27%], LDL [-8 to -16%], triglycerides [-14 to -35%] with an increase in HDL [16% to 26%]. In addition to the above mentioned reduction in LDL levels, nicotinic acid causes a shift in LDL composition from the small dense LDL particles (major atherogenic lipoprotein) to the larger, more buoyant LDL particles (less atherogenic). The increase in HDL is also associated with a shift in the distribution of HDL sub-fractions including an increase in the HDL2 to HDL3 ratio, the protective effect of HDL being mainly due to HDL2. Moreover, nicotinic acid increases serum levels of apolipoprotein A1 (Apo 1), one of the two major lipoproteins of HDL, while decreases concentrations of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions known to play important roles in atherogenesis. The serum levels of lipoprotein a, [Lp (a)], which present great homology with LDL but considered as an independent risk factor for coronary heart disease, are also significantly reduced by Niaspan.

Data from clinical trials suggest that women have a greater hypolipidaemic response than men at equivalent doses of Niaspan.

There are no specific studies of the combination of Niaspan with statins.

The beneficial effect of Niaspan on morbidity and mortality has not been directly assessed. However, relevant clinical data are available with immediate release (IR) nicotinic acid.

5.2 Pharmacokinetic Properties

Absorption

Nicotinic acid is rapidly and extensively absorbed when administered orally (at least 60-76% of dose).

Peak steady-state nicotinic acid concentrations were 0.6, 4.9, and 15.5 microgram/ml after doses of 1000, 1500, and 2000mg Niaspan once daily (given as two 500mg, two 750mg, and two 1000mg tablets, respectively).

Single-dose bioavailability studies have demonstrated that Niaspan tablet strengths are not interchangeable.

Distribution

Studies using radio-labelled nicotinic acid in mice show that nicotinic acid and its metabolites concentrate in the liver, kidney and adipose tissue.

Metabolism

The pharmacokinetic profile of nicotinic acid is complicated due to rapid and extensive first-pass metabolism which is species and dose-rate specific. In humans, one pathway (Pathway 1) is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to nicotinic acid. There is evidence to suggest that nicotinic acid metabolism along this pathway leads to flush. The other pathway (Pathway 2) results in the formation of nicotinamide adenine dinucleotide (NAD). A predominance of metabolism down Pathway 2 may lead to hepatotoxicity. It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolised to at least N-methylnicotinamide (MNA) and nicotinamide N-oxide (NNO). MNA is further metabolised to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidaemia, these metabolic pathways are saturable, which explains the non-linear relationship between nicotinic acid dose and plasma concentrations following multiple dose Niaspan administration.

Nicotinamide does not have hypolipidaemic activity; the activity of the other metabolites is unknown.

Elimination

Nicotinic acid and its metabolites are rapidly eliminated in the urine. Following single and multiple doses, approximately 60-76% of the dose administered as Niaspan was recovered in the urine as nicotinic acid and metabolites; up to 12% was recovered as unchanged nicotinic acid after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered.

Gender differences

Steady state plasma concentrations of nicotinic acid and metabolites after administration of Niaspan are generally higher in women than in men, with the magnitude of difference varying with dose and metabolite. Recovery of nicotinic acid and metabolites in urine, however, is generally similar for men and women, indicating the absorption is similar for both genders. The gender differences observed in plasma levels of nicotinic acid and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution.

5.3 Preclinical Safety Data

Nicotinic acid has been shown to be of low toxicity in customary animal studies.

Female rabbits have been dosed with 0.3g nicotinic acid per day from pre-conception to lactation, and gave birth to offspring without teratogenic effects. Further specific animal reproduction studies have not been conducted with nicotinic acid or with Niaspan.

In a life-time study in mice, high dose levels of nicotinic acid showed no treatment-related carcinogenic effects and no effects on survival rates.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone

Hypromellose

Stearic acid

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C

Blister: Store in the original package to protect from moisture

6.5 Nature And Contents Of Container

Starter Pack: Niaspan Prolonged Release Tablets Starter Pack are presented in a 21 tablet starter pack containing three weeks supply of medication packed in three individually sealed strips (PVC/Chlortrifluoroethylene/PE/aluminium) as follows:

Week 1: seven Niaspan 375mg Prolonged Release Tablets

Week 2: seven Niaspan 500mg Prolonged Release Tablets

Week 3: seven Niaspan 750mg Prolonged Release Tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Abbott Laboratories Ltd.,

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

Berkshire,

SL6 4XE,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00037/0635

9. Date Of First Authorisation/Renewal Of The Authorisation

04^th June 2009

10. Date Of Revision Of The Text

28^th January 2011

ketorolac Oral, Intravenous, Injection, Intramuscular

kee-toe-ROLE-ak

Oral route(Tablet)

For short term use only (up to 5 days in adults). Not for use in pediatric patients and not indicated for minor or chronic pain. Contraindicated in patients with peptic ulcer disease, recent GI bleeding or perforation, peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, advanced renal impairment, risk of renal failure due to volume depletion, cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis, high-risk of bleeding, prophylactic analgesic before major surgery, labor and delivery use, nursing mothers, and concomitant aspirin or NSAID use. Use caution with elderly patients due to high risk of GI adverse events and in patients with cardiovascular disease or risk factors. Adjust dosages for elderly patients, patients under 50 kg, and patients with moderately elevated serum creatinine .

