Inderal LA 160mg

1. Name Of The Medicinal Product

Inderal LA 160mg.

2. Qualitative And Quantitative Composition

Propranolol hydrochloride Ph Eur 160 mg

3. Pharmaceutical Form

Pink/lavender or white opaque capsules containing propranolol hydrochloride in a controlled release formulation.

4. Clinical Particulars

4.1 Therapeutic Indications

a) Control of hypertension

b) Management of angina

c) Prophylaxis of migraine

d) Management of essential tremor

e) Management of anxiety

f) Adjunctive management of thyrotoxicosis

g) Prophylaxis of upper gastro-intestinal bleeding in patients with portal hypertension and oesophageal varices

4.2 Posology And Method Of Administration

For oral administration.

Adults

Hypertension: The usual starting dose is one 160 mg Inderal LA capsule daily, taken either morning or evening. An adequate response is seen in most patients at this dosage. If necessary, it can be increased in 80 mg Half-Inderal LA increments until an adequate response is achieved. A further reduction in blood pressure can be obtained if a diuretic or other antihypertensive agent is given in addition to Inderal LA and Half-Inderal LA.

Angina, anxiety, essential tremor, thyrotoxicosis and the prophylaxis of migraine: One Half-Inderal LA capsule daily, taken either morning or evening, may be sufficient to provide adequate control in many patients. If necessary the dose may be increased to one Inderal LA capsule per day and an additional Half-Inderal LA increment may be given.

Portal hypertension: Dosage should be titrated to achieve approximately 25% reduction in resting heart rate. Dosing should begin with one 80 mg Half-Inderal LA capsule daily, increasing to one 160 mg Inderal LA capsule daily depending on heart rate response. Further 80 mg Half-Inderal LA increments may be added up to a maximum dose of 320 mg once daily.

Patients who are already established on equivalent daily doses of Inderal tablets should be transferred to the equivalent doses of Half-Inderal LA or Inderal LA daily, taken either morning or evening.

Children

Inderal LA and Half-Inderal LA are not intended for use in children.

Elderly Patients

Evidence concerning the relation between blood level and age is conflicting. It is suggested that treatment should start with one Half-Inderal LA capsule once daily. The dose may be increased to one Inderal LA capsule daily or higher as appropriate.

4.3 Contraindications

Inderal LA and Half-Inderal LA must not be used if there is a history of bronchial asthma or bronchospasm. The product label states the following warning: “Do not take Inderal LA if you have a history of asthma or wheezing”. A similar warning appears in the Patient Information Leaflet.

Bronchospasm can usually be reversed by beta₂ agonist bronchodilators such as salbutamol. Large doses of the beta₂ agonist bronchodilator may be required to overcome the beta blockade produced by propranolol and the dose should be titrated according to the clinical response; both intravenous and inhalational administration should be considered. The use of intravenous aminophylline and/or the use of ipratropium (given by nebuliser) may also be considered. Glucagon (1 to 2 mg given intravenously) has also been reported to produce a bronchodilator effect in asthmatic patients. Oxygen or artificial ventilation may be required in severe cases.

Inderal LA and Half-Inderal LA, as with other beta-blockers, must not be used in patients with any of the following conditions: known hypersensitivity to the substance, bradycardia, cardiogenic shock, hypotension, metabolic acidosis, after prolonged fasting, severe peripheral arterial circulatory disturbances, second or third degree heart block, sick sinus syndrome, untreated phaeochromocytoma, uncontrolled heart failure or Prinzmetal's angina.

Inderal LA and Half-Inderal LA must not be used in patients prone to hypoglycaemia, i.e., patients after prolonged fasting or patients with restricted counter-regulatory reserves.

4.4 Special Warnings And Precautions For Use

Inderal LA and Half-Inderal LA as with other beta-blockers:

• although contra-indicated in uncontrolled heart failure (see Section 4.3) may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.

• should not be used in combination with calcium channel blockers with negative inotropic effects (e.g. verapamil, diltiazem), as it can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

• should not be used in patients with Prinzmetal's angina and beta-1 selective agents should be used with care. (see section 4.3).

• although contra-indicated in severe peripheral arterial circulatory disturbances (see Section 4.3) may also aggravate less severe peripheral arterial circulatory disturbances.

• due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.

• may block/modify the signs and symptoms of the hypoglycaemia (especially tachycardia). Inderal LA and Half-Inderal LA occasionally causes hypoglycaemia, even in non-diabetic patients, e.g., elderly patients, patients on haemodialysis or patients suffering from chronic liver disease and patients suffering from overdose. Severe hypoglycaemia associated with Inderal LA and Half-Inderal LA has rarely presented with seizures and/or coma in isolated patients. Caution must be exercised in the concurrent use of Inderal LA and Half-Inderal LA and hypoglycaemic therapy in diabetic patients. Inderal LA and Half-Inderal LA may prolong the hypoglycaemic response to insulin. (see section 4.3).

• may mask the signs of thyrotoxicosis.

