Isosorbide Dinitrate Injection Concentrate BP 1mg / ml

1. Name Of The Medicinal Product

Isosorbide Dinitrate Injection Concentrate 1mg/ml, 10ml

2. Qualitative And Quantitative Composition

Isosorbide dinitrate 10mg in 10ml.

3. Pharmaceutical Form

Clear, colourless, sterile aqueous solution intended for parenteral administration to human beings.

4. Clinical Particulars

4.1 Therapeutic Indications

Isosorbide dinitrate is indicated in the treatment of unresponsive left ventricular failure of various aetiology, including left ventricular failure secondary to acute myocardial infarction. It is also indicated in the management of severe or unstable angina pectoris.

4.2 Posology And Method Of Administration

Recommended Route : Intravenously, after dilution.

Adults, including the elderly: The dose must be adjusted according to the patients response. A dose of between 2 and 12mg per hour is generally suitable, although doses as high as 20mg per hour may be necessary.

Children: The safety and efficacy of isosorbide dinitrate injection has not been established in children.

Administration: This is a concentrated solution and should never be administered in bolus form. It should be administered only as an admixture, intravenously, with a suitable vehicle such as Sodium Chloride Injection BP or Dextrose Injection BP. Admixtures are prepared by exchanging the required volume of Isosorbide Dinitrate Injection Concentrate with an equal volume of the infusion vehicle. For example, if the dose requirement is 6mg per hour, 50ml of Isosorbide Dinitrate Injection Concentrate should be added to 450ml of the infusion vehicle. The admixture now contains 1mg in 10ml and the required dosage can be achieved by administering 60ml per hour (equivalent to 20 standard drops or 60 paediatric microdrops per minute).

If further reduction in fluid intake is required, 100ml of Isosorbide Dinitrate Injection Concentrate made up to 500ml with a suitable infusion vehicle produces an admixture containing 2mg in 10ml which may be infused at a drip rate of 30ml per hour for a required dosage of 6mg per hour.

Where fluid intake is strictly limited, a dilution of 50% is advocated to produce a solution containing 0.5mg in 1ml.

Admixtures should be made up under aseptic conditions. Loss of potency will occur on contact with PVC and the use of PVC infusion bags or administration sets should, therefore, be avoided.

4.3 Contraindications

Cardiogenic shock, unless some means of maintaining an adequate diastolic aortic pressure are undertaken: circulatory collapse or low filling pressure: patients with a known sensitivity to nitrates or to those with marked anaemia, head trauma, cerebral haemorrhage, severe hypotension or hypovolaemia: hypertrophic obstructive cardiomyopathy: aortic stenosis: cardiac tamponade: constrictive pericarditis: mitral stenosis: closed-angle glaucoma

The hypotensive effects of nitrates are potentiated by sildenafil and their co-administration is contra-indicated.

4.4 Special Warnings And Precautions For Use

Close monitoring of the pulse and blood pressure is essential during infusion of isosorbide dinitrate.

Isosorbide dinitrate should be used with caution in patients with a recent history of myocardial infarction or in patients with hypothyroidism, hypothermia, malnutrition, severe hepatic or renal disease.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Isosorbide dinitrate may potentiate the effects of antihypertensive drugs.

The hypotensive effects of nitrates are potentiated by sildenafil (see contra-indications).

4.6 Pregnancy And Lactation

Although there are no reported data to indicate the possibility of adverse effects resulting from administration of isosorbide dinitrate in pregnancy, safety in pregnancy has not been established. Isosorbide dinitrate should only be used in pregnancy or lactation if, in the opinion of the physician, the possible benefits outweigh the possible risks.

4.7 Effects On Ability To Drive And Use Machines

Not relevant, as patients would be too ill to engage in these activities.

4.8 Undesirable Effects

As with all nitrates, the vasodilatory effects may cause a fall in systemic arterial pressure which could give rise to symptoms of cerebral flow insufficiency or decreased coronary perfusion. In common with other nitrates, headache, severe hypotension, nausea and retching, excessive sweating, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, abdominal pain, syncope and bradycardia may occur during therapy with isosorbide dinitrate (particularly if infused too rapidly). Methaemoglobinaemia has been known to occur, rarely. If methaemoglobinaemia is diagnosed, treatment with methylene blue at a dose of 1 to 2 mg/kg intravenously may be administered, depending on the degree and rapidity of methaemoglobin formation.

4.9 Overdose

Toxic effects of overdose include: vomiting, restlessness, cyanosis, hypertension, tachycardia and syncope.

Overdosage or too rapid infusion, especially in heart failure will result in excessively reduced filling pressures, hypotension, decreased ventricular performance and decreased perfusion of tissues. If the arterial systolic blood pressure drops below 90mm Hg and if the heart rate increases above 10% of its initial value, the infusion should be discontinued. Where necessary, hypotension may be treated by keeping the patient recumbent in a shock position and/or use hypertensive agents such as methoxamine or phenylephrine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Isosorbide dinitrate is a member of the organic nitrate group of vasodilators. It decreases both preload and afterload as a result of respective dilatation of venous capacitance and arteriolar resistance vessels. In left ventricular failure, isosorbide dinitrate produces a significant increase in the ejection fraction, stroke volume, cardiac output and tissue perfusion.

Isosorbide dinitrate decreases myocardial oxygen demand by increasing the venous capacitance and thereby reducing ventricular end-diastolic pressure and volume. It also influences oxygen supply, by improving the distribution of the myocardial blood flow to the subendocardial regions.

5.2 Pharmacokinetic Properties

The biotransformation of organic nitrates is the result of reductive hydrolysis catalysed by the hepatic enzyme glucathione-organic nitrate reductase. The major route of metabolism of isosorbide dinitrate in man is by enzymatic denitration followed by formation of glucuronides. The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, have longer half lives (2 - 5 hours) and are presumed to be responsible, at least in part, for the therapeutic efficacy of isosorbide dinitrate.

Denitration markedly reduces its activity. Hepatic denitration is also influenced by hepatic disease and blood flow. The terminal elimination half life is 54.7 minutes following intravenous injection. The total plasma clearance is 136 litres per hour.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride BP

Sodium Hydroxide BP

Water for Injections BP

6.2 Incompatibilities

Isosorbide dinitrate is incompatible with infusion bags and giving sets made from PVC - loss of potency will occur on contact with PVC.

6.3 Shelf Life

3 years (36 months).

6.4 Special Precautions For Storage

Protect from light.

Store below 30°C.

6.5 Nature And Contents Of Container

10ml, clear glass ampoules, glass type 1 Ph.Eur., packed in cardboard cartons to contain 10 x 10ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

Solutions containing visible solid particles should not be used.

Dilute before use with a suitable vehicle such as Sodium Chloride Intravenous Infusion.

Not for direct injection.

For administration by IV infusion only.

Use by slow infusion only, with haemodynamic monitoring of the patient.

