Bendroflumethiazide Tablets BP 2.5mg

1. Name Of The Medicinal Product

BENDROFLUMETHIAZIDE TABLETS BP 2.5mg

2. Qualitative And Quantitative Composition

Each tablet contains 2.5mg Bendroflumethiazide PhEur.

3. Pharmaceutical Form

White uncoated tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Bendroflumethiazide is indicated for:

1. Cases where the reduction of fluid retention by diuresis is required; oedema of cardiac, renal or hepatic origin and iatrogenic oedema

2. Bendroflumethiazide produces a moderate but usefully prolonged fall of blood pressure in hypertensive patients. It may be used as the sole antihypertensive agent, or, as an adjunct to other drugs whose action it potentiates. In non-oedematous patients, there may be little noticeable diuretic effect.

4.2 Posology And Method Of Administration

Posology

It is recommended that the tablets should be taken in the morning to avoid nocturia.

Adults and children aged 12 years and over:

Oedema:	Initially 5-10mg once daily or on alternate days.
	Maintenance: 2.5-10mg two or three times weekly.

Hypertension: 2.5-5mg once daily. When Bendroflumethiazide is used concurrently with other specific hypotensive agents, the dosage of such agents should be reduced and then adjusted as necessary.

Children under 12 years: Initial dose of 400micrograms/kg of body weight daily reducing to the maintenance dose of 50-100micrograms/kg daily.

A more appropriate dosage form may be required.

Elderly: Dosage may need to be reduced in the elderly, especially where there is impairment of renal function.

Method of Adminstration

For oral administration.

4.3 Contraindications

• Hypersensitivity to thiazides and any other ingredient in bendroflumethiazide tablets.

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

• Severe renal or hepatic insufficiency.

• Hypercalcaemia; refractory hypokalaemia; hyponatraemia; symptomatic hyperuricaemia.

• Addison's disease.

4.4 Special Warnings And Precautions For Use

• Bendroflumethiazide may raise serum uric acid levels with consequent exacerbation of gout in susceptible patients.

• Thiazide diuretics should be used with caution in patients with mild or moderate renal or hepatic dysfunction. Renal function should be monitored during bendroflumethiazide therapy. Thiazides can cause electrolyte imbalance which is more severe in patients with hepatic and renal impairment and in those receiving higher or prolonged doses. Elderly patients and those on long term treatment need regular blood tests to monitor electrolyte levels. Hypokalaemia should be corrected by adding potassium supplements to the regimen. The risk of hypomagnesaemia is increased in alcoholic cirrhosis.

• Systemic lupus erythematosus (SLE) may be exacerbated by bendroflumethiazide.

• Diabetes Mellitus may be aggravated by bendroflumethiazide.

• Caution is required when treating patients with porphyria.

• Patients taking pimozide or thioridazine. (see section 4.5)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

• Allopurinol: Bendroflumethiazide may antagonise the action of allopurinol by causing retention of urate in the kidney. Caution is advised when using this combination.

• Anion exchange resins: Colestyramine and colestipol reduce absorption of bendroflumethiazide. This can be prevented by leaving an interval of two hours between doses of bendroflumethiazide and the anion exchange resin.

• Antiarrhythmics: The cardiotoxicity of disopyramide, amiodarone, flecainide and quinidine is increased if hypokalaemia occurs following the administration of bendroflumethiazide. The actions of lidocaine and mexiletine are antagonised by hypokalaemia.

• Antidepressants: There is an increased risk of postural hypotension if bendroflumethiazide is given with tricyclic antidepressants. There may also be a risk of hypokalaemia if thiazides are given with reboxetine. Concomitant use with MAOIs may result in an enhanced hypotensive effect.

• Antidiabetics: Bendroflumethiazide antagonises the hypoglycaemic effects of sulfonylureas, with a potential loss of diabetic control.

• Antiepileptics: There is an increased risk of hyponatraemia when bendroflumethiazide and carbamazepine are take concurrently.

• Antifungals: The risk of hypokalaemia is increased when amphotericin and bendroflumethiazide are taken concurrently.

• Antihypertensives: Bendroflumethiazide may enhance the antihypertensive effect of ACE inhibitors and angiotensin-II antagonists. There is an increased risk of first dose hypotension if prazosin is given to a patient taking bendroflumethiazide.

• Antipsychotics: Hypokalaemia increases the risk of ventricular arrhythmias with pimozide or thioridazine so concomitant use should be avoided.

• Calcium salts: Bendroflumethiazide reduces urinary excretion of calcium so there is an increase risk of hypercalcaemia when calcium salts are taken concurrently. Serum calcium levels should be monitored to ensure that they do not become excessive.

• Calcium channel blockers and peripheral vasodilators: The hypotensive effect of calcium channel blockers and moxisylyte may be enhanced when co-administered with bendroflumethiazide.

• Corticosteroids: Corticosteroids may exacerbate hypokalaemia associated with bendroflumethiazide and its diuretic activity may be antagonised.

• Cytotoxics: Concomitant use with cisplatin can lead to an increased risk of nephrotoxicity and ototoxicity.

• Digoxin: The hypokalaemic effect of bendroflumethiazide may enhance sensitivity to digoxin when taken concurrently. Patients should be monitored for signs of digoxin intoxication, especially arrhythmias. The dose of digoxin should be reduced and potassium supplements given, should digoxin toxicity develop.

• Hormone antagonists: There is an increased risk of hyponatraemia when bendroflumethiazide is used concomitantly with aminoglutethamide. Bendroflumethiazide can cause an increased risk of hypercalcaemia when co-administered with toremifene.

• Lithium: Bendroflumethiazide inhibits the tubular elimination of lithium, resulting in an elevated plasma lithium concentration and risk of toxicity. Plasma lithium concentrations must be monitored when these drugs are given concurrently.

• Muscle relaxants: The hypotensive activity of bendroflumethiazide may be increased by baclofen and tizanidine. Bendroflumethiazide may enhance the neuromuscular blocking activity of non-depolarising muscle relaxants, such as tubocurarine, gallamine, alcuronium and pancuronium.