Injection route(Solution)

For short term use only (up to 5 days in adults). Not for use in pediatric patients and not indicated for minor or chronic pain. Contraindicated in patients with peptic ulcer disease, recent GI bleeding or perforation, peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, advanced renal impairment, risk of renal failure due to volume depletion, cerebrovascular bleeding, hemorrhagic diathesis, incomplete homeostasis, high-risk of bleeding, prophylactic analgesic before major surgery, previously demonstrated hypersensitivity reactions, intrathecal or epidural administration, labor and delivery use, nursing mothers, and concomitant aspirin or NSAID use. Use caution with elderly patients due to high risk of GI adverse events and in patients with cardiovascular disease or risk factors. Adjust dosages for elderly patients, patients under 50 kg, and patients with moderately elevated serum creatinine .

Commonly used brand name(s)

In the U.S.

• Toradol


• Toradol IV/IM

Available Dosage Forms:

• Tablet


• Solution


• Injectable

Therapeutic Class: Analgesic

Pharmacologic Class: NSAID

Chemical Class: Acetic Acid (class)

Uses For ketorolac

Ketorolac is used to relieve moderately severe pain, usually pain that occurs after an operation or other painful procedure. It belongs to the group of medicines called nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac is not a narcotic and is not habit-forming. It will not cause physical or mental dependence, as narcotics can. However, ketorolac is sometimes used together with a narcotic to provide better pain relief than either medicine used alone.

Ketorolac has side effects that can be very dangerous. The risk of having a serious side effect increases with the dose of ketorolac and with the length of treatment. Therefore, ketorolac should not be used for more than 5 days. Before using ketorolac, you should discuss with your doctor the good that ketorolac can do as well as the risks of using it.

Ketorolac is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, ketorolac is used in certain patients with the following medical conditions:

• Pain after surgery in children

Before Using ketorolac

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For ketorolac, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to ketorolac or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on ketorolac have been done only in adult patients, and there is no specific information comparing use of ketorolac in children up to 16 years of age with use in other age groups.

Geriatric

Stomach or intestinal problems, swelling of the face, feet, or lower legs, or sudden decrease in the amount of urine may be especially likely to occur in elderly patients, who are usually more sensitive than younger adults to the effects of ketorolac. Also, elderly people are more likely than younger adults to get very sick if the medicine causes stomach problems. Studies in older adults have shown that ketorolac stays in the body longer than it does in younger people. Your doctor will consider this when deciding on how much ketorolac should be given for each dose and how often it should be given.

Pregnancy

	Pregnancy Category	Explanation
1st Trimester	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.
2nd Trimester	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.
3rd Trimester	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking ketorolac, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ketorolac with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Aceclofenac


• Acemetacin


• Alclofenac


• Apazone


• Aspirin


• Benoxaprofen


• Bufexamac


• Carprofen


• Clometacin


• Clonixin


• Dexketoprofen


• Diclofenac


• Diflunisal


• Dipyrone


• Droxicam


• Etodolac


• Etofenamate


• Felbinac


• Fenbufen


• Fenoprofen


• Fentiazac


• Floctafenine


• Flufenamic Acid


• Flurbiprofen


• Ibuprofen


• Indomethacin


• Indoprofen


• Isoxicam


• Ketoprofen


• Lornoxicam


• Meclofenamate


• Mefenamic Acid


• Meloxicam


• Nabumetone


• Naproxen


• Niflumic Acid


• Nimesulide


• Oxaprozin


• Oxyphenbutazone


• Pentoxifylline


• Phenylbutazone


• Pirazolac


• Piroxicam


• Pirprofen


• Probenecid


• Propyphenazone


• Proquazone


• Sulindac


• Suprofen


• Tenidap


• Tenoxicam


• Tiaprofenic Acid


• Tolmetin


• Zomepirac

Using ketorolac with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Ardeparin