• should not be used in untreated phaeochromocytoma. However, in patients with phaeochromocytoma, an alpha-blocker may be given concomitantly.

• should be used to treat the elderly with caution starting with a lower dose. (see section 4.2).

• will reduce heart rate as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms that may be attributable to a slow heart rate, the dose may be reduced.

• may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

Abrupt withdrawal of beta-blockers is to be avoided. The dosage should be withdrawn gradually over a period of 7 to 14 days. An equivalent dosage of another beta-blocker may be substituted during the withdrawal period to facilitate a reduction in dosage below Inderal LA 80mg. Patients should be followed during withdrawal especially those with ischaemic heart disease.

When a patient is scheduled for surgery and a decision is made to discontinue beta-blocker therapy, this should be done at least 24 hours prior to the procedure.

The risk/benefit of stopping beta blockade should be made for each patient.

Since the half-life may be increased in patients with significant hepatic or renal impairment, caution must be exercised when starting treatment and selecting the initial dose.

Inderal LA and Half-Inderal LA must be used with caution in patients with decompensated cirrhosis. (see section 4.2)

In patients with portal hypertension, liver function may deteriorate and hepatic encephalopathy may develop. There have been reports suggesting that treatment with propranolol may increase the risk of developing hepatic encephalopathy (see section 4.2).

Interference with laboratory tests: Inderal LA and Half-Inderal LA have been reported to interfere with the estimation of serum bilirubin by the diazo method and with the determination of catecholamines by methods using fluorescence.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Inderal LA and Half-Inderal LA modify the tachycardia of hypoglycaemia. Caution must be exercised in the concurrent use of Inderal LA or Half-Inderal LA and hypoglycaemic therapy in diabetic patients. Propranolol may prolong the hypoglycaemic response to insulin.(see section 4.3 and 4.4).

Class I anti-arrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.

Digitalis glycosides, in association with beta-blockers, may increase atrio-ventricular conduction time.

Combined use of beta-blockers and calcium channel blockers with negative inotropic effects eg, verapamil, diltiazem, can lead to an exaggeration of these effects, particularly in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

Concomitant therapy with dihydropyridine calcium channel blockers eg, nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

Concomitant use of sympathomimetic agents, eg, adrenaline, may counteract the effect of beta-blockers. Caution must be exercised in the parenteral administration of preparations containing adrenaline to patients taking beta-blockers as, in rare cases, vasoconstriction, hypertension and bradycardia may result.

Administration of propranolol during infusion of lidocaine may increase the plasma concentration of lidocaine by approximately 30%. Patients already receiving propranolol tend to have higher lidocaine levels than controls. The combination should be avoided.

Concomitant use of cimetidine will increase plasma levels of propranolol, and concomitant use of alcohol may increase the plasma levels of propranolol.

Beta-blockers may exacerbate the rebound hypertension, which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.

Caution must be exercised if ergotamine, dihydroergotamine or related compounds are given in combination with propranolol since vasospastic reactions have been reported in a few patients.

Concomitant use of prostaglandin synthetase inhibiting drugs, eg, ibuprofen or indometacin, may decrease the hypotensive effects of propranolol.

Concomitant administration of propranolol and chlorpromazine may result in an increase in plasma levels of both drugs. This may lead to an enhanced antipsychotic effect for chlorpromazine and an increased antihypertensive effect for propranolol.

Caution must be exercised when using anaesthetic agents with Inderal LA and Half-Inderal LA. The anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-blockers with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.

Pharmacokinetic studies have shown that the following agents may interact with propranolol due to effects on enzyme systems in the liver which metabolise propranolol and these agents: quinidine, propafenone, rifampicin, theophylline, warfarin, thioridazine and dihydropyridine calcium channel blockers such as nifedipine, nisoldipine, nicardipine, isradipine and lacidipine. Owing to the fact that blood concentrations of either agent may be affected, dosage adjustments may be needed according to clinical judgement. (See also the interaction above concerning concomitant therapy with dihydropyridine calcium channel blockers).

4.6 Pregnancy And Lactation

Pregnancy: As with all drugs, Inderal LA and Half-Inderal LA should not be given during pregnancy unless their use is essential. There is no evidence of teratogenicity with Inderal. However beta-blockers reduce placental perfusion, which may result in intra-uterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia in the neonate and bradycardia in the foetus) may occur. There is an increased risk of cardiac and pulmonary complications in the neonate in the post-natal period.

Lactation: Most beta-blockers, particularly lipophilic compounds, will pass into breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of these compounds.

4.7 Effects On Ability To Drive And Use Machines

The use of Inderal LA or Half-Inderal LA is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable Effects

Inderal LA and Half-Inderal LA are usually well tolerated. In clinical studies, the undesired events reported are usually attributable to the pharmacological actions of propranolol.

The following undesired events, listed by body system, have been reported.

Common (1-9.9%)

General: Fatigue and/or lassitude (often transient)

Cardiovascular: Bradycardia, cold extremities, Raynaud's phenomenon.