• NSAIDs: Bendroflumethiazide may enhance the nephrotoxicity of NSAIDs. Indometacin and ketorolac antagonise the diuretic effect of bendroflumethiazide, this occurs to a lesser extent with ibuprofen, piroxicam and naproxen. The effects of concurrent use should be monitored and the dose of bendroflumethiazide modified if necessary.

• Oestrogens and progestogens: Oestrogens and combined oral contraceptives antagonise the diuretic effect of bendroflumethiazide.

• Sympathomimetics: Sympathomimetics can cause hypokalaemia. The risk of serious heart arrhythmias in asthmatic patients may be increased if bendroflumethiazide is added to their medication.

• Theophylline: Concomitant administration of theophylline and bendroflumethiazide increases the risk of hypokalaemia.

• Ulcer healing drugs: There is an increased risk of hypokalaemia and a decrease in diuretic activity when carbenoxolone and bendroflumethiazide are taken together. Patients should be monitored and given potassium supplements when required.

• Vitamins: The risk of hypercalcaemia is increased if bendroflumethiazide is given with vitamin D.

4.6 Pregnancy And Lactation

Bendroflumethiazide is best avoided for the management of oedema or hypertension in pregnancy as it crosses the placenta and its use may be associated with hypokalaemia, increased blood viscosity and reduced placental perfusion.

There is insufficient evidence of safety in human pregnancy and foetal bone marrow depression, thrombocytopenia and neonatal jaundice have been described.

Bendroflumethiazide suppresses lactation and, although the amounts passing into breast milk are small, it should be avoided in breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

As bendroflumethiazide can cause dizziness, patients should make sure they are not affected before driving or operating machinery.

4.8 Undesirable Effects

• Effects on blood

Rarely, blood dyscrasias, including agranulocytosis, aplastic anaemia, thrombocytopenia and leucopenia, have been reported.

• Hypersensitivity reactions

Rashes (including exfoliative dermatitis), photosensitivity, pneumonitis and pulmonary oedema have been reported occasionally.

• Metabolic effects

Bendroflumethiazide may lower carbohydrate tolerance and the insulin dosage of some diabetic patients may require adjustment. Care is required when bendroflumethiazide is administered to patients with a known predisposition to diabetes. Bendroflumethiazide may raise serum uric acid levels and exacerbate gout in susceptible individuals. Plasma lipids may be altered in patients taking bendroflumethiazide.

• Effects on electrolytes

Bendroflumethiazide administration may cause hypokalaemia, hypomangnesaemia, hyponatraemia, hypercalcaemia and hypochloraemic alkalosis. Hypokalaemia may result in polyuria, malaise, muscle weakness or cramp, dizziness, nausea, anorexia or vomiting.

• Gastrointestinal effects

Nausea, vomiting, diarrhoea, constipation and gastric irritation have all been reported.

• Other reactions

Pancreatitis, intrahepatic cholestasis and impotence (reversible on discontinuing the drug) have been reported. Postural hypotension or dizziness may also occur.

4.9 Overdose

Symptoms: Nausea, vomiting, diarrhoea, dehydration, dizziness, weakness, muscle cramps, diuresis, increased frequency of micturition with polyuria and thirst. Extreme cases may show depletion of intravascular volume, hypotension and peripheral circulatory failure. Hypokalaemia and mild hypoglycaemia are likely to be present if diuresis is profound. CNS depression (eg drowsiness, lethargy and coma) may occur without cardiovascular or respiratory depression.

Treatment: Activated charcoal may help reduce absorption of substantial amounts if given within one hour of ingestion. Treatment should be symptomatic and directed at fluid and electrolyte replacement which should be monitored together with the blood pressure and renal function. Hyponatraemia should be treated with water deprivation rather than by the administration of sodium chloride. Cathartics should be avoided.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC CODE; C03A A01

Bendroflumethiazide is a thiazide diuretic.

The mechanism whereby the thiazides exert their antihypertensive effect has not been clearly established.

Bendroflumethiazide inhibits the renal tubular absorption of salt and water by its action at the beginning of the distal convoluted tubule. Sodium and chloride ions are excreted in equivalent proportions. Because potassium excretion is promoted, metabolic alkalosis may occur secondary to hypokalaemia. There is no important effect upon carbonic anhydrase. Bendroflumethiazide exerts its diuretic effect in about 2 hours and this lasts for 12 to 18 hours or longer.

5.2 Pharmacokinetic Properties

Absorption: Bendroflumethiazide has been reported to be completely absorbed from the gastrointestinal tract. Diuresis is initiated in about 2 hours and lasts for 12-18 hours or longer.

Distribution: Bendroflumethiazide is more than 90% bound to plasma proteins.

Metabolism: There are indications that it is fairly extensively metabolised. Peak plasma levels are reached in 2 hours and a plasma half- life of between 3 and 8.5 hours on average.

Elimination: About 30% is excreted unchanged in the urine with the remainder excreted as uncharacterized metabolites.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Also contains: lactose, magnesium stearate, maize starch, pregelatinised maize starch, stearic acid, water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.

Pack sizes: 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0380

9. Date Of First Authorisation/Renewal Of The Authorisation

27.6.94

10. Date Of Revision Of The Text

February 2007

Nurofen Express 684mg Caplets

1. Name Of The Medicinal Product

Nurofen Maximum Strength Migraine Pain 684mg Caplets

Nurofen Express 684mg Caplets

2. Qualitative And Quantitative Composition

Ibuprofen Lysine 684mg/tablet (equivalent to 400mg ibuprofen)

For excipients, see 6.1

3. Pharmaceutical Form

Coated tablet

A white, film-coated, capsule-shaped tablet, printed with an identifying logo in black on one face.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of headache and migraine

4.2 Posology And Method Of Administration

For oral administration and short-term use only.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Take 1 caplet with water, up to three times a day as required.

Leave at least 4 hours between doses.

Do not take more than 3 caplets in any 24 hour period.

4.3 Contraindications

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

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

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

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

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

Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings And Precautions For Use

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

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

Respiratory:

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

Other NSAIDs:

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

SLE and mixed connective tissue disease:

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

Renal:

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

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8)

Cardiovascular and cerebrovascular effects:

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

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

Impaired female fertility:

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

Gastrointestinal:

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

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

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

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

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

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

Dermatological:

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

The label will include:

Read the enclosed leaflet before taking this product

Do not take if you:

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

• are allergic to ibuprofen, to any of the ingredients, or to aspirin or other painkillers

• are taking other NSAID pain killers or aspirin with a daily dose above 75mg

• or the patient is under 12 years of age.