• Argatroban


• Beclamide


• Beta Glucan


• Bivalirudin


• Caramiphen


• Carbamazepine


• Certoparin


• Chlormethiazole


• Cilostazol


• Citalopram


• Clopidogrel


• Clovoxamine


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Desirudin


• Diazepam


• Dipyridamole


• Enoxaparin


• Escitalopram


• Ethotoin


• Felbamate


• Femoxetine


• Flesinoxan


• Fluoxetine


• Fluvoxamine


• Fondaparinux


• Fosphenytoin


• Gabapentin


• Ginkgo


• Heparin


• Lacosamide


• Lepirudin


• Levetiracetam


• Mephenytoin


• Mephobarbital


• Methotrexate


• Nadroparin


• Nefazodone


• Oxcarbazepine


• Paraldehyde


• Paramethadione


• Parnaparin


• Paroxetine


• Pemetrexed


• Phenacemide


• Phenobarbital


• Phenytoin


• Piracetam


• Pregabalin


• Protein C


• Reviparin


• Rivaroxaban


• Rufinamide


• Sertraline


• Sibutramine


• Stiripentol


• Tacrolimus


• Tiagabine


• Ticlopidine


• Tinzaparin


• Tirofiban


• Topiramate


• Trimethadione


• Valproic Acid


• Vigabatrin


• Vilazodone


• Zimeldine


• Zonisamide

Using ketorolac with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Acetohexamide


• Alacepril


• Alprenolol


• Amiloride


• Arotinolol


• Atenolol


• Azilsartan Medoxomil


• Azosemide


• Befunolol


• Bemetizide


• Benazepril


• Bendroflumethiazide


• Benzthiazide


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Bucindolol


• Bumetanide


• Bupranolol


• Buthiazide


• Candesartan Cilexetil


• Canrenoate


• Captopril


• Carteolol


• Carvedilol


• Celiprolol


• Chlorothiazide


• Chlorpropamide


• Chlorthalidone


• Cilazapril


• Clopamide


• Cyclopenthiazide


• Cyclosporine


• Delapril


• Desvenlafaxine


• Dilevalol


• Duloxetine


• Enalaprilat


• Enalapril Maleate


• Eprosartan


• Esmolol


• Ethacrynic Acid


• Fosinopril


• Furosemide


• Gliclazide


• Glimepiride


• Glipizide


• Gliquidone


• Glyburide


• Hydrochlorothiazide


• Hydroflumethiazide


• Imidapril


• Indapamide


• Irbesartan


• Labetalol


• Landiolol


• Levobetaxolol


• Levobunolol


• Lisinopril


• Lithium


• Losartan


• Mepindolol


• Methyclothiazide


• Metipranolol


• Metolazone


• Metoprolol


• Milnacipran


• Moexipril


• Nadolol


• Nebivolol


• Nipradilol


• Olmesartan Medoxomil


• Oxprenolol


• Penbutolol


• Pentopril


• Perindopril


• Pindolol


• Piretanide


• Polythiazide


• Propranolol


• Quinapril


• Ramipril


• Sotalol


• Spirapril


• Spironolactone


• Talinolol


• Tasosartan


• Telmisartan


• Temocapril


• Tertatolol


• Timolol


• Tolazamide


• Tolbutamide


• Torsemide


• Trandolapril


• Triamterene


• Trichlormethiazide


• Valsartan


• Venlafaxine


• Xipamide


• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of ketorolac. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse or


• Diabetes mellitus (sugar diabetes) or


• Edema (swelling of face, fingers, feet or lower legs caused by too much fluid in the body) or


• Kidney disease or


• Liver disease (severe) or


• Systemic lupus erythematosus (SLE)—The chance of serious side effects may be increased

• Asthma or


• Heart disease or


• High blood pressure—Ketorolac may make your condition worse.

• Bleeding in the brain (history of) or


• Hemophilia or other bleeding problems—Ketorolac may increase the chance of serious bleeding

• Bleeding from the stomach or intestines (history of) or


• Colitis, stomach ulcer, or other stomach or intestinal problems (or history of)—Ketorolac may make stomach or intestinal problems worse. Also, bleeding from the stomach or intestines is more likely to occur during ketorolac treatment in people with these conditions

Proper Use of ketorolac

For patients taking ketorolac tablets:

• To lessen stomach upset, ketorolac tablets should be taken with food (a meal or a snack) or with an antacid.


• Take ketorolac with a full glass of water. Also, do not lie down for about 15 to 30 minutes after taking it. This helps to prevent irritation that may lead to trouble in swallowing.

For patients using ketorolac injection:

• Medicines given by injection are sometimes used at home. If you will be using ketorolac at home, your health care professional will teach you how the injections are to be given. You will also have a chance to practice giving injections. Be certain that you understand exactly how the medicine is to be injected.

For safe and effective use of ketorolac, do not use more of it, do not use it more often, and do not use it for more than 5 days. Using too much of ketorolac increases the chance of unwanted effects, especially in elderly patients.

Ketorolac should be used only when it is ordered by your doctor for treating certain kinds of pain. Because of the risk of serious side effects, do not save any leftover ketorolac for use in the future, and do not share it with other people.