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

7. Marketing Authorisation Holder

Antigen International Ltd.,

Roscrea,

Co. Tipperary,

Ireland.

8. Marketing Authorisation Number(S)

PL 2848/0160.

9. Date Of First Authorisation/Renewal Of The Authorisation

25/10/1991.

10. Date Of Revision Of The Text

October 2002

Isoniazid Ampoules 50 mg / 2 ml.

1. Name Of The Medicinal Product

Isoniazid Ampoules 50 mg/2 ml.

2. Qualitative And Quantitative Composition

Each ampoule contains 50 mg Isoniazid BP in 2 ml of solution.

3. Pharmaceutical Form

Ampoules

4. Clinical Particulars

4.1 Therapeutic Indications

For all forms of pulmonary and extra-pulmonary tuberculosis.

4.2 Posology And Method Of Administration

Isoniazid ampoules are for intramuscular, intravenous, intrapleural, or intrathecal injection.

Adults and children

The usual intramuscular or intravenous dose for adults is 200 to 300 mg as a single daily dose, for children 100 to 300 mg daily (10 - 20 mg/kg), but doses much larger than these are sometimes given, especially in conditions such as tuberculous meningitis. It is recommended to give an intravenous dose slowly as an undiluted bolus injection, although other methods may be employed.

Neonates

The recommended intravenous or intramuscular dose for neonates is 3-5 mg/kg with a maximum of 10 mg/kg daily. Isoniazid may be present in the milk of lactating mothers.

The elderly

No dosage reduction is necessary in the elderly.

Intrapleural use

50 to 250 mg may be instilled intrapleurally after aspiration of pus, the dosage of oral isoniazid on that day being correspondingly reduced. The ampoule solution is also used for the local treatment of tuberculous ulcers, for irrigation of fistulae, etc.

Intrathecal use:

It should be noted that CSF concentrations of isoniazid are approximately 90% of plasma concentrations. Where intrathecal use is required, 25 - 50 mg daily has been given to adults and 10 - 20 mg daily for children, according to age.

It is usual to give Isoniazid together with other antituberculous therapy, as determined by current practice and/or sensitivity testing.

It is recommended that pyridoxine 10 - 50mg daily be given during Isoniazid therapy to minimise adverse reactions, especially in malnourished patients and those predisposed to neuropathy (eg. diabetics and alcoholics).

4.3 Contraindications

Isoniazid should not be given to patients with a history of sensitivity to isoniazid.

4.4 Special Warnings And Precautions For Use

Use in renal and hepatic impairment: no dosage reduction of Isoniazid is necessary when given to patients with mild renal failure. Patients with severe renal failure (glomerular filtration rate of less than 10 ml/minute) and slow acetylator status might require a dose reduction of about 100mg to maintain trough plasma levels at less than 1 mcg/ml. The possible risks of administration of Isoniazid to patients with pre-existing non-tuberculous hepatic disease should be balanced against the benefits expected from treating tuberculosis.

Care is also required in chronic alcoholism and when prescribing isoniazid for patients with pre-existing hepatitis. Convulsions and psychotic reactions have occurred, especially in patients with a previous history of these conditions. These manifestations usually subside rapidly when the drug is withdrawn. Isoniazid should therefore be given with caution to patients with convulsive disorders and should be avoided in those with manic or hypomanic psychoses.

Isoniazid is metabolised by acetylation, which is subject to genetic variation. The 'slow acetylators' may be more susceptible to drug-induced peripheral neuropathy. However, dose adjustment is not normally required.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Isoniazid may inhibit the metabolism of phenytoin, primidone and carbamazepine. Plasma levels of these drugs should be monitored if concurrent therapy with Isoniazid is necessary. See also statement under 4.8 regarding Rifampicin.

4.6 Pregnancy And Lactation

While Isoniazid is generally regarded to be safe in pregnancy, there is a possibility of an increased risk of foetal malformations occurring when Isoniazid is given in early pregnancy. If pregnancy cannot be excluded possible risks should be balanced against therapeutic benefits. Isoniazid is excreted in breast milk at concentrations equivalent to those found in maternal plasma, ie. 6-12 mcg/ml. This could result in an infant ingesting up to 2 mg/kg/day.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Isoniazid is generally well tolerated. Side-effects have been reported mainly in association with high doses or in slow acetylators who develop higher blood levels of the drug. Fever, peripheral neuropathy (preventable with pyridoxine), optic neuritis and atrophy, allergic skin conditions (including erythema multiforme), and rarely lupoid syndrome, pellagra, purpura and haematological reactions have occurred during isoniazid therapy. Hyperglycaemia and gynaeco-mastia have been reported with isoniazid treatment. Isoniazid, especially if given with rifampicin, may induce abnormalities in liver function, particularly in patients with pre-existing liver disorders, in the elderly, the very young and the malnourished. Monthly review is suggested to detect and limit the severity of this side-effect by stopping treatment if plasma transaminases exceed three times the upper limit of normal. There is conflicting opinion as to the relationship of this side-effect to acetylator status.

4.9 Overdose

In severe poisoning the main risk is of epileptiform convulsions. In addition any of the side-effects listed above may occur together with metabolic acidosis and hyperglycaemia. Treatment should be directed to the control of convulsions and large doses of pyridoxine may limit the occurrence of other adverse effects. Metabolic acidosis may require sodium bicarbonate infusion. The drug is removed by dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Isoniazid is a highly active tuberculostatic drug, and at high concentrations it is bactericidal to mycobacterium tuberculosis, possibly acting by interference with the synthesis of mycolic acid (a constituent of the bacterial cell wall).

5.2 Pharmacokinetic Properties

Isoniazid is not appreciably protein-bound and diffuses readily throughout the body. It affects intracellular as well as extracellular bacilli. The primary metabolic route involves acetylation the rate of which is determined genetically.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hydrochloric Acid

Water for Injections BP

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

The recommended maximum storage temperature is 25ºC.

Protect from light.

6.5 Nature And Contents Of Container

Colourless glass ampoules coded with dark red and orange colour ring each containing 2 ml of solution, in packs of 10 ampoules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Limited

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

UK

8. Marketing Authorisation Number(S)

PL 16853/0109

9. Date Of First Authorisation/Renewal Of The Authorisation

21 April 1992

10. Date Of Revision Of The Text

27^th July 2010

Iodine Tincture BP

1. Name Of The Medicinal Product

Alcoholic Iodine Solution BP

Iodine Tincture BP

2. Qualitative And Quantitative Composition

Iodine 2.5% w/v, Potassium Iodide 2.5% w/v

3. Pharmaceutical Form

Cutaneous solution.

A dark brown, clear, mobile liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

As an antiseptic for use on minor wounds, cuts and abrasions.

4.2 Posology And Method Of Administration

For cutaneous use.

The product is suitable for use by adults, children and the elderly.

Apply to the affected part with cotton wool or a small brush.

4.3 Contraindications

Contraindicated for patients hypersensitive to iodine or iodides.