Speak to your doctor or pharmacist before use if you

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

• are a smoker

• are pregnant

If symptoms persist or worsen, or if new symptoms occur, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen (like other NSAIDs) should not be used in combination with:

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

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

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

Ibuprofen should be used with caution in combination with:

Corticosteroids: as these may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4)

Antihypertensives and diuretics: since NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

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

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

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

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

Methotrexate: There is evidence for the potential increase in plasma levels of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

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

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

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

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

4.6 Pregnancy And Lactation

No specific studies have been conducted with ibuprofen lysine.

Whilst no teratogenic effects have been demonstrated with ibuprofen acid in animal experiments, the use of ibuprofen during pregnancy should, if possible, be avoided during the first 6 months of pregnancy. It should not be used for the last trimester of pregnancy as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration increased with an increased bleeding tendency in both mother and child. (See section 4.3).

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

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended dose and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of

a. non-specific allergic reactions and anaphylaxis;

b. respiratory tract reactivity e.g. asthma, aggravated asthma, bronchospasm, dyspnoea;

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

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

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritis.

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

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea, dyspepsia.

Rare: Diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (section 4.4).

Nervous System:

Uncommon: Headache

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

Renal:

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

Hepatic:

Very rare: liver disorders.

Haematological:

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

Dermatological:

Uncommon: Various skin rashes

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

Immune System:

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

Cardiovascular and Cerebrovascular:

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

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

4.9 Overdose

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

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

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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

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

Each tablet contains 684mg of ibuprofen lysine. Following oral administration, ibuprofen lysine dissociates to ibuprofen acid and lysine. Lysine has no recognised pharmacological activity. The pharmacological properties of ibuprofen lysine, therefore, are the same as those of ibuprofen acid.

5.2 Pharmacokinetic Properties

Most pharmacokinetic data obtained following the administration of ibuprofen acid also apply to ibuprofen lysine.

Ibuprofen is well absorbed from the gastrointestinal tract. Ibuprofen is extensively bound to plasma proteins. Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food peak serum concentration occurs 1 - 2 hours after administration. However, ibuprofen is more rapidly absorbed from the gastrointestinal tract following the administration of Ibuprofen Lysine 400mg Tablets, with peak serum concentration occurring approximately 38 minutes after administration when taken on an empty stomach.

Ibuprofen is metabolised in the liver to two major metabolites with primary excretion via the kidneys, either as such or as major conjugates, together with a negligible amount of unchanged ibuprofen. Excretion by the kidney is both rapid and complete.

Elimination half-life is approximately 2 hours.

No significant differences in pharmacokinetic profile are observed in the elderly.

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

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone, sodium starch glycollate, magnesium stearate, hypromellose, talc, Opaspray White M-1-7111B (contains hypromellose and titanium dioxide (E171)) and Black Printing Ink (contains shellac, Iron oxide black (E172) and propylene glycol).

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 30ºC

Store tablets in the original packaging

6.5 Nature And Contents Of Container

Either:

A blister pack consisting of opaque, white 250µm polyvinyl chloride (PVC)/ 23µm polychlorotrifluoroethylene (Aclar) laminate heat sealed to 20µm aluminium foil. The blisters are packed in cardboard cartons.

Or:

A blister pack consisting of an opaque, white 250µm polyvinyl chloride (PVC)/ 40gsm polyvinylidene chloride (PVdC) laminate heat sealed to 20µm aluminium foil. The blisters are packed in cardboard cartons.

Pack sizes: 4, 6, 8, 12, 16 and 24 tablets

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 4AQ

8. Marketing Authorisation Number(S)

PL 00063/0384

9. Date Of First Authorisation/Renewal Of The Authorisation

17/01/2006 / 24/11/2010

10. Date Of Revision Of The Text

19/04/2011

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

Humira 40 mg solution for injection in pre-filled syringe

Humira

40 mg solution for injection in pre-filled syringe

Adalimumab

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

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


• Your doctor must also give you a Patient Alert Card, which contains important safety information that you need to be aware of before you are given Humira and during treatment with Humira. Keep this Patient Alert Card with you.


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


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


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

In this leaflet:

1. What Humira is and what it is used for

2. Before you use Humira

3. How to use Humira

4. Possible side effects

5 How to store Humira

6. Further information

What Humira Is And What It Is Used For

Humira is intended for treatment of rheumatoid arthritis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis. It is a medicine that decreases the inflammation process of these diseases. The active ingredient, adalimumab, is a human monoclonal antibody produced by cultured cells. Monoclonal antibodies are proteins that recognise and bind to other unique proteins. Adalimumab binds to a specific protein (tumour necrosis factor or TNFα), which is present at increased levels in inflammatory diseases such as rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis.

Rheumatoid arthritis

Rheumatoid arthritis is an inflammatory disease of the joints. If you have moderate to severe active rheumatoid arthritis, you may first be given other disease-modifying medicines, such as methotrexate. If you do not respond well enough to these medicines, you will be given Humira to treat your rheumatoid arthritis.

Humira can also be used to treat severe, active and progressive rhuematoid arthritis without previous methotrexate treatment.

Humira has been shown to slow down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function.

Usually, Humira is used with methotrexate. If your doctor determines that methotrexate is inappropriate, Humira can be given alone.

Polyarticular juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis is an inflammatory disease, affecting one or more joints, with diagnosis typically occurring in children under the age of 16 years. You may first be given other disease-modifying medicines, such as methotrexate. If you do not respond well enough to these medicines, you will be given Humira to treat your polyarticular juvenile idiopathic arthritis.

Psoriatic arthritis

Psoriatic arthritis is an inflammation of the joints associated with psoriasis. Humira has been shown to slow down the damage to the cartilage and bone of the joints caused by the disease and to improve physical function.

Ankylosing spondylitis

Ankylosing spondylitis is an inflammatory disease of the spine. If you have ankylosing spondylitis you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Humira to reduce the signs and symptoms of your disease.