CNS: Sleep disturbances, nightmares.

Uncommon (0.1-0.9%)

GI: Gastrointestinal disturbance, such as nausea, vomiting, diarrhoea.

Rare (0.01-0.09%)

General: Dizziness.

Blood: Thrombocytopaenia.

Cardiovascular: Heart failure deterioration, precipitation of heart block, postural hypotension, which may be associated with syncope, exacerbation of intermittent claudication.

CNS: Hallucinations, psychoses, mood changes, confusion, memory loss.

Skin: Purpura, alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes.

Neurological: Paraesthesia.

Eyes: Dry eyes, visual disturbances.

Respiratory: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints, sometimes with fatal outcome.

Very rare (<0.01%)

Endocrine system: Hypoglycaemia in neonates, infants, children, elderly patients, patients on haemodialysis, patients on concomitant antidiabetic therapy, patients with prolonged fasting and patients with chronic liver disease has been reported.

Investigations: an increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear.

Nervous system: Isolated reports of myasthenia gravis like syndrome or exacerbation of myasthenia gravis have been reported.

Discontinuance of the drug should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions. Cessation of therapy with a beta-blocker should be gradual. In the rare event of intolerance manifested as bradycardia and hypotension, the drug should be withdrawn and, if necessary, treatment for overdosage instituted.

4.9 Overdose

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock.

Excessive bradycardia can be countered with atropine 1 to 2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1 to 10 mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoceptor stimulant such as dobutamine 2.5 to 10 microgram/kg/minute by intravenous infusion may be given. Dobutamine, because of its positive inotropic effect, could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Propranolol is a competitive antagonist at both beta₁ and beta₂-adrenoceptors. It has no agonist activity at the beta adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1 to 3 mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta agonists such as isoprenaline.

Propranolol, as with other beta-blockers, has negative inotropic effects, and is therefore contra-indicated in uncontrolled heart failure.

Propranolol is a racemic mixture and the active form is the S (-) isomer. With the exception of inhibition of the conversion of thyroxine to triiodothyronine it is unlikely that any additional ancillary properties possessed by R (+) propranolol, in comparison with the racemic mixture will give rise to different therapeutic effects.

Propranolol is effective and well tolerated in most ethnic populations, although the response may be less in black patients.

The sustained release preparation of propranolol maintains a higher degree of beta₁-blockade 24 hours after dosing compared with conventional propranolol.

5.2 Pharmacokinetic Properties

Propranolol is completely absorbed after oral administration and peak plasma concentrations occur 1-2 hours after dosing in fasting patients. Following oral dosing with the sustained release preparation of propranolol, the blood profile is flatter than after conventional Inderal but the half-life is increased to between 10 and 20 hours. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Propranolol is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Propranolol is highly protein bound (80 to 95%).

5.3 Preclinical Safety Data

Propranolol is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in this Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Erythrosine (E127)

Ethyl cellulose Ph Eur. (E462)

Gelatin Ph Eur. (E441)

Glycerol Ph Eur. (E422)

Iron oxide, red (E172)

Iron oxide, black (E172)

Methylhydroxypropylcellulose Ph Eur. (E464)

Microcrystalline cellulose Ph Eur. (E460)

Titanium dioxide Ph Eur. (E171)

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 25°C, protected from light and moisture.

6.5 Nature And Contents Of Container

Patient calendar pack of 28 capsules.

6.6 Special Precautions For Disposal And Other Handling

Use as directed by the prescriber.

7. Marketing Authorisation Holder

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU

UK

8. Marketing Authorisation Number(S)

PL 17901/0019

9. Date Of First Authorisation/Renewal Of The Authorisation

11^th June 2000

10. Date Of Revision Of The Text

19^th May 2009

Ibuprofen Caplets 200mg (24,48 pack) (Boots Company plc)

Boots Ibuprofen Caplets 200 mg

Read all of this leaflet carefully because it contains important information for you.

This medicine is available without prescription to treat minor conditions. However, you still need to take it carefully to get the best results from it.

• Keep this leaflet, you may need to read it again


• Ask your pharmacist if you need more information or advice

What this medicine is for

This medicine contains ibuprofen which belongs to a group called non-steroidal anti-inflammatory medicines, which act to relieve pain and reduce swelling. It can be used to relieve headaches, rheumatic and muscular pain, pain from non-serious arthritic conditions, backache, migraine, period pain, dental pain and neuralgia. It can also be used to reduce fever and relieve the symptoms of colds and flu.

Before you take this medicine

This medicine can be taken by adults and children aged 12 years and over. However, some people should not take this medicine or should seek the advice of their pharmacist or doctor first.