Contradicted for use in newborn infants.

Contradicted in patients with thyroid disorders or those receiving lithium therapy.

4.4 Special Warnings And Precautions For Use

Avoid prolonged use.

For external use only.

Keep all medicines out of the reach and sight of children.

Solutions of iodine applied to the skin should not be covered with occlusive dressings, (otc packs to state the shortened warning, “DO NOT COVER”).

Do not use on large, open wounds.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Administration of this product may interfere with tests of thyroid function.

4.6 Pregnancy And Lactation

Use with caution during pregnancy and lactation. Iodides cross the placenta and are excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

None or negligible influence.

4.8 Undesirable Effects

May cause allergic reactions, including urticaria, angioedema, cutaneous haemorrhage or purpuras, fever, arthralgia, lymphadenopathy and eosinophilia.

4.9 Overdose

This product is not intended for internal use.

Symptoms of acute poisoning from ingestion of iodine include a disagreeable metallic taste, vomiting, abdominal pain and diarrhoea, thirst and headache may occur. The fatal dose of iodine is 2 to 3g. Symptomatic treatment for allergic reactions and iodism may be required, although symptoms usually subside rapidly when administration of iodine or iodide is stopped.

In acute poisoning copious draughts of milk and starch mucilage should be given.

Lavage should probably not be attempted and certainly not unless iodine had been ingested in sufficiently dilute form not to produce gastrointestinal corrosion. Other treatments include activated charcoal and sodium thiosulphate solution 1% or 5% to reduce iodine to the less toxic iodides. Electrolyte and water losses should be replaced and the circulation should be maintained. Pethidine or morphine sulphate may be given for pain, under medical supervision. A tracheotomy may become necessary.

Provided the product is not applied to large, open wounds or used for prolonged periods, clinically significant systemic absorption is unlikely. Systemic toxicity may lead to shock, tachycardia, fever, metabolic acidosis and renal impairment Death may be due to circulatory failure, oedema of the epiglottis resulting in asphyxia, aspiration pneumonia or pulmonary oedema. Oesophageal stricture may occur if the patient survives the acute stage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

D08A G03 - Antiseptics and disinfectants, iodine products

Iodine has a powerful bactericidal action and is used for disinfecting unbroken skin before operations. Iodine is active against fungi, viruses, protozoa, cysts and spores.

5.2 Pharmacokinetic Properties

Iodine is only slightly absorbed when applied to the skin.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Purified water

Ethanol (96%)

6.2 Incompatibilities

None known.

6.3 Shelf Life

25ml:	36months unopened
50ml:	36Months unopened
500ml:	36 Months unopened
2000ml:	36 Months unopened

6.4 Special Precautions For Storage

Store below 25°C in a well closed container.

6.5 Nature And Contents Of Container

25ml:	Glass bottle with plastic lined cap
50ml:	Glass bottle with plastic lined cap
500ml:	Glass bottle with plastic lined cap
2000ml:	Glass bottle with plastic lined cap

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

L.C.M. Ltd.,

Linthwaite Laboratories

Huddersfield

HD7 5QH

8. Marketing Authorisation Number(S)

PL 12965/0019

9. Date Of First Authorisation/Renewal Of The Authorisation

25^th August 1993

10. Date Of Revision Of The Text

06/08/2009

Isosorbide mononitrate 20mg tablets (Aurobindo Pharma Ltd)

1. Name Of The Medicinal Product

Monomil 20 mg Tablets

Carmil 20 mg Tablets

Isosorbide Mononitrate 20 mg tablets.

2. Qualitative And Quantitative Composition

Isosorbide-5-mononitrate Ph. Eur. 20 mg/tablet.

3. Pharmaceutical Form

Tablets

White to off-white, round flat tablets with 'I15' embossing on one side.

4.1 Therapeutic Indications

For the prophylaxis of angina pectoris

As adjunctive therapy in congestive heart failure not responding to cardiac glycosides or diuretics.

4.2 Posology And Method Of Administration

Adults: One tablet to be taken asymmetrically (to allow a nitrate low period) two or three times a day. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose of isosorbide mononitrate be 20mg twice a day. The dosage may be increased to 120mg per day. The lowest effective dose should be used.

Children: The safety and efficacy of Isosorbide Mononitrate 20mg tablets in children has not been established.

Elderly: There is no evidence to suggest that an adjustment of the dosage is necessary.

Treatment with Isosorbide mononitrate tablets, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4)

4.3 Contraindications

Isosorbide mononitrate tablets should not be used in cases of acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse), or very low blood pressure, hypertrophic obstructive cardiomyopathy (HOCM), constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/mitral valve stenosis and diseases associated with a raised intra-cranial pressure e.g. following a head trauma and including cerebral haemorrhage.

This product should not be given to patients with a known sensitivity to isosorbide mononitrate, the listed ingredients or other nitrates.

Isosorbide mononitrate Tablets should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.

Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5)

4.4 Special Warnings And Precautions For Use

Isosorbide mononitrate Tablets should be used with caution in patients who have recent history of myocardial infarction, or who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

This product may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

Isosorbide mononitrate Tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate Tablets.

If the tablets are not taken as indicated (see section 4.2), tolerance to the medication could develop. The lowest effective dose should be used.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.2)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists etc. and/or alcohol may potentiate the hypotensive effects of Isosorbide mononitrate Tablets. This may occur with neuroleptics and tricyclic antidepressants.

Any blood pressure lowering effect of Isosorbide mononitrate tablets will be increased if used together with phosphodiesterase type-5- inhibitors, which are used for erectile dysfunction (see special warning and contraindications). This may lead to life threatening cardiovascular complications. Patients who are on Isosorbide mononitrate therapy therefore must not use phosphodiesterase type-5 inhibitors.

Reports suggest that concomitant administration of Isosorbide mononitrate tablets may increase the blood levels of dihydroergotamine and its hypertensive effects.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy and lactation and use during pregnancy and lactation is not recommended unless considered essential by the patient's physician.

4.7 Effects On Ability To Drive And Use Machines

Dizziness, tiredness or blurred vision might occur at the start of the treatment. The patient should therefore be advised that if affected, they should not drive or operate machinery. This effect may be increased by alcohol.

4.8 Undesirable Effects

A very common (>10% of patients) adverse reaction to Isosorbide mononitrate Tablets is throbbing headache. The incidence of headache diminishes gradually with time and continued use.

At the start of therapy or when the dosage is increased, hypotension and/or light-headedness in the upright position are commonly observed (i.e. in 1-10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachycardia and a feeling of weakness.

Infrequently (i.e. in less than 1% patients) nausea, vomiting, flushing and allergic skin reactions (e. g. rash) may occur sometimes severely. In single cases exfoliative dermatitis may occur.

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.

A few reports of heartburn most likely due to a nitrate induced sphincter relaxation have been reported.

Tachycardia and paroxysmal bradycardia have been reported.