Crohn’s disease

Crohn’s disease is an inflammatory disease of the digestive tract. If you have Crohn’s disease you will first be given other medicines. If you do not respond well enough to these medicines, you will be given Humira to reduce the signs and symptoms of your disease.

Psoriasis

Psoriasis is an inflammatory disease of the skin. If you have moderate to severe plaque psoriasis, you will first be given other medicines or e.g. phototherapy. If you do not respond well enough to these treatments, you will be given Humira to reduce the signs and symptoms of your psoriasis.

Before You Use Humira

Do not use Humira:

• If you are allergic (hypersensitive) to adalimumab or any of the other ingredients of Humira.


• If you have a severe infection, including active tuberculosis (see “Take special care with Humira”). It is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, feeling tired, dental problems.


• If you have moderate or severe heart failure. It is important to tell your doctor if you have had or have a serious heart condition (see “Take special care with Humira”).

Take special care with Humira:

• If you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash do not inject more Humira and contact your doctor immediately.


• The needle cover of the syringe contains natural rubber (latex). This may cause severe allergic reactions in patients sensitive to latex. Patients who have a known sensitivity to latex should be advised to avoid touching the inner shield.


• If you have an infection, including long-term or localized infection (for example, leg ulcer) consult your doctor before starting Humira. If you are unsure, please contact your doctor.


• You might get infections more easily while you are receiving Humira treatment. This risk may increase if your lung function is impaired. These infections may be serious and include, tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be life-threatening. It is important to tell your doctor if you get symptoms such as fever, wounds, feeling tired or dental problems. Your doctor may recommend temporary discontinuation of Humira.


• As cases of tuberculosis have been reported in patients treated with Humira, your doctor will check you for signs and symptoms of tuberculosis before starting Humira. This will include a thorough medical history, a chest X-ray and a tuberculin test. The conduct of these tests should be recorded on your Patient Alert Card. It is very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close contact with someone who has had tuberculosis. If symptoms of tuberculosis (persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy tell your doctor immediately.


• Advise your doctor if you reside or travel in regions where fungal infections such as histoplasmosis coccidioidomycosis or blastomycosis are epidemic.


• Advise your doctor if you have a history of recurrent infections or other conditions that increase the risk of infections.


• Advise your doctor if you are a carrier of the hepatitis B virus (HBV), if you have active HBV or if you think you might be at risk of contracting HBV. Humira can cause reactivation of HBV in people who carry this virus. In some rare cases, especially if you are taking other medicines that suppress the immune system, reactiviation of HBV can be life-threatening.


• If you are over 65 years you may be more susceptible for infections while taking HUMIRA. You and your doctor should pay special attention to signs of infection while you are being treated with HUMIRA. It is important to tell your doctor if you got symptoms of infections, such as fever, wounds, feeling tired or dental problems.


• If you are about to undergo surgery or dental procedures, please inform your doctor that you are taking Humira. Your doctor may recommend temporary discontinuation of Humira.


• If you have demyelinating disease such as multiple sclerosis, your doctor will decide if you should receive Humira.


• Some vaccines should not be given while receiving Humira. Please check with your doctor before you receive any vaccines. It is recommended that polyarticular juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Humira therapy.


• If you have mild heart failure and you are being treated with Humira, your heart failure status must be closely monitored by your doctor. It is important to tell your doctor if you have had or have a serious heart condition. If you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor immediately. Your doctor will decide if you should receive Humira.


• In some patients the body may fail to produce enough of the blood cells that help your body fight infections or help you to stop bleeding. If you develop a fever that does not go away, bruise or bleed very easily or look very pale, call your doctor right away. Your doctor may decide to stop treatment.


• There have been very rare cases of certain kinds of cancer in children and adult patients taking Humira or other TNF blockers. People with more serious rheumatoid arthritis that have had the disease for a long time may have a higher than average risk of getting lymphoma, (a kind of cancer that affects the lymph system), and leukemia (a kind of cancer that affects the blood and bone marrow). If you take Humira the risk of getting lymphoma, leukemia, or other cancers may increase. On rare occasions, a specific and severe type of lymphoma, has been observed in patients taking Humira. Some of those patients were also treated with azathioprine or 6- mercaptopurine. In addition very rare cases of non-melanoma skin cancer have been observed in patients taking Humira. If new skin lesions appear during or after therapy or if existing lesions change appearance, tell your doctor.


• There have been cases of cancers, other than lymphoma, in patients with a specific type of lung disease called Chronic Obstructive Pulmonary Disease (COPD) treated with another TNF blocker. If you have COPD, or are a heavy smoker, you should discuss with your doctor whether treatment with a TNF blocker is appropriate for you.

Using other medicines

Humira can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or pain medications including non-steroidal anti-inflammatory drugs (NSAIDs).

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

You should not take Humira with medicines containing the active substance, anakinra or abatacept. If you have questions, please ask your doctor.

Using Humira with food and drink

Since Humira is injected under the skin (subcutaneously), food and drink should not affect Humira.

Pregnancy and breast-feeding

The effects of Humira in pregnant women are not known and so the use of Humira in pregnant women is not recommended. You are advised to avoid becoming pregnant and must use adequate contraception while using Humira and for at least 5 months after the last Humira treatment.

It is not known whether adalimumab passes into breast milk.

If you are a breast-feeding mother, you should stop breast-feeding during Humira treatment and for at least 5 months after the last Humira treatment.

Driving and using machines

Humira may have a minor influence on your ability to drive and use machines. Dizziness (including room spinning sensation, blurred vision and tiredness) may occur after you take Humira.

How To Use Humira

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

Humira is injected under the skin (subcutaneous use). The usual dose for adults with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis is 40 mg adalimumab given every other week as a single dose.

In rheumatoid arthritis, methotrexate is continued while using Humira. If your doctor determines that methotrexate is inappropriate, Humira can be given alone.

If you have rheumatoid arthritis and you do not receive methotrexate with your Humira therapy, your doctor may decide to give 40 mg adalimumab every week.

The recommended dose of Humira for patients with polyarticular juvenile idiopathic arthritis, aged 13 years and above, is 40 mg adalimumab administered every other week as a single dose via subcutaneous injection.