Do not take:

• 
  If you have a stomach ulcer, perforation or bleeding, or have had one twice or more in the past


• 
  If you have had perforation or a bleeding stomach after taking a non-steroidal anti-inflammatory medicine (you may have been sick and it contained blood or dark particles that look like coffee grounds, passed blood in your stools or passed black tarry stools)


• 
  If you are allergic to ibuprofen or any other ingredients of the product, aspirin or other non-steroidal anti-inflammatory medicines (you have ever had asthma, runny nose, itchy skin or swelling of the lips, face or throat after taking these medicines)


• 
  If you are taking aspirin with a daily dose above 75 mg, or other non-steroidal anti-inflammatory medicines


• 
  If you have severe heart, kidney or liver failure
  


• 
  If you have an intolerance to some sugars, unless your doctor tells you to (this medicine contains lactose)


• 
  If you are pregnant, and in the last 3 months of pregnancy

Talk to your pharmacist or doctor:

• If you have asthma, a history of asthma or other allergic disease, bowel problems, ulcerative colitis or Crohn’s disease


• If you have other kidney, heart or liver problems (see above)


• If you have a connective tissue disorder such as SLE (Systemic Lupus Erythematosus)


• If you are elderly – you may get more side effects (see back of leaflet)


• If you are taking any other painkillers or receiving regular treatment from your doctor


• If you have had a stroke, or have heart problems, high blood pressure, diabetes, high cholesterol, or you smoke – see ‘Risk of heart attack or stroke’ below


• If you are pregnant, and in the first 6 months of pregnancy


• If you are breastfeeding

Other important information

Risk of heart attack or stroke: Ibuprofen may increase the risk if you take large amounts for a long time. The risk is small. Take the lowest amount for the shortest possible time to reduce this risk.

Woman of childbearing age: If you take this medicine, it may reduce your ability to become pregnant. This effect will be reversed when you stop the medicine.

If you take other medicines

Before you take these caplets, make sure that you tell your pharmacist about ANY other medicines you might be using at the same time, particularly the following:

• Other painkillers


• Aspirin 75 mg (to prevent heart attacks and strokes) – the protection may be reduced when you take ibuprofen


• Tablets to thin your blood (e.g. warfarin)


• Mifepristone (for termination of pregnancy) – do not take ibuprofen if you have taken mifepristone in the last 12 days


• Water tablets (diuretics), medicines to treat high blood pressure, medicines for heart problems


• Corticosteroids, lithium, methotrexate, zidovudine


• Quinolone antibiotics (for infections)


• Medicines for depression


• Ciclosporin or tacrolimus (given after transplant surgery, or for psoriasis or rheumatism)

If you are unsure about interactions with any other medicines, talk to your pharmacist. This includes medicines prescribed by your doctor and medicine you have bought for yourself, including herbal and homeopathic remedies.

How to take this medicine

Check the foil is not broken before use. If it is, do not take that caplet.

Adults and children of 12 years and over

Take one or two caplets

Every 4 hours, if you need to.

Don't take more than 6 caplets in 24 hours.

Take the lowest amount for the shortest possible time to relieve your symptoms.

Swallow each caplet with water

Do not give to children under 12 years.

Do not take more than the amount recommended above.

If your symptoms worsen at any time, talk to your doctor.

If your symptoms do not go away within 10 days, talk to your doctor.

If you take too many caplets: Talk to a doctor straight away. Take your medicine and this leaflet with you.

Possible side effects

Most people will not have problems, but some may get some.

If you are elderly you may be more likely to have some of these side effects.

If you get any of these serious side effects, stop taking the caplets. See a doctor at once:

• You are sick and it contains blood or dark particles that look like coffee grounds


• Pass blood in your stools or pass black tarry stools


• Stomach problems including pain, indigestion or heartburn


• Allergic reactions such as skin rash (which can sometimes be severe and include peeling and blistering of the skin), swelling of the face, neck or throat, worsening of asthma, difficulty in breathing


• Meningitis (e.g. stiff neck, fever, disorientation)

These other effects are less serious. If they bother you talk to a pharmacist:

• Kidney problems, which may lead to kidney failure


• Feeling sick, being sick


• Headache


• High blood pressure, heart failure


• Fluid retention, which may cause swelling of the limbs


• Rarely, liver problems, diarrhoea, wind, constipation, worsening of colitis or Crohn’s disease


• Very rarely, tiredness or severe exhaustion, changes in the blood which may cause unusual bruising and an increase in the number of infections that you get (e.g. sore throats, mouth ulcers, flu-like symptoms)


• A small increased risk of heart attack or stroke if you take large amounts for a long time

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Store in a dry place.

Store in the original package.

Keep this medicine in a safe place out of the sight and reach of children, preferably in a locked cupboard.

Use by the date on the end flap of the carton.

What is in this medicine

Each tablet contains Ibuprofen 200 mg, which is the active ingredient.

As well as the active ingredient, the tablets also contain microcrystalline cellulose, lactose, hypromellose, croscarmellose sodium, sodium laurilsulfate, magnesium stearate, french chalk, colloidal silicon dioxide, titanium dioxide (E171).

The pack contains 24 or 48 white capsule shaped tablets.