4.9 Overdose

Symptoms and signs: Headache, hypotension, nausea, vomiting, sweating, tachycardia, vertigo, restlessness, warm flushed skin, blurred vision and syncope. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur. Methaemoglobinaemia (cyanosis, hypoxaemia, restlessness, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure) occurs rarely.

Management:

Consider oral activated charcoal if ingestion of a potentially toxic amount has occurred within 1 hour. Observe for at least 12 hours after the overdose. Monitor blood pressure and pulse. Correct hypotension by raising the foot of the bed and /or by expanding the intravascular volume. Other measures as indicated by the patient's clinical condition. If severe hypotension persists despite the above measures consider use of inotropes.

If methaemoglobinaemia (symptoms or >30% methaemoglobin), IV administration of methylene blue 1-2mg/kg body-weight. If therapy fails with second dose after 1 hour or contraindicated, consider red blood cell concentrates or exchange transfusion. In case of cerebral convulsions, diazepam or clonazepam IV, or if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.

5.1 Pharmacodynamic Properties

ATC code: C01D A14 Vasodilatator used in cardiac diseases

Isosorbide mononitrate is an organic nitrate, which, in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.

Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.

It reduces the requirements of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.

5.2 Pharmacokinetic Properties

Isosorbide 5—mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.

Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.

Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosrbide-5-mn-2-glucoronide, which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.

After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, oncogenicity and toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose Ph. Eur., Lactose Monohydrate Ph. Eur., Colloidal Anhydrous Silica Ph. Eur., Maize starch Ph. Eur., Talc Ph. Eur., and Magnesium stearate Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25ºC.

6.5 Nature And Contents Of Container

PVC/Aluminium foil blisters on a cardboard carton.

Each sheet of blisters contains 10 tablets and there are six sheets of ten tablets per carton (60's pack).

Each strip of blister contains 14 tablets and there are four such strips per carton (56's pack).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

21^st September 1998

10. Date Of Revision Of The Text

16/10/2007

Iopidine 1.0% Ophthalmic Solution

1. Name Of The Medicinal Product

IOPIDINE 1.0% Eye Drops, Solution

2. Qualitative And Quantitative Composition

Apraclonidine 1.0% w/v (10mg/ml)

(as hydrochloride)

For a full list of excipients see section 6.1.

3. Pharmaceutical Form

Eye Drops, Solution

IOPIDINE 1.0% is a pale yellow solution.

4. Clinical Particulars

4.1 Therapeutic Indications

IOPIDINE 1.0% is indicated to control or prevent postsurgical elevations in intraocular pressure that occur in patients after anterior segment laser surgery. (Clinical trials have been conducted in trabeculoplasty, iridotomy and capsulotomy).

4.2 Posology And Method Of Administration

Adults(including the elderly):

One drop of IOPIDINE 1.0% should be instilled into the eye scheduled for operation one hour before initiating anterior segment laser surgery. A second drop should be instilled into the same eye immediately upon completion of the laser surgical procedure.

If for any reason, the drop of IOPIDINE 1.0% does not remain in the eye, repeat the dose by placing another drop in the eye.

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medications administered via the ocular route and result in a decrease in systemic side effects.

There are no special precautions for administration to the elderly.

Children:

Safety and effectiveness of IOPIDINE in children have not been established and therefore IOPIDINE 1.0% is not recommended for use in children.

4.3 Contraindications

IOPIDINE 1.0% is contraindicated in patients with a history of severe or unstable and uncontrolled cardiovascular disease.

IOPIDINE 1.0% is contraindicated for children, for patients receiving monamine oxidase inhibitor therapy, systemic sympathomimetic agents, tricyclic antidepressants, and for patients with hypersensitivity to any component of the preparation or to clonidine.

4.4 Special Warnings And Precautions For Use

Warnings:

For topical ophthalmic use only. Not for injection or oral ingestion.

While the topical administration of two drops of IOPIDINE 1.0% had minimal effect on heart rate or blood pressure in clinical studies evaluating patients undergoing anterior segment laser surgery, including those with cardiovascular disease, the possibility of a vasovagal attack should be considered and caution should be exercised in patients with a history of such episodes. IOPIDINE 1.0% should be used with caution in patients with a history of angina, severe coronary insufficiency, recent myocardial infarction, overt cardiac failure, cerebrovascular disease, chronic renal failure, Raynaud's disease or thromboangiitis obliterans. Caution in and monitoring of depressed patients are advised since apraclonidine has been rarely associated with depression.

Precautions:

No data are available on the topical use of apraclonidine in patients with renal or hepatic failure. Systemic absorption of apraclonidine following topical administration is low, resulting in plasma levels less than 1.0 ng/ml. Nonetheless, monitoring of patients with impaired renal or hepatic function is advised. Close monitoring of cardiovascular parameters in patients with impaired liver function is also advised as the systemic dosage form of clonidine is partly metabolised in the liver.

Since apraclonidine is a potent depressor of intraocular pressure, patients who develop an exaggerated reduction in intraocular pressure should be closely monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The risk of clinically relevant interactions appears low considering the plasma levels of apraclonidine given by the ocular route.

Although no specific drug interactions with topical glaucoma drugs or systemic medicaments were identified in clinical studies of IOPIDINE 1.0%, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, anaesthetics) should be considered. There is a theoretical possibility that use of IOPIDINE 1.0% in conjunction with topical sympathomimetics may give rise to a systemic pressor response and blood pressure should be checked initially in patients receiving these drug combinations.

Caution,is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

An additive hypotensive effect has been reported with the combination of systemic clonidine and neuroleptic therapy. Systemic clonidine may inhibit the production of catecholamine in response to insulin-induced hypoglycaemia and mask the signs and symptoms of hypoglycaemia.

Since apraclonidine may reduce pulse and blood pressure, caution in using drugs such as beta-blockers (ophthalmic and systemic), antihypertensives, and cardiac glycosides is advised. Patients using cardiovascular drugs concurrently with IOPIDINE 1.0% should have pulse and blood pressure frequently monitored. Caution should be exercised with simultaneous use of clonidine and other similar pharmacologic agents.

4.6 Pregnancy And Lactation

There are no adequate data from the use of Iopidine 1% in pregnant women. Preclinical studies with apraclonidine have shown embryotoxicity (see 5.3). The potential risk for humans is unknown.

It is not known if topically applied apraclonidine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IOPIDINE 1.0% is administered to nursing women.

4.7 Effects On Ability To Drive And Use Machines

Clonidine-like drugs may cause drowsiness; patients if so affected should not drive or operate machinery.

4.8 Undesirable Effects

The following adverse events occurring in less than 2% of patients were reported in association with the use of IOPIDINE 1% in laser surgery:

Eye Disorders

Common (> 1/100 to < 1/10): Ocular hyperaemia.