The usual dose regimen for Crohn’s disease is 80 mg at Week 0 and followed by 40 mg every other week starting at Week 2. In cases where a more rapid response is required your doctor may prescribe a dose of 160 mg at Week 0 (as 4 injections in one day or 2 injections per day for two consecutive days), 80 mg (2 injections) at Week 2, and thereafter as 40 mg (1 injection) every other week. Depending on your response, your doctor may increase the dose to 40 mg every week. The usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. You should continue to inject Humira for as long as your doctor has told you.

Instructions for preparing and giving an injection of Humira:

The following instructions explain how to inject Humira. Please read the instructions carefully and follow them step by step. You will be instructed by your doctor or his/her assistant on the technique of self-injection. Do not attempt to self-inject until you are sure that you understand how to prepare and give the injection. After proper training, the injection can be self-administered or given by another person, for example a family member or friend.

This injection should not be mixed in the same syringe or vial with any other medicine.

1) Setting up

• Wash your hands thoroughly


• Set up the following items on a clean surface
  
  
  • One pre-filled syringe of Humira for injection
  • One alcohol pad


• Look at the expiry date on the syringe. Do not use the product after the month and year shown.

2) Choosing and preparing an injection site

• Choose a site on your thigh or stomach


• Each new injection should be given at least 3 cm from the last injection site.
  
  
  • Do not inject in an area where the skin is reddened, bruised, or hard. This may mean there is an infection.
  • Wipe the injection site with the enclosed alcohol pad, using a circular motion.
  • Do not touch the area again before injecting.

3) Injecting Humira

• Do NOT shake the syringe.


• Remove cap from needle syringe, being careful not to touch the needle or let it touch any surface.


• With one hand, gently grasp the cleaned areas of skin and hold firmly


• With the other hand, hold syringe at 45-degree angle to skin, with the grooved side up.


• With one quick, short motion, push needle all the way into skin


• Release the skin with the first hand


• Push plunger to inject solution – it can take from 2 to 5 seconds to empty the syringe


• When the syringe is empty, remove the needle from skin, being careful to keep it at the same angle as when it was inserted


• Using your thumb or a piece of gauze, apply pressure over the injection site for 10 seconds. A little bleeding may occur. Do not rub the injection site. Use a plaster if you want to.

4) Throwing away supplies

• The Humira syringe should NEVER be reused. NEVER recap a needle.


• After injecting Humira, immediately throw away the used syringe in a special container as instructed by your doctor, nurse or pharmacist.


• Keep this container out of the reach and sight of children

If you use more Humira than you should:

If you accidentally inject Humira more frequently than told to by your doctor, you should call your doctor and tell him/her that you have taken more. Always take the outer carton of medicine with you, even if it is empty.

If you forget to take Humira:

If you forget to give yourself an injection, you should inject the next dose of Humira as soon as you remember. Then take your next dose as you would have on your originally scheduled day, had you not forgotten a dose.

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

Possible Side Effects

Like all medicines, Humira can have side effects, although not everybody gets them. Most side effects are mild to moderate. However, some may be serious and require treatment. Side effects may occur at least up to 5 months after the last Humira injection.

Tell your doctor immediately if you notice any of the following:

• Severe rash, hives or other signs of allergic reaction;


• Swollen face, hands, feet;


• Trouble breathing, swallowing;


• Shortness of breath with exertion or upon lying down or swelling of the feet;


• Signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, paleness;

Tell your doctor as soon as possible if you notice any of the following:

• Signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination;


• Feeling weak or tired;


• Coughing;


• Tingling;


• Numbness;


• Double vision;


• Arm or leg weakness;


• A bump or open sore that doesn’t heal.

The symptoms described above can be signs of the below listed side effects, which have been observed with Humira:

Very common (in more than 1 in 10 patients):

• injection site reactions (including pain, swelling, redness or itching);


• respiratory tract infections (including cold, runny nose, sinus infection, pneumonia);


• headache;


• abdominal pain;


• nausea and vomiting;


• rash;


• musculoskeletal pain.

Common (in more than 1 in 100 patients but less than 1 in 10 patients):

• serious infections (including blood poisoning and influenza);


• skin infections (including cellulitis and shingles);


• ear infections;


• oral infections (including tooth infections and cold sores);


• reproductive tract infections;


• urinary tract infection;


• fungal infections;


• benign tumors;


• skin cancer;


• allergic reactions (including seasonal allergy);


• mood swings (including depression);


• anxiety;


• feeling sleepy and difficulty sleeping;


• sensation disorders such as tingling, prickling or numbness;


• migraine;


• sciatica (including low back pain and leg pain);


• vision disturbances;


• eye inflammation;


• vertigo;


• sensation of heart beating rapidly;


• high blood pressure;


• flushing;


• haematoma;


• cough;


• asthma;


• shortness of breath;


• gastrointestinal bleeding;


• dyspepsia (indigestion, bloating, heart burn);


• acid reflux disease;


• sicca syndrome (including dry eyes and dry mouth);


• itching;


• itchy rash;


• bruising;


• inflammation of the skin (such as eczema);


• breaking of finger nails and toe nails;


• increased sweating;


• muscle spasms;


• blood in urine;


• kidney problems;


• chest pain;


• oedema;


• reduction in blood platelets which increases risk of bleeding or bruising;


• impaired healing.

Uncommon (in more than 1 in 1,000 patients but less than 1 in 100 patients):

• opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered);


• neurological infections (including viral meningitis);


• joint infections;


• eye infections;


• bacterial infections;


• cancer;


• cancer that affects the lymph system;


• melanoma;


• dehydration;


• tremor;


• inflammation of the eye lid and eye swelling;


• double vision;


• hearing loss, buzzing;


• sensation of heart beating irregularly such as skipped beats;


• heart problems that can cause shortness of breath or ankle swelling;


• lung diseases causing shortness of breath (including inflammation);


• inflammation of the pancreas which causes severe pain in the abdomen and back;


• difficulty in swallowing;


• facial oedema;


• gallbladder inflammation, gallbladder stones;


• fatty liver;


• night sweats;


• scar;


• abnormal muscle breakdown;


• sleep interruptions;


• impotence;


• inflammations.

Rare ( in more than 1 in 10,000 patients but less than 1 in 1,000 patients )

• multiple sclerosis;


• heart stops pumping;


• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel;


• systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ systems).