Who makes this medicine

Manufactured for the Marketing Authorisation holder

The Boots Company PLC

Nottingham

NG2 3AA

by

Hamol Limited

Nottingham

NG90 2DB

Leaflet prepared October 2008

If you would like any further information about this medicine, please contact

The Boots Company PLC

Nottingham

NG2 3AA

P

Other formats

To request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product Name: Boots Ibuprofen Caplets 200 mg (24 or 48 caplets)

Reference number: 00014/0497

This is a service provided by the Royal National Institute of the Blind.

BTC12668 vN 02/12/08

Ibandronic acid Avansor 50mg tablets

1. Name Of The Medicinal Product

Ibandronic acid Avansor 50 mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronic sodium monohydrate).

Excipients:

Each film-coated tablet contains 54 mg lactose monohydrate.For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White to off-white, oblong, biconvex film-coated tablets, 9 mm in length and debossed with “I9BE” on one side and on the other side with “50”.

4. Clinical Particulars

4.1 Therapeutic Indications

Ibandronic acid is indicated for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

4.2 Posology And Method Of Administration

Ibandronic acid therapy should only be initiated by physicians experienced in the treatment of cancer.

For oral use.

The recommended dose is one 50 mg film-coated tablet daily.

Ibandronic acid tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements (including calcium) should similarly be avoided prior to taking ibandronic acid tablets. Fasting should be continued for at least 30 minutes after taking the tablet. Plain water may be taken at any time during the course of ibandronic acid treatment.

- The tablets should be swallowed whole with a full glass of plain water (180 to 240 ml) while the patient is standing or sitting in an upright position.

- Patients should not lie down for 60 minutes after taking ibandronic acid.

- Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.

- Plain water is the only drink that should be taken with ibandronic acid. Please note that some mineral waters may have a higher concentration of calcium and therefore should not be used.

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2 ).

Patients with renal impairment

No dosage adjustment is necessary for patients with mild renal impairment (CLcr

For patients with moderate renal impairment (CLcr

For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mg film-coated tablet once weekly. See dosing instructions, above.

Elderly

No dose adjustment is necessary.

Children and adolescents

Ibandronic acid is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.

4.3 Contraindications

• Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

• Inability to stand or sit upright for at least 60 minutes

• Hypocalcaemia

• Hypersensitivity to ibandronic acid or to any of the excipients.

Ibandronic acid should not be used in children.

4.4 Special Warnings And Precautions For Use

Caution is indicated in patients with known hypersensitivity to other bisphosphonates.

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ibandronic acid therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2).

Physicians should be alert to signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue ibandronic acid and seek medical attention if they develop dysphagia, odynophagia, , retrosternal pain, or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Since NSAIDS are associated with gastrointestinal irritation, caution should be taken during concomitant oral medication with ibandronic acid.

Clinical studies have not shown any evidence of deterioration in renal function with long term ibandronic acid therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with ibandronic acid.

Ibandronic acid tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Drug-Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of ibandronic acid tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration.

Bioavailability was reduced by approximately 75% when ibandronic acid tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2).

Drug-Drug Interactions

When co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when ibandronic acid is administered with H2-antagonists or other drugs that increase gastric pH.

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

In clinical studies, ibandronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

4.6 Pregnancy And Lactation

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, ibandronic acid should not be used during pregnancy.

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Ibandronic acid should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The safety profile of ibandronic acid is derived from controlled clinical trials in the approved indication and after the oral administration of ibandronic acid at the recommended dose.

In the pooled database from the 2 pivotal phase III trials (286 patients treated with ibandronic acid 50 mg), the proportion of patients who experienced an adverse reaction with a possible or probable relationship to ibandronic acid was 27%.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Table 1 lists common adverse reactions from the pooled phase III trials. Adverse reactions that are equally frequent in both active and placebo or more frequent in placebo-treated patients are excluded.

Table 1: Adverse Reactions Reported Commonly and Greater than Placebo

Adverse reaction	Placebo p. o. daily (n=277 patients) No. (%)	Ibandronic acid 50 mg p.o. daily (n=286 patients) No. (%)
Metabolism and Nutrition Disorders Hypocalcaemia	14 (5.1)	27 (9.4)
Gastrointestinal Disorders Dyspepsia Nausea Abdominal Pain Oesophagitis	13 (4.7) 4 (1.4) 2 (0.7) 2 (0.7)	20 (7.0) 10 (3.5) 6 (2.1) 6 (2.1)
General Disorders Asthenia	2 (0.7)	4 (1.4)

Adverse drug reactions occurring at a frequency <1%:

The following list provides information on adverse drug reactions reported in study MF 4414 and MF 4434 occurring more frequently with ibandronic acid 50 mg than with placebo:

Uncommon:

Blood and Lymphatic System Disorders:	anaemia
Nervous System Disorders:	paraesthesia, dysgeusia (taste perversion)
Gastrointestinal Disorders:	haemorrage, duodenal ulcer, gastritis, dysphagia, abdominal pain, dry mouth
Skin and Subcutaneous Tissue Disorders:	pruritus
Renal and Urinary Disorders:	azotaemia (uraemia)
General Disorders:	chest pain, influenza-like illness, malaise, pain
Investigations:	blood parathyroid hormone increased

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

4.9 Overdose

No case of overdose has been reported.