Uncommon > 1/1000 to

Respiratory, Thoracic and Mediastinal Disorders

Uncommon (> 1/1000 to

Investigations

Uncommon (> 1/1000 to

The following adverse events were observed in non-laser investigational studies dosing IOPIDINE 1% once or twice daily for up to 28 days:

Psychiatric Disorders

Uncommon (> 1/1000 to

Nervous System Disorders

Uncommon (> 1/1000 to

Rare (> 1/10,000 to

Eye Disorders

Uncommon (> 1/1000 to

Cardiac Disorders

Uncommon (> 1/1000 to

Vascular Disorders

Uncommon (> 1/1000 to

Respiratory, Thoracic and Mediastinal Disorders

Rare (> 1/10,000 to

Gastrointestinal Disorders

Uncommon (> 1/1000 to

Rare (> 1/10,000 to

Skin and Subcutaneous Tissue Disorders

Rare (> 1/10,000 to

Musculoskeletal, Connective Tissue and Bone Disorders

Rare (> 1/10,000 to

General Disorders and Administration Site Conditions

Rare (> 1/10,000 to

4.9 Overdose

In the case of accidental overdose, Iopidine 1% can be removed by rinsing the eye with water or sterile saline solution.

A 2 month old female child received IOPIDINE 1% 1 drop in each eye. Two to three hours later, the infant presented with extreme pallor, hypothermia and miosis. She became comatose and was treated with glucose perfusion. The infant became responsive, but lethargic and heart rate was noted to be slow but regular. The infant made a full recovery with no sequelae.

A 23 month old male child ingested orally an unknown amount of IOPIDINE 5 mg/ml. The child was admitted to the hospital with hypothermia, bradycardia and drowsiness. Blood analysis revealed an apraclonidine serum level of 2.9ng/ml. The child was warmed and treated with atropine and dopamine with resolution of hypothermia and bradycardia within 4 hours. The child remained somnolent for 24 hours and was discharged 48 hours after admission with no reported sequelae.

Overdose with the oral form of clonidine has been reported to cause hypotension, transient hypertension, asthenia, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, sedation or coma, pallor, hypothermia, bradycardia, conduction defects, arrhythmias, dryness of the mouth, miosis, apnoea, respiratory depression, hypoventilation, and seizure. Treatment of an oral overdose includes supportive and symptomatic therapy, a patent airway should be maintained. Haemodialysis is of limited value since a maximum of 5% of circulating drug is removed.

5. Pharmacological Properties

Ophthalmologicals; Antiglaucoma Preparation and Miotics.

ATC Code: SO1E A03

5.1 Pharmacodynamic Properties

Apraclonidine is a relatively selective alpha-2-adrenergic agonist which does not possess significant membrane stabilising (local anaesthetic) activity. When instilled into the eye, apraclonidine has the action of reducing intraocular pressure. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters. Aqueous fluorophotometry studies in man suggest that the mechanism of the ocular hypotensive action of apraclonidine is related to a reduction in aqueous formation.

The onset of action of IOPIDINE 1.0% can usually be noted within one hour and the maximum intraocular pressure reduction usually occurs three to five hours after application of a single dose.

5.2 Pharmacokinetic Properties

Following topical ocular administration to New Zealand albino rabbits, apraclonidine reached peak concentrations after two hours in the aqueous humor, iris, ciliary body and lens. The cornea exhibited the greatest concentration and peaked at the earliest time point (20 minutes). The tissue distribution of apraclonidine from highest to lowest concentration in microgram equivalents per gram of tissue was cornea, iris-ciliary body, aqueous humor, lens and vitreous humor. The elimination half-life of apraclonidine from the aqueous humor was determined to be approximately two hours.

Plasma concentration of apraclonidine following three times daily, bilateral, topical ocular dosing of 0.5% apraclonidine ophthalmic solution to normal human volunteers was less than 1.0 ng/ml. A steady state level was attained after five days of dosing. The systemic elimination half-life of apraclonidine was approximately 8 hours.

5.3 Preclinical Safety Data

Administration of apraclonidine intravenously and via the topical ocular route to both cats and monkeys resulted in a reduced anterior segment blood flow whereas flow to the posterior segment (i.e., retina, choroid or optic nerve head) was not affected. Chronic treatment of primates with apraclonidine hydrochloride 1.5% ocularly three times a day for one year did not result in morphological effects.

Acute Toxicity

Acute toxicity was evaluated intravenously and orally in rats and mice and orally in primates. The approximate oral LD₅₀ ranged from 5.04 mg/kg (mice) to 63.9 mg/kg (rats); no lethalities were observed in primates at 55 mg/kg. In rodents toxic signs included lethargy, hypothermia, cornea cloudiness, and haemorrhagic areas as well as distension of the gastrointestinal tract. Pronounced inhibition of gastrointestinal motility is considered the cause of mortality in mice. The reduced intestinal motility was observed in mice after intravenous administration of 0.1 mg/kg. Lethargy and disturbed defecation were found in monkeys after oral administration of 55 mg/kg. The normal human dose from ophthalmic use is approximately 0.01 mg/kg/d.

Subchronic and Chronic Toxicity

Rabbits tolerated apraclonidine hydrochloride solutions of 0.5%, 1% or 1.5% (2 drops t.i.d.) over a period of one month without signs of systemic toxicity. Minimal corneal cloudiness was observed sporadically in some eyes receiving the 1.5% apraclonidine hydrochloride solution.

Rats and mice received daily oral doses of up to 1.2 mg/kg and 2 mg/kg, respectively, over a period of 13 weeks. Mortalities occurred in rats at 1.2 mg/kg/d and in mice at 1.6 mg/kg/d. Pharmacotoxic reactions included disturbed defecation and distended abdomen plus corneal cloudiness predominantly in female mice of the high-dose group. Rats in the high-dose group that died before the end of the study showed lymphocytic effects in the spleen and thymus, but these effects were not seen in animals which survived to the end of the study. No drug-related toxic or ophthalmic findings were observed when monkeys received apraclonidine hydrochloride solutions of 0.5%, 1% and 1.5% by topical ocular administration t.i.d. for one year.

Local Tolerance

The topical ocular administration of apraclonidine hydrochloride solutions of 0.5%, 1% and 1.5% (2 drops instilled at 30 min intervals into one eye for 6 h) led to dose-dependent conjunctival and corneal irritation in the rabbit.

Assessment of the sensitization potential in the guinea pig proved apraclonidine hydrochloride to be moderately sensitizing.

Mutagenic and Tumorigenic Potential

Mutagenicity testing of apraclonidine hydrochloride using different standard systems all produced negative results.

Two-year long-term studies evaluating the carcinogenic potential in rats (at doses of 0.1, 0.3 and 1.0 mg/kg/d) and mice (at doses of 0.1, 0.3 and 0.6 mg/kg/d) revealed no signs of a carcinogenic potential of apraclonidine hydrochloride.

Both species showed an increased incidence of ocular changes (mineralization and neo-vascularization of the cornea, and keratitis), which are considered related to the pharmacological effect of the drug in reducing the tear film. In addition, renal changes (mineralisation) were found in rats from 0.3 mg/kg/d onward.