Some adverse experiences seen in clinical trials do not have symptoms and may only be discovered through blood tests.

These include:

Very common (in more than 1 in 10 patients):

• low blood measurements for white blood cells;


• low blood measurements for red blood cells;


• increased lipids in the blood;


• elevated liver enzymes.

Common (in more than 1 in 100 patients but less than 1 in 10 patients):

• high blood measurements for white blood cells;


• low blood measurements for platelets;


• abnormal blood measurements for potassium;


• increased uric acid in the blood;


• abnormal blood measurements for sodium;


• low blood measurements for calcium;


• low blood measurements for phosphate;


• high blood sugar;


• high blood measurements for lactate dehydrogenase;


• autoantibodies present in the blood.

Rare (in more than 1 in 10,000 patients but less than 1 in 1,000 patients):

• low blood measurements for white blood cells, red blood cells and platelet count.

The following side effects have been observed in patients taking Humira with not known frequency:

• severe allergic reaction with shock;


• nerve disorders (such as eye nerve inflammation and Guillain-Barré syndrome that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body);


• intestinal perforation;


• reactivation of hepatitis B;


• cutaneous vasculitis (inflammation of blood vessels in the skin);


• Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash);


• erythema multiforme (inflammatory skin rash);


• hair loss;


• facial oedema associated with allergic reactions;


• lupus-like syndrome;


• hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal);


• leukemia (cancer affecting the blood and bone marrow);


• new onset or worsening of psoriasis;


• heart attack;


• stroke


• diverticulitis (inflammation and infection of the large intestine);


• pulmonary embolism (blockage in an artery of the lung).

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

How To Store Humira

Keep out of the reach and sight of children.

Do not use the Humira pre-filled syringe after the expiry date stated on the label/blister/carton after EXP:. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C – 8°C). Do not freeze.

Keep the pre-filled syringe in the outer carton.

Further Information

HUMIRA 40 mg solution for injection does not contain preservatives;

Any unused product or waste material should be disposed of in accordance with local requirements.

What Humira contains

The active substance is adalimumab.

The other ingredients are mannitol, citric acid monohydrate, sodium citrate, sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, polysorbate 80, sodium hydroxide and water for injections.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. essentially ‘sodium-free’.

What the Humira pre-filled syringe looks like and contents of the pack

Humira 40 mg solution for injection in pre-filled syringe is supplied as a sterile solution of 40 mg adalimumab dissolved in 0.8 ml solution.

The Humira pre-filled syringe is a glass syringe containing a solution of adalimumab.

Each pack contains 1, 2, 4 or 6 pre-filled syringes for patient use with 1, 2, 4 or 6 alcohol pads, respectively. Not all pack sizes may be marketed.

Humira is also available as a vial or a pre-filled pen.

Marketing Authorisation Holder:

Abbott Laboratories Ltd

Abbott House

Vanwall Business Park

Vanwall Road

Maidenhead

Berkshire

SL6 4XE

United Kingdom

Manufacturer:

Abbott Biotechnology Deutschland GmbH

Max-Planck-Ring 2

D - 65205 Wiesbaden

Germany

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Abbott Laboratories Ltd

Abbott House

Vanwall Road

Vanwall Business Park

Maidenhead

Berkshire

SL6 4XE

UK

Tel:+ 44 (0) 1628 773355

This leaflet was last approved in June 2010

3799(53)

Zaroxolyn

Generic Name: metolazone (me TOL a zone)

Brand Names: Zaroxolyn

What is Zaroxolyn (metolazone)?

Metolazone is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Metolazone treats fluid retention (edema) in people with congestive heart failure, or a kidney disorder such as nephrotic syndrome. This medication is also used to treat high blood pressure (hypertension).

Metolazone may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Zaroxolyn (metolazone)?

Do not use this medication if you are unable to urinate, or if you have severe liver disease.

Before using this medication, tell your doctor if you have liver disease, kidney disease, asthma, allergies, gout, diabetes, or an allergy to sulfa drugs.

Avoid drinking alcohol, which can increase some of the side effects of metolazone.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

There are many other medicines that can interact with metolazone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

What should I discuss with my doctor before taking Zaroxolyn (metolazone)?

Do not use this medication if you are allergic to metolazone, or if you have:

• severe liver disease; or


• if you are unable to urinate.

If you have certain conditions, you may need a dose adjustment or special tests to safely take this medication. Before using metolazone, tell your doctor if you have:

• kidney disease;


• liver disease;


• 
  

  gout;

  
  


• 
  

  diabetes; or

  
  


• 
  

  an allergy to sulfa drugs.

  
  

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Metolazone can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Zaroxolyn (metolazone)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results from this medication.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Do not miss any scheduled appointments.

Your blood and urine may both be tested if you have been vomiting or are dehydrated.

If you need to have any type of surgery, tell the surgeon ahead of time that you are taking metolazone. You may need to stop using the medicine for a short time.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

Store the tablets at room temperature away from heat, light, and moisture.

See also: Zaroxolyn dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include nausea, weakness, dizziness, dry mouth, thirst, muscle pain or weakness, feeling light-headed, or fainting.

What should I avoid while taking Zaroxolyn (metolazone)?

Avoid drinking alcohol, which can increase some of the side effects of metolazone.

Avoid using other medicines that make you light-headed (narcotic pain medication, muscle relaxers, and medicine for seizures). They can add to the side effects of metolazone. Tell your doctor if you regularly use any of these medicines, or any other blood pressure medications.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Zaroxolyn (metolazone) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  dry mouth, thirst, nausea, vomiting;

  
  


• 
  

  feeling weak, drowsy, restless, or light-headed;

  
  


• 
  

  fast or uneven heartbeat;

  
  


• 
  

  muscle pain or weakness;

  
  


• 
  

  chest pain;

  
  


• 
  

  urinating less than usual or not at all; or

  
  


• 
  

  numbness or tingly feeling.

  
  

Less serious side effects may include:

• 
  

  dizziness;

  
  


• 
  

  headache;

  
  


• 
  

  joint pain;

  
  


• 
  

  a red, blistering, peeling skin rash; or

  
  


• 
  

  blurred vision.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Zaroxolyn (metolazone)?