No specific information is available on the treatment of overdosage with ibandronic acid. However, oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind ibandronic acid. Owing to the risk of oesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: Bisphosphonates, ATC Code: M05B A 06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with ibandronic acid 50 mg tablets was assessed in two randomized placebo controlled phase III trials with duration of 96 weeks.

Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (277 patients) or 50 mg ibandronic acid (287 patients). The results from these trials are summarised below.

Primary Efficacy Endpoints

The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore, counted only once in any given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrated a significant advantage for ibandronic acid 50 mg p.o. over placebo in the reduction in SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an SRE for ibandronic acid treated patients when compared with placebo (relative risk 0.62, p=0.003). Efficacy results are summarised in Table 2.

Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

	All Skeletal Related Events (SREs)
Placebo n=277	Ibandronic acid 50 mg, n=287	p-value
SMPR (per patient year)	1.15	0.99	P=0.041
SRE relative risk	-	0.62	P=0.003

Secondary Efficacy Endpoints

A statistically significant improvement in bone pain score was shown for ibandronic acid 50 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in Quality of Life and WHO performance status was significantly less in ibandronic acid treated patients compared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminal telopeptide released from Type I collagen) were significantly reduced in the ibandronic acid group compared to placebo. This reduction in urinary CTx levels was significantly correlated with the primary efficacy endpoint SMPR (Kendall-tau-b (p<0.001)). A tabular summary of the secondary efficacy results is presented in Table 3.

Table 3 Secondary Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

	Placebo n=277	Ibandronic acid n=287	p-value
Bone pain*	0.20	-0.10	p=0.001
Analgesic use*	0.85	0.60	p=0.019
Quality of life*	-26.8	-8.3	p=0.032
WHO performance score*	0.54	0.33	p=0.008
Urinary CTx**	10.95	-77.32	p=0.001

* Mean change from baseline to last assessment.

** Median change from baseline to last assessment

5.2 Pharmacokinetic Properties

Absorption

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration.

Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other than plain water). Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability is approximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal.

Bioavailability was reduced by approximately 75% when Ibandronic acid tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see Section 4.2).

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug interaction due to displacement is unlikely.

Metabolism

There is no evidence that ibandronic acid is metabolized in animals or humans.

Elimination

The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.

Pharmacokinetics in Special Populations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

Patients with renal impairment

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr >30 ml/min). Subjects with severe renal impairment (CLcr

Patients with hepatic impairment

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

Elderly

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor to take into consideration (see renal impairment section).

Children and adolescents

There are no data on the use of Ibandronic acid in patients less than 18 years old.

5.3 Preclinical Safety Data

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of genetic activity for ibandronic acid.

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid in intravenously or orally treated rats and rabbits. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drugs (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Lactose Monohydrate

Crospovidone (E1202)

Cellulose, microcrystalline (E460)

Sylica, Colloidal Anhydrous (E551)

Sodium Stearyl Fumarate

Tablet coating

Poly (Vinyl Alcohol)

Macrogols/PEG 3350

Talc (E553b)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

OPA/Al/PVC:Al blisters in carton boxes containing 1, 28, 30, 84, 90 and 100 tablets

PVC/PVDC:Al blisters in carton boxes containing 1, 28, 30, 84, 90 and 100 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Avansor Pharma Oy

Tekniikantie 14

Espoo

02150

8. Marketing Authorisation Number(S)

PL 29834/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

23/11/2010

10. Date Of Revision Of The Text

23/11/2010

LEGAL CATEGORY

POM

IntronA 18,30 and 60 million IU solution for injection, multidose pen

1. Name Of The Medicinal Product

IntronA 18, 30 or 60 million IU solution for injection, in multidose pen

2. Qualitative And Quantitative Composition

One pen contains 18, 30 or 60 million IU of recombinant interferon alfa-2b produced in E. coli by recombinant DNA technology in 1.2 ml solution.

One ml contains 15, 25 or 50 million IU of interferon alfa-2b.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection

Clear and colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Chronic hepatitis B

Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or fibrosis.

Chronic hepatitis C

Before initiating treatment with IntronA, consideration should be given to the results from clinical trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients

IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for hepatitis C virus RNA (HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents

IntronA is indicated in a combination regimen with ribavirin, for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain

The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia

Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia

Monotherapy

Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic myelogenous leukaemia.

Clinical experience indicates that a haematological and cytogenetic major/minor response is obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ leukaemic cells in the bone marrow, whereas a minor response is

Combination therapy

The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses and to significantly prolong the overall survival at three years when compared to interferon alfa-2b monotherapy.

Multiple myeloma

As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction in myeloma protein) following initial induction chemotherapy.

Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma

Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour

Treatment of carcinoid tumours with lymph node or liver metastases and with “carcinoid syndrome”.

Malignant melanoma

As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology And Method Of Administration

Treatment must be initiated by a physician experienced in the management of the disease.

Multidose presentations must be for individual patient use only.

IntronA 18 million IU solution for injection, multidose pen

The pen is designed to deliver its contents of 18 million IU in doses ranging from 1.5 to 6 million IU. The pen will deliver a maximum of 12 doses of 1.5 million IU over a period not to exceed 4 weeks.

IntronA 30 million IU solution for injection, multidose pen

The pen is designed to deliver its contents of 30 million IU in doses ranging from 2.5 to 10 million IU. The pen will deliver a maximum of 12 doses of 2.5 million IU over a period not to exceed 4 weeks.

IntronA 60 million IU solution for injection, multidose pen

The pen is designed to deliver its contents of 60 million IU in doses ranging from 5 to 20 million IU. The pen will deliver a maximum of 12 doses of 5 million IU over a period not to exceed 4 weeks.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment with IntronA. At the discretion of the physician, the patient may self-administer the dose for maintenance dose regimens administered subcutaneously.

Chronic hepatitis B

The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders (white blood cells < 1,500/mm³, granulocytes < 1,000/mm³, thrombocytes < 100,000/mm³). Treatment should be discontinued in case of severe leukopaenia (< 1,200/mm³), severe neutropaenia (< 750/mm³) or severe thrombocytopaenia (< 70,000/mm³).

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment (at the maximum tolerated dose), discontinue IntronA therapy.

Chronic hepatitis C

Adults

IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents

IntonA 3 MIU/m² is administered subcutaneously 3 times a week (every other day) in combination with ribavirin capsules or oral solution administered orally in two divided doses daily with food (morning and evening).

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see ribavirin oral solution SPC)

Relapse patients (adults)

IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are available for 6 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for 6 months.

Naïve patients (adults)

The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin

Based on the results of clinical trials, in which data are available for 12 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment (HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone:

The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point HCV-RNA status should be determined. Treatment should be continued in patients who exhibit negative HCV-RNA.

Naïve patients (children and adolescents)

The efficacy and safety of IntronA in combination with ribavirin has been studied in children and adolescents who have not been previously treated for chronic hepatitis C.

Duration of treatment for children and adolescents

• Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders (negative predictive value 96 %). Therefore, it is recommended that children and adolescent patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log₁₀ compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.

• Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia

The recommended dose is 2 million IU/m² administered subcutaneously three times a week (every other day) for both splenectomised and non-splenectomised patients. For most patients with Hairy Cell Leukaemia, normalisation of one or more haematological variables occurs within one to two months of IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet count and haemoglobin level) may require six months or more. This regimen must be maintained unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia

The recommended dose of IntronA is 4 to 5 million IU/m² administered daily subcutaneously. Some patients have been shown to benefit from IntronA 5 million IU/m² administered daily subcutaneously in association with cytarabine (Ara-C) 20 mg/m² administered daily subcutaneously for 10 days per month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, administer the maximum tolerated dose of IntronA (4 to 5 million IU/m² daily) to maintain haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma

Maintenance therapy

In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, subcutaneously, at a dose of 3 million IU/m² three times a week (every other day).

Follicular lymphoma

Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, doxorubicin, teniposide and prednisolone).

Carcinoid tumour

The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week (every other day). Patients with advanced disease may require a daily dose of 5 million IU. The treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long as the patient responds to interferon alfa-2b treatment.

Malignant melanoma

As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m² daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to sodium chloride 9 mg/ml (0.9 %)solution for injection and administered as a 20-minute infusion (see section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m² administered subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes decrease to < 500/mm³ or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to > 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after dose adjustment or if granulocytes decrease to < 250/mm³ or ALT/AST rises to > 10 x upper limit of normal, discontinue interferon alfa-2b therapy.

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at the recommended dose, with dose reduction for toxicity as described.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients.

- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, recent myocardial infarction, severe arrhythmic disorders.

- Severe renal or hepatic dysfunction; including that caused by metastases.

- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).

- Chronic hepatitis with decompensated cirrhosis of the liver.

- Chronic hepatitis in patients who are being or have been treated recently with immunosuppressive agents excluding short term corticosteroid withdrawal.

- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant recipients.

- Pre-existing thyroid disease unless it can be controlled with conventional treatment.

- Combination of IntronA with telbivudine.

Children and adolescents:

- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicide attempt.

Combination therapy with ribavirin

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.

4.4 Special Warnings And Precautions For Use

Psychiatric and central nervous system (CNS) Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during IntronA therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Among children and adolescents treated with IntronA in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and the patient followed, with psychiatric intervention as appropriate. Patients with existence of, or history of severe psychiatric conditions: If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition. - The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Patients with substance use/abuse: HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C) During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment for more than 5 years. Case by case benefit/risk assessment in children The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1). - It is important to consider that the combination therapy induced a growth inhibition, the reversibility of which is uncertain. - This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV genotype and viral load). Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, discontinue the medicne and institute appropriate medical therapy. Transient rashes do not necessitate interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities

Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in some cases, termination of IntronA therapy.

Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of coagulation markers which might indicate liver decomposition.

Any patient developing liver function abnormalities during treatment with IntronA must be monitored closely and treatment discontinued if signs and symptoms progress.

Hypotension

Hypotension may occur during IntronA therapy or up to two days post-therapy and may require supportive treatment.

Need for adequate hydration

Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia

While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions

IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. While this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Ocular adverse events

Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, and retinal artery or vein obstruction have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual examinations during IntronA therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy

More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of IntronA.

Patients with pre-existing cardiac abnormalities

Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac disease.

Hypertriglyceridemia

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Kidney and liver graft rejection

Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Auto-antibodies and autoimmune disorders

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C

Combination therapy with ribavirin

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.

Monotherapy:

Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid dysfunction occurring during treatment (also see Children and adolescents, Thyroid monitoring).

Thyroid supplemental monitoring specific for children and adolescents:

Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid abnormalities are detected, the patient's thyroid status should be evaluated and treated as clinically appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).

HCV/HIV Coinfection

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia.

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests

Standard haematological tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and symptoms of liver failure are observed. During ALT flare, the following liver function tests must be monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and differential must be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.

Effect on fertility

Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA

This medicinal product contains less than 1 mmol sodium (23 mg) per 1.2 ml, i.e., essentially “sodium-free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with IntronA.

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution must be exercised when administering IntronA in combination with other potentially myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant therapy with medicinal products metabolised by this route, such as the xanthine derivatives theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see section 4.3).

4.6 Pregnancy And Lactation

Women of childbearing potential/contraception in males and females

Women of childbearing potential have to use effective contraception during treatment. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in combination with ribavirin. Females of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and their female partners must each use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SPC).

Pregnancy

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding

It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior to initiation of treatment.

4.7 Effects On Ability To Drive And Use Machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

4.8 Undesirable Effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 6 MIU/m²/week in hairy cell leukaemia up to 100 MIU/m²/week in melanoma), the most commonly reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were often reversible within 72 hours of interruption or cessation of treatment.

Adults

In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is presented from clinical trials in naïve patients treated for one year. Severity was generally mild to moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and post-marketing. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (>1/1,000 to <1/100); rarely (

Table 1 Adverse reactions reported during clinical trials or following the marketing use of IntronA alone or in combination with ribavirin
System Organ Class	Adverse Reactions
Infections and infestations Very common: Common: Uncommon Rarely:	Pharyngitis*, infection viral* Bronchitis, sinusitis, herpes simplex (resistance), rhinitis Bacterial infection Pneumonia§, sepsis
Blood and lymphatic system disorders Very common: Common: Very rarely: Not known:	Leukopaenia Thrombocytopaenia, lymphadenopathy, lymphopenia Aplastic anaemia Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders§ Very rarely: Not known:	Sarcoidosis, exacerbation of sarcoidosis Systemic lupus erythematosus, vasculitis, rheumatoid arthritis (new or aggravated), Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis§
Endocrine disorders Common: Very rarely:	Hypothyroidism§, hyperthyroidism§ Diabetes, aggravated diabetes
Metabolism and nutrition disorders Very common: Common: Very rarely:	Anorexia Hypocalcaemia, dehydration, hyperuricemia, thirst Hyperglycaemia, hypertriglyceridaemia§, increased appetite
Psychiatric disorders§ Very common: Common: Rarely: Very rarely: Not known:	Depression, insomnia, anxiety, emotional lability*, agitation, nervousness Confusion, sleep disorder, libido decreased   Suicide ideation Suicide, suicide attempts, aggressive behaviour (sometimes directed against others), psychosis including hallucinations, Homicidal ideation, mental status change§, mania, bipolar disorders
Nervous system disorders§ Very common: Common: Uncommon: Very rarely: Not known:	Dizziness, headache, concentration impaired, mouth dry Tremor, paresthesia, hypoesthesia, migraine, flushing, somnolence, taste perversion Peripheral neuropathy Cerebrovascular haemorrhage, cerbrovascular ischaemia, seizure, impaired consciousness, encephalopathy Mononeuropathies, coma§
Eye disorders Very common: Common: Rarely:	Vision blurred Conjunctivitis, vision abnormal, lacrimal gland disorder, eye pain Retinal haemorrhages§, retinopathies (including macular oedema), retinal artery or vein obstruction§, optic neuritis, papilloedema, loss of visual acuity or visual field, cotton-wool spots§
Ear and labyrinth Common: Very rarely:	Vertigo, tinnitus Hearing loss, hearing disorder
Cardiac disorders Common: Rarely: Very rarely: Not known:	Palpitation, tachycardia Cardiomyopathy Myocardial infarction, cardiac ischaemia Congestive heart failure, pericardial effusion, arrhythmia