Reproduction Toxicity

Studies performed in rats and rabbits did not suggest any teratogenic effects of apraclonidine. Embryotoxicity has been observed when pregnant rabbits were dosed orally with doses of apraclonidine (doses > 1.25 mg/kg/day) that were maternally toxic, and administered over the entire period of organogenesis at exposure levels > 100 times the recommended daily dosage regimen for IOPIDINE 1.0% based on a 50 kg person.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium acetate, sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH) and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Unopened: 2 years.

Use immediately after first opening the container.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the container in the outer carton

6.5 Nature And Contents Of Container

Two sealed LDPE form/fill/seal single-dose containers each containing 0.25 mL and wrapped in a foil pouch.

The following pack sizes are available:

1 box containing 1 pouch of 2 single dose containers

1 box containing 5 pouches of 2 single dose containers

1 box containing 6 pouches of 2 single dose containers

1 box containing 10 pouches of 2 single dose containers

1 box containing 15 pouches of 2 single dose containers

1 box containing 20 pouches of 2 single dose containers

1 box containing 25 pouches of 2 single dose containers

Not all the pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

Discard any unused contents immediately after use.

7. Marketing Authorisation Holder

Alcon Laboratories (U.K.) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts. HP2 7UD

United Kingdom

8. Marketing Authorisation Number(S)

PL 0649/0120

9. Date Of First Authorisation/Renewal Of The Authorisation

09/04/2006

10. Date Of Revision Of The Text

09/04/2006

Isentress 400 mg Film-coated Tablets

1. Name Of The Medicinal Product

ISENTRESS® 400 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 400 mg of raltegravir (as potassium).

Excipient: Each tablet contains 26.06 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Pink, oval tablet, marked with "227" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

ISENTRESS is indicated in combination with other anti-retroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on safety and efficacy data from two double-blind, placebo-controlled trials in treatment-experienced patients and one double-blind, active-controlled trial in treatment-naïve patients (see sections 4.4 and 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection. ISENTRESS should be used in combination with other active anti-retroviral therapies (ARTs) (see sections 4.4 and 5.1). The use of raltegravir in previously ART-naïve patients is based on a study in which it was co-administered with two NRTIs (see sections 4.4 and 5.1).

Posology

Adults

The recommended dosage of ISENTRESS is 400 mg administered twice daily with or without food. The effect of food on absorption of raltegravir is uncertain (see section 5.2). It is not recommended to chew, crush or split the tablets.

Elderly

There is limited information regarding the use of ISENTRESS in the elderly (see section 5.2). Therefore ISENTRESS should be used with caution in this population.

Children and adolescents

Safety and efficacy have not been established in patients below 16 years of age (see sections 5.1 and 5.2).

Renal impairment

No dosage adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Method of administration

Oral

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Patients should be advised that current anti-retroviral therapy does not cure HIV and has not been proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be employed.

Overall, considerable inter- and intra-subject variability was observed in the pharmacokinetics of raltegravir (see sections 4.5 and 5.2).

Raltegravir has a relatively low genetic barrier to resistance. Therefore, whenever possible, raltegravir should be administered with two other active ARTs to minimise the potential for virological failure and the development of resistance (see section 5.1).

In treatment-naïve patients, the clinical study data on use of raltegravir are limited to use in combination with two nucleotide reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate).

The safety and efficacy of ISENTRESS have not been established in patients with severe underlying liver disorders. Therefore ISENTRESS should be used with caution in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination anti-retroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

There are very limited data on the use of raltegravir in patients co-infected with HIV and hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients with chronic hepatitis B or C and treated with combination anti-retroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination anti-retroviral therapy. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination anti-retroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Caution should be used when co-administering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.5).

Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.8).

Severe skin and hypersensitivity reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking ISENTRESS, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing ISENTRESS + darunavir compared to patients receiving ISENTRESS without darunavir or darunavir without ISENTRESS (see section 4.8).

ISENTRESS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro studies indicated that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce CYP3A4 and does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or P-glycoprotein.

Based on in vitro and in vivo studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Although in vitro studies indicated that raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically important drug-drug interactions.

Considerable inter- and intra-individual variability was observed in the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric Mean values; the effect for an individual patient cannot be predicted precisely.

Effect of raltegravir on the pharmacokinetics of other medicinal products

In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.

Effect of other agents on the pharmacokinetics of raltegravir

Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co-administering ISENTRESS with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4). The impact of other strong inducers of drug metabolising enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of ISENTRESS.

Co-administration of ISENTRESS with medicinal products that are known to be potent UGT1A1 inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors (e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma levels, in the optimised background regimens. The safety profile observed in patients who used atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use these agents. Therefore no dose adjustment is required.

In healthy subjects, co-administration of ISENTRESS with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH on the absorption of raltegravir in HIV-infected patients are uncertain, use ISENTRESS with medicinal products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if unavoidable.

Table 1

Pharmacokinetic Interaction Data

Medicinal products by therapeutic area	Interaction (mechanism, if known)	Recommendations concerning co-administration
ANTI-RETROVIRAL
Protease inhibitors (PI)
atazanavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑41% raltegravir C12hr ↑77% raltegravir Cmax ↑24% (UGT1A1 inhibition)	No dose adjustment required for ISENTRESS.
tipranavir /ritonavir (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
efavirenz (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	No dose adjustment required for ISENTRESS.
etravirine (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction) etravirine AUC ↑ 10% etravirine C12hr ↑ 17% etravirine Cmax ↑ 4%	No dose adjustment required for ISENTRESS or etravirine.
Nucleoside/tide reverse transcriptase inhibitors
tenofovir (raltegravir 400 mg Twice Daily)	raltegravir AUC ↑49% raltegravir C12hr ↑3% raltegravir Cmax ↑64% (mechanism of interaction unknown) tenofovir AUC tenofovir C12hr tenofovir Cmax	No dose adjustment required for ISENTRESS or tenofovir disoproxil fumarate.
CCR5 inhibitors
maraviroc (raltegravir 400 mg Twice Daily)	raltegravir AUC raltegravir C12hr raltegravir Cmax (mechanism of interaction unknown) maraviroc AUC maraviroc C12hr maraviroc Cmax	No dose adjustment required for ISENTRESS or maraviroc.
ANTIMICROBIALS
Antimycobacterial
rifampicin (raltegravir 400 mg Single Dose)	raltegravir AUC raltegravir C12hr raltegravir Cmax (UGT1A1 induction)	Rifampicin reduces plasma levels of ISENTRESS. If co-administration with rifampicin is unavoidable, a doubling of the dose of ISENTRESS can be considered (see section 4.4).
SEDATIVE
midazolam (raltegravir 400 mg Twice Daily)	midazolam AUC midazolam Cmax↑3%	No dosage adjustment required for ISENTRESS or midazolam. These results indicate that raltegravir is not an inducer or inhibitor of CYP3A4, and raltegravir is thus not anticipated to affect the pharmacokinetics of medicinal products which are CYP3A4 substrates.
ANTI-ULCER
omeprazole (raltegravir 400 mg Single Dose)	raltegravir AUC ↑ 212% raltegravir C12 hr↑ 46% raltegravir Cmax↑ 315%	Co-administration of proton pump inhibitors or other antiulcer medicinal products may increase plasma levels of raltegravir. Do not use ISENTRESS with medicinal products that increase gastric pH unless this is unavoidable.
HORMONAL CONTRACEPTIVES
Ethinyl Estradiol Norelgestromin (raltegravir 400 mg Twice Daily)	Ethinyl Estradiol AUC Ethinyl Estradiol Cmax↑ 1% Norelgestromin AUC ↑ 14% Norelgestromin Cmax↑ 29%	No dosage adjustment required for ISENTRESS or hormonal contraceptives (estrogen- and/or progesterone-based)
OPIOID ANALGESICS
methadone (raltegravir 400 mg Twice Daily)	methadone AUC ↔ methadone Cmax↔	No dose adjustment required for ISENTRESS or methadone.