Before taking this medication, tell your doctor if you are using any of the following drugs:

• 
  

  lithium (Lithobid, Eskalith);

  
  


• 
  

  digoxin (Lanoxin);

  
  


• 
  

  methenamine (Hiprex, Mandelamine, Urex);

  
  


• 
  

  steroids (prednisone and others);

  
  


• 
  

  insulin or diabetic medicine you take by mouth;

  
  


• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  furosemide (Lasix) or other blood pressure medications;

  
  


• 
  

  salicylates such as aspirin, Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others; or

  
  


• 
  

  NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Motrin, Advil), diclofenac (Voltaren), indomethacin, naproxen (Aleve, Naprosyn), piroxicam (Feldene), nabumetone (Relafen), etodolac (Lodine), and others.

  
  

This list is not complete and there may be other drugs that can interact with metolazone. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Zaroxolyn resources

• Zaroxolyn Side Effects (in more detail)
• Zaroxolyn Dosage
• Zaroxolyn Use in Pregnancy & Breastfeeding
• Drug Images
• Zaroxolyn Drug Interactions
• Zaroxolyn Support Group
• 1 Review for Zaroxolyn - Add your own review/rating

• Zaroxolyn MedFacts Consumer Leaflet (Wolters Kluwer)


• Zaroxolyn Monograph (AHFS DI)


• Zaroxolyn Advanced Consumer (Micromedex) - Includes Dosage Information


• Zaroxolyn Prescribing Information (FDA)


• Metolazone Professional Patient Advice (Wolters Kluwer)


• Metolazone Prescribing Information (FDA)


• Mykrox Prescribing Information (FDA)

Compare Zaroxolyn with other medications

• Edema
• High Blood Pressure

Where can I get more information?

• Your pharmacist can provide more information about metolazone.

See also: Zaroxolyn side effects (in more detail)

Zolinza

Generic Name: vorinostat (vor IN o stat)

Brand Names: Zolinza

What is vorinostat?

Vorinostat is used to treat skin problems caused by cutaneous T-cell lymphoma.

Vorinostat is usually given after other treatments have been tried without successful treatment of symptoms.

Vorinostat may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about vorinostat?

Do not use this medication without telling your doctor if you are pregnant. It could cause harm to the unborn baby. Use an effective form of birth control, and tell your doctor if you become pregnant during treatment. Drink at least 2 liters of water each day to keep from getting dehydrated while you are taking vorinostat. Tell your doctor if you have severe vomiting or diarrhea during treatment.

Call your doctor at once if you have symptoms of bleeding in your stomach or intestines. This includes black, bloody, or tarry stools, or coughing up blood or vomit that looks like coffee grounds.

Do not crush or open a vorinostat capsule. Swallow the pill whole. The medicine inside the capsule can be dangerous if it gets in your eyes, mouth, or nose, or on your skin. If contact occurs, wash the skin area with soap and water or rinse the eyes thoroughly with plain water. If you must handle a broken capsule, ask your doctor or pharmacist how to safely dispose of it.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney function may also need to be tested. Do not miss any scheduled visits to your doctor.

What should I discuss with my health care provider before taking vorinostat?

Do not use this medication if you are allergic to vorinostat.

Before using this medication, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  diabetes;

  
  


• 
  

  liver disease;

  
  


• 
  

  kidney disease;

  
  


• 
  

  an electrolyte imbalance (such as high or low potassium levels);

  
  


• 
  

  a personal or family history of "Long QT syndrome";

  
  


• 
  

  a history of stroke or blood clot; or

  
  


• 
  

  if you have recently been vomiting or had diarrhea.

  
  

If you have any of these conditions, you may not be able to use vorinostat, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category D. This medication can cause harm to an unborn baby. Do not use vorinostat without your doctor's consent if you are pregnant. Tell your doctor if you become pregnant during treatment. Use an effective form of birth control while you are using this medication. It is not known whether vorinostat passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take vorinostat?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results from this medication.

Vorinostat is usually taken once daily with food. Drink at least 2 liters of water each day to keep from getting dehydrated while you are taking vorinostat. Tell your doctor if you have severe vomiting or diarrhea during treatment. Do not crush or open a vorinostat capsule. Swallow the pill whole. The medicine inside the capsule can be dangerous if it gets in your eyes, mouth, or nose, or on your skin. If contact occurs, wash the skin area with soap and water or rinse the eyes thoroughly with plain water. If you must handle a broken capsule, ask your doctor or pharmacist how to safely dispose of it.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney function may also need to be tested. Do not miss any scheduled visits to your doctor.

Store vorinostat at room temperature away from moisture and heat.

See also: Zolinza dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a vorinostat overdose are not known.

What should I avoid while taking vorinostat?

Avoid becoming overheated or dehydrated during exercise and in hot weather. Drink at least 2 liters of water each day while you are taking vorinostat.

Vorinostat side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using vorinostat and call your doctor at once if you have any of these serious side effects:

• 
  

  sudden shortness of breath, chest pain that gets worse with breathing, coughing up blood, fainting;

  
  


• 
  

  pain or swelling in one or both legs;

  
  


• 
  

  pale skin, easy bruising or bleeding, unusual weakness;

  
  


• 
  

  black, bloody, or tarry stools;

  
  


• 
  

  severe or prolonged vomiting or diarrhea;

  
  


• 
  

  increased thirst or urination;

  
  


• 
  

  dry mouth, confusion, nausea, vomiting, feeling light-headed, fainting, decreased sweating, and hot, dry skin;

  
  

Continue taking vorinostat and talk with your doctor if you have any of these less serious side effects:

• 
  

  nausea, vomiting, diarrhea, constipation;

  
  


• 
  

  headache, tired feeling;

  
  


• 
  

  loss of appetite;

  
  


• 
  

  dry mouth, changes in the way things taste;

  
  


• 
  

  weight loss;

  
  


• 
  

  chills;

  
  


• 
  

  hair loss; or

  
  


• 
  

  muscle spasms.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect vorinostat?

Before taking vorinostat, tell your doctor if you are using any of the following drugs:

• 
  

  valproic acid; or

  
  


• 
  

  a blood thinner such as warfarin (Coumadin).