Dosing

The dose of ketorolac will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of ketorolac. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For pain:
    
    • Adults (patients 16 years of age and older)—One 10-milligram (mg) tablet four times a day, four to six hours apart. Some people may be directed to take two tablets for the first dose only.
    
    
    • Children up to 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  


• For injection dosage form:
  
  • For pain:
    
    • Adults (patients 16 years of age and older)—15 or 30 mg, injected into a muscle or a vein four times a day, at least 6 hours apart. This amount of medicine may be contained in 1 mL or in one-half (0.5) mL of the injection, depending on the strength. Some people who do not need more than one injection may receive one dose of 60 mg, injected into a muscle.
    
    
    • Children up to 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of ketorolac, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Do not refrigerate. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using ketorolac

Taking certain other medicines together with ketorolac may increase the chance of unwanted effects. The risk will depend on how much of each medicine you take every day, and on how long you take the medicines together. Therefore, do not take acetaminophen (e.g., Tylenol) together with ketorolac for more than a few days, unless otherwise directed by your medical doctor or dentist. Also, do not take any of the following medicines together with ketorolac, unless your medical doctor or dentist has directed you to do so and is following your progress:

• Aspirin or other salicylates


• Diclofenac (e.g., Voltaren®)


• Diflunisal (e.g., Dolobid®)


• Etodolac (e.g., Lodine®)


• Fenoprofen (e.g., Nalfon®)


• Floctafenine (e.g., Idarac®)


• Flurbiprofen (e.g., Ansaid®)


• Ibuprofen (e.g., Motrin®)


• Indomethacin (e.g., Indocin®)


• Ketoprofen (e.g., Orudis®)


• Meclofenamate (e.g., Meclomen®)


• Mefenamic acid (e.g., Ponstel®)


• Nabumetone (e.g., Relafen®)


• Naproxen (e.g., Naprosyn®)


• Oxaprozin (e.g., Daypro®)


• Phenylbutazone (e.g., Butazolidin®)


• Piroxicam (e.g., Feldene®)


• Sulindac (e.g., Clinoril®)


• Tenoxicam (e.g., Mobiflex®)


• Tiaprofenic acid (e.g., Surgam®)


• Tolmetin (e.g., Tolectin®)


• Zomepirac (e.g., Zomax®)

Ketorolac may cause some people to become dizzy or drowsy. If either of these side effects occurs, do not drive, use machines, or do anything else that could be dangerous if you are not alert.

Serious side effects can occur during treatment with ketorolac. Sometimes serious side effects can occur without any warning. However, possible warning signs often occur, including swelling of the face, fingers, feet, and/or lower legs; severe stomach pain, black, tarry stools, and/or vomiting of blood or material that looks like coffee grounds; unusual weight gain; and/or skin rash. Also, signs of serious heart problems could occur such as chest pain, tightness in chest, fast or irregular heartbeat, or unusual flushing or warmth of skin. Stop taking ketorolac and check with your doctor immediately if you notice any of these warning signs.

ketorolac Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Swelling of face, fingers, lower legs, ankles, and/or feet


• weight gain (unusual)

Less common

• Bruising (not at place of injection)


• high blood pressure


• skin rash or itching


• small, red spots on skin


• sores, ulcers, or white spots on lips or in mouth

Rare

• Abdominal or stomach pain, cramping, or burning that is severe


• bleeding from the rectum or bloody or black, tarry stools


• bloody or cloudy urine


• blue lips and fingernails


• blurred vision of other vision change


• burning, red, tender, thick, scaly, or peeling skin


• chest pain


• convulsions


• cough or hoarseness


• dark urine


• decrease in amount of urine that is sudden


• fainting


• fast, irregular, noisy, or troubled breathing


• fever with severe headache, drowsiness, confusion, and stiff neck or back


• fever with or without chills or sore throat


• hallucinations (seeing, hearing, or feeling things that are not there)


• hearing loss


• hives


• increase in amount of urine or urinating often


• light-colored stools


• loss of appetite


• low blood pressure


• mood changes or unusual behavior


• muscle cramps or pain


• nausea, heartburn, or indigestion that is severe and continues


• nosebleeds


• pain in lower back and/or side


• pain, tenderness, or swelling in the upper stomach area


• painful or difficult urination


• pale skin


• puffiness or swelling of the eyelids or eyes


• ringing or buzzing in ears


• runny nose


• severe restlessness


• shortness of breath


• swollen or painful glands


• swollen tongue


• thirst that continues


• tightness in the chest with or without wheezing


• unusual tiredness or weakness


• vomiting of blood or material that looks like coffee grounds


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Abdominal or stomach pain (mild or moderate)


• bruising at place of injection


• diarrhea


• dizziness


• drowsiness


• headache


• indigestion


• nausea

Less common or rare

• Bloating or gas


• burning or pain at place of injection


• constipation


• feeling of fullness in abdominal or stomach area


• increased sweating


• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

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