4.6 Pregnancy And Lactation

Pregnancy

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

Anti-retroviral Pregnancy Registry

To monitor maternal-foetal outcomes in patients inadvertently administered ISENTRESS while pregnant, an Anti-retroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Lactation

It is not known whether raltegravir is secreted in human milk. However, raltegravir is secreted in the milk of lactating rats. In rats, at a maternal dose of 600 mg/kg/day, mean active substance concentrations in milk were approximately 3-fold greater than in maternal plasma. Breastfeeding is not recommended while taking ISENTRESS. In addition, it is recommended that HIV-infected mothers should not breastfeed their infants to avoid risking postnatal transmission of HIV.

4.7 Effects On Ability To Drive And Use Machines

No studies have been performed on the effects of ISENTRESS on the ability to drive and use machines. However, dizziness has been reported in some patients during treatment with regimens containing ISENTRESS, which may influence some patients' ability to drive and use machines (see section 4.8).

4.8 Undesirable Effects

The safety profile of ISENTRESS was based on the pooled safety data from two Phase III clinical studies in treatment-experienced patients and one Phase III clinical study in treatment-naïve patients; described below.

In treatment-experienced patients, the two randomised clinical studies used the recommended dose of 400 mg twice daily in combination with optimised background therapy (OBT) in 462 patients, in comparison to 237 patients taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 708 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 244 patient-years in the group receiving placebo.

In treatment-naïve patients, the multi-centre, randomised, double-blind, active-controlled clinical study used the recommended dose of 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 245 mg in 281 patients, in comparison to 282 patients taking efavirenz (EFV) 600 mg (at bedtime) in combination with emtricitabine (+) tenofovir. During double-blind treatment, the total follow-up was 480 patient-years in the group receiving ISENTRESS 400 mg twice daily, and 463 patient-years in the group receiving efavirenz 600 mg at bedtime.

In the pooled analysis of treatment-experienced patients, the rates of discontinuation of therapy due to adverse reactions were 3.9 % in patients receiving ISENTRESS + OBT and 4.6 % in patients receiving placebo + OBT. The rates of discontinuation of therapy in naïve patients due to adverse reactions were 3.6 % in patients receiving ISENTRESS + emtricitabine (+) tenofovir and 6.7 % in patients receiving efavirenz + emtricitabine (+) tenofovir.

Adverse reactions considered by investigators to be causally related to ISENTRESS (alone or in combination with other ART) are listed below by System Organ Class. Any term that includes at least one serious adverse reaction is identified with a dagger (^†). Adverse reactions identified from post-marketing experience are included in italics.

Frequencies are defined as common (

System Organ Class	Frequency	Adverse reactions ISENTRESS (alone or in combination with other ART)
Infections and infestations	uncommon	genital herpes†, folliculitis, gastro-enteritis, herpes simplex, herpes virus infection, herpes zoster, influenza, molluscum contagiosum, nasopharyngitis, upper respiratory tract infection
Neoplasms benign, malignant and unspecified (including cysts and polyps)	uncommon	skin papilloma
Blood and lymphatic system disorders	uncommon	anaemia†, iron deficiency anaemia, lymph node pain, lymphadenopathy, neutropenia
uncommon	thrombocytopenia‡‡
Immune system disorders	uncommon	immune reconstitution syndrome†, drug hypersensitivity, hypersensitivity
Metabolism and nutrition disorders	uncommon	anorexia, cachexia, decreased appetite, diabetes mellitus, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hyperphagia, increased appetite, polydipsia
Psychiatric disorders	common uncommon uncommon	abnormal dreams, insomnia mental disorder†, suicide attempt†, anxiety, confusional state, depressed mood, depression, major depression, middle insomnia, mood altered, nightmare, panic attack, sleep disorder suicidal ideation‡‡, suicidal behaviour (particularly in patients with a pre-existing history of psychiatric illness) ‡‡
Nervous system disorders	common uncommon	dizziness, headache amnesia, carpal tunnel syndrome, cognitive disorder, disturbance in attention, dizziness postural, dysgeusia, hypersomnia, hypoaesthesia, lethargy, memory impairment, migraine, neuropathy peripheral, paraesthesia, somnolence, tension headache, tremor
Eye disorders	uncommon	visual impairment
Ear and labyrinth disorders	common uncommon	vertigo tinnitus
Cardiac disorders	uncommon	palpitations, sinus bradycardia, ventricular extrasystoles
Vascular disorders	uncommon	hot flush, hypertension
Respiratory, thoracic and mediastinal disorders	uncommon	dysphonia, epistaxis, nasal congestion
Gastro-intestinal disorders	common uncommon	abdominal distention, abdominal pain, diarrhoea, flatulence, nausea, vomiting gastritis†, abdominal discomfort, abdominal pain upper, abdominal tenderness, anorectal discomfort, dry mouth, constipation, dyspepsia, epigastric discomfort, erosive duodenitis, eructation, gastro-oesophageal reflux disease, gingivitis, glossitis, odynophagia, pancreatitis acute, peptic ulcer, rectal haemorrhage
Hepato-biliary disorders	uncommon	hepatitis†, hepatic steatosis
Skin and subcutaneous tissue disorders	common uncommon   uncommon	rash‡ acne, alopecia, dermatitis acneiforme, dry skin, erythema, facial wasting, hyperhidrosis, lipodystrophy acquired, lipohypertrophy, night sweats, prurigo, pruritus, pruritus generalised, rash macular, rash maculo-papular, rash pruritic, skin lesion, urticaria, xeroderma Stevens Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS) ‡‡
Musculoskeletal and connective tissue disorders	uncommon	arthralgia, arthritis, back pain, flank pain, musculoskeletal pain, myalgia, neck pain, osteopenia, pain in extremity, tendonitis
Uncommon	rhabdomyolysis‡‡
Renal and urinary disorders	uncommon	renal failure†, nephritis, nephrolithiasis, nocturia, renal cyst, renal impairment, tubulointerstitial nephritis
Reproductive system and breast disorders	uncommon	erectile dysfunction, gynaecomastia, menopausal symptoms
General disorders and administration site conditions	common uncommon	asthenia, fatigue, pyrexia chest discomfort, chills, face oedema, fat tissue increased, feeling jittery, malaise, oedema peripheral, pain
Investigations	common uncommon	alanine aminotransferase increased, atypical lymphocytes, aspartate aminotransferase increased, blood triglycerides increased, lipase increased absolute neutrophil count decreased, alkaline phosphatase increased, blood albumin decreased, blood amylase increased, blood bilirubin increased, blood cholesterol increased, blood creatinine increased, blood glucose increased, blood urea nitrogen increased, creatine phosphokinase increased, fasting blood glucose increased, glucose urine present, high density lipoprotein increased, low density lipoprotein decreased, low density lipoprotein increased, platelet count decreased, red blood cells urine positive, waist circumference increased, weight increased, white blood cell count decreased
Injury, poisoning and procedural complications	uncommon	accidental overdose†
† Includes at least one serious adverse reaction ‡ In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens containing ISENTRESS + darunavir compared to those containing ISENTRESS without darunavir or darunavir without ISENTRESS. Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section 4.4). ‡‡ This adverse reaction was identified through post-marketing surveillance but not reported as drug-related in randomised controlled Phase III clinical trials (Protocols 018, 019, and 021). The frequency category of "uncommon" was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with ISENTRESS in the Phase III clinical program (n=743).

Cancers were reported in treatment-experienced and treatment-naïve patients who initiated ISENTRESS in conjunction with other antiretroviral agents. The types and rates of specific cancers were those expected in a highly immunodeficient population. The risk of developing cancer in these studies was similar in the groups receiving ISENTRESS and in the groups receiving comparators.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS. Myopathy and rhabdomyolysis have been reported. Use with caution in patients who have had myopathy or rhabdomyolysis in the past or have any predisposing issues including other medicinal products associated with these conditions (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Patients co-infected with hepatitis B and/or hepatitis C virus

In Phase III studies, treatment-experienced patients (N = 114/699 or 16%; HBV=6 %, HCV=9 %, HBV+HCV=1%) and treatment-naïve patients (N = 34/563 or 6 %; HBV=4 %, HCV=2 %, HBV+HCV=0.2 %) with chronic (but not acute) active hepatitis B and/or hepatitis C co-infection were permitted to enrol provided that baseline liver function tests did not exceed 5 times the upper limit of normal. In general the safety profile of ISENTRESS in patients with hepatitis B and/or hepatitis C virus co-infection was similar to that in patients without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were somewhat higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In treatment-experienced patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29 %, 34 % and 13 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 11 %, 10 % and 9 % of all other subjects treated with ISENTRESS. In treatment-naïve patients, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17 %, 28 % and 17 %, respectively, of co-infected subjects treated with ISENTRESS as compared to 6 %, 6 % and 3 % of all other subjects treated with ISENTRESS.

4.9 Overdose

No specific information is available on the treatment of overdosage with ISENTRESS.

In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastro-intestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. It should be taken into account that raltegravir is presented for clinical use as the potassium salt. The extent to which ISENTRESS may be dialysable is unknown.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiviral for systemic use, Other Antivirals, ATC code: J05AX08.

Mechanism of action

Raltegravir is an integrase strand transfer inhibitor active against the Human Immunodeficiency Virus (HIV-1). Raltegravir inhibits the catalytic activity of integrase, an HIV-encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of the HIV genome into the host cell genome. HIV genomes that fail to integrate cannot direct the production of new infectious viral particles, so inhibiting integration prevents propagation of the viral infection.

Antiviral activity in vitro

Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (IC₉₅) of HIV-1 replication (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, raltegravir inhibited viral replication in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV-1, including isolates from 5 non-B subtypes, and isolates resistant to reverse transcriptase inhibitors and protease inhibitors. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV isolates representing 5 non-B subtypes and 5 circulating recombinant forms with IC50 values ranging from 5 to 12 nM.

Resistance

Most viruses isolated from patients failing raltegravir had high-level raltegravir resistance resulting from the appearance of two or more mutations. Most had a signature mutation at amino acid 155 (N155 changed to H), amino acid 148 (Q148 changed to H, K, or R), or amino acid 143 (Y143 changed to H, C, or R), along with one or more additional integrase mutations (e.g., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, S230R). The signature mutations decrease viral susceptibility to raltegravir and addition of other mutations results in a further decrease in raltegravir susceptibility. Factors that reduced the likelihood of developing resistance included lower baseline viral load and use of other active anti-retroviral agents. Preliminary data indicate that there is potential for at least some degree of cross-resistance to occur between raltegravir and other integrase inhibitors.

Clinical experience

The evidence of efficacy of ISENTRESS is based on the analyses of 96-week data from two ongoing, randomised, double-blind, placebo-controlled trials, (BENCHMRK 1 and BENCHMRK 2, Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult patients and the analysis of 96-week data from an ongoing, randomised, double-blind, active-control trial, (STARTMRK, Protocol 021) in antiretroviral treatment-naïve HIV-1 infected adult patients.

Efficacy

Treatment-experienced patients

BENCHMRK 1 and BENCHMRK 2 (ongoing multi-centre, randomised, double-blind, placebo-controlled trials) evaluate the safety and anti-retroviral activity of ISENTRESS 400 mg twice daily vs. placebo in a combination with optimised background therapy (OBT), in HIV-infected patients, 16 years or older, with documented resistance to at least 1 drug in each of 3 classes (NRTIs, NNRTIs, PIs) of anti-retroviral therapies. Prior to randomisation, OBT were selected by the investigator based on the patient's prior treatment history, as well as baseline genotypic and phenotypic viral resistance testing.

Patient demographics (gender, age and race) and baseline characteristics were comparable between the groups receiving ISENTRESS 400 mg twice daily and placebo. Patients had prior exposure to a median of 12 anti-retrovirals for a median of 10 years. A median of 4 ARTs was used in OBT.

Results 48-week and 96-week analyses

Durable outcomes (Week 48 and Week 96) for patients on the recommended dose ISENTRESS 400 mg twice daily from the pooled studies BENCHMRK 1 and BENCHMRK 2 are shown in Table 2.

Table 2

Efficacy Outcome at Weeks 48 and 96

BENCHMRK 1 and 2 Pooled Parameter	48 Weeks	96 Weeks
ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)	ISENTRESS 400 mg twice daily + OBT (N = 462)	Placebo + OBT (N = 237)
Percent HIV-RNA < 400 copies/ml (95% CI)
All patients†	72 (68, 76)	37 (31, 44)	62 (57, 66)