  
  

If you are using any of these drugs, you may not be able to use vorinostat, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect vorinostat. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Zolinza resources

• Zolinza Side Effects (in more detail)
• Zolinza Dosage
• Zolinza Use in Pregnancy & Breastfeeding
• Zolinza Drug Interactions
• Zolinza Support Group
• 0 Reviews for Zolinza - Add your own review/rating

• Zolinza Prescribing Information (FDA)


• Zolinza Monograph (AHFS DI)


• Zolinza Advanced Consumer (Micromedex) - Includes Dosage Information


• Zolinza Consumer Overview


• Zolinza MedFacts Consumer Leaflet (Wolters Kluwer)


• Vorinostat Professional Patient Advice (Wolters Kluwer)

Compare Zolinza with other medications

• Cutaneous T-cell Lymphoma

Where can I get more information?

• Your pharmacist has information about vorinostat written for health professionals that you may read.

See also: Zolinza side effects (in more detail)

Adipine XL 30mg & 60mg tablets

1. Name Of The Medicinal Product

Adipine XL 30mg Tablets

Adipine XL 60mg Tablets

2. Qualitative And Quantitative Composition

Each Adipine XL 30mg tablet contains 30mg of nifedipine

Each Adipine XL 60mg tablet contains 60mg of nifedipine

For excipients see 6.1

3. Pharmaceutical Form

Prolonged release tablet

Each pale red tablet is round and biconvex and embossed with "30" or "60" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

The tablets are indicated for:

- the treatment of all grades of hypertension

- the prophylaxis of chronic stable angina pectoris, either as monotherapy or in combination with a beta-blocker.

4.2 Posology And Method Of Administration

Route of Administration

For oral use

These tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed.

Dosage Recommendations

It is recommended that each dose should be taken at approximately 24 hours intervals i.e. at the same time each day, preferably in the morning.

Adults: In mild to moderate hypertension, the recommended initial dose is one 20mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris, the recommended initial dose is one 30mg tablet once daily. The dose may be adjusted to a maximum of 90mg once daily.

Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists e.g. verapamil or diltiazem. When patients are switched, the recommended initial dose is 30mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.

Elderly: The pharmacokinetics of nifedipine may be altered in the elderly therefore, a lower maintenance dose may be necessary when treating elderly patients.

Patients with Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.

Patients with Hepatic Impairment: Nifedipine prolonged release tablets should not be administered to patients with impaired hepatic function.

Children: Nifedipine is not recommended for use in children.

Treatment with nifedipine may be continued long term.

4.3 Contraindications

Nifedipine XL Tablets are contraindicated:

- in patients with a known hypersensitivity to the drug or other constituents of the tablets

- in patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity

- in women who are or may become pregnant, are capable of child bearing or to nursing mothers

- in patients with clinically significant aortic stenosis, in cardiogenic shock or unstable angina or for the treatment of acute attacks of angina

- in patients with inflammatory bowel disease, Crohn's disease or with a history of gastrointestinal obstruction, oesophageal obstruction or with decreased diameter of the gastrointestinal lumen

- in patients with hepatic impairment

- for secondary prevention of myocardial infarction or during or within one month of a myocardial infarction

Nifedipine XL Tablets should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).

The safety of nifedipine prolonged release tablets has not been established in patients with malignant hypertension.

4.4 Special Warnings And Precautions For Use

Nifedipine should be used with caution in patients with hypotension, as there is a risk of blood pressure decreasing further and in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

Cardiac ischaemic pain has been reported to occur in a small proportion of patients following the introduction of nifedipine therapy. In such cases, treatment with nifedipine should be discontinued.

Caution should be exercised when nifedipine tablets are given to diabetic patients as they may require adjustment of their diabetic therapy.

In patients with malignant hypertension and hypovolaemia and who are on dialysis, a significant decrease in blood pressure can occur.

Nifedipine may be used in combined therapy with other antihypertensive agents including beta-blocker drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Withdrawal of any previous antihypertensive agents should be gradual, as nifedipine will not prevent any possible rebound effects.

Nifedipine is contra-indicated in pregnancy. However, caution must be exercised when nifedipine with intravenous magnesium sulphate is given to pregnant women.

Nifedipine XL Tablets must not be administered to patients with Kock pouch (ileostomy after proctocolectomy).

A false positive effect may be obtained when carrying out a barium contrast X-ray.

Nifedipine XL Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g., galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should be advised not to take these tablets.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Known Interactions

Nifedipine should not be taken with grapefruit juice because bioavailability is increased.

Cimetidine may potentiate the antihypertensive effect of nifedipine tablets if it is administered simultaneously.

It is reported that serum quinidine levels have been reduced when it is used in combination with nifedipine, irrespective of the quinidine dose taken.

The administration of nifedipine and digoxin concurrently may lead to reduced digoxin clearance and therefore, bring about an increase in the plasma digoxin level. Close monitoring of plasma digoxin levels should take place and, if necessary, a reduction in the dosage of digoxin.

Phenytoin induces the cytochrome P450 3A4 system. When nifedipine is co-administered with phenytoin, nifedipine's bioavailability is reduced and consequently, its efficacy is weakened. In such cases, the clinical response to nifedipine should be monitored following concomitant administration and, if necessary, consideration should be given to increasing the nifedipine dose. If the nifedipine dose is increased during the co-administration of both drugs, consideration should be given to reducing the nifedipine dose when phenytoin therapy is discontinued.

Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Caution should be exercised when both drugs are given simultaneously. A reduction of nifedipine dose may be required when the two are used together.

Nifedipine may falsely increase the spectrophotometric values of urinary vanillylmandelic acid. HPLC measurements are not affected.

Nifedipine should not be administered concomitantly with rifampicin, as effective plasma levels of nifedipine may not be achieved as a result of enzyme induction.

Simultaneous administration of cisapride and nifedipine or quinupristin/dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Hence, the blood pressure may need to be monitored and a reduction in the nifedipine dose may be necessary.

Nifedipine enhances the effect of non-polarising muscle relaxants.

Theoretical Interactions

Nifedipine is metabolised via the cytochrome P450 3A4 system. Therefore, there are theoretical interactions with drugs such as erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir, nelfinavir, ritonavir and saquinavir that are known to inhibit this enzyme system. Although no in vivo interaction studies with these drugs have been carried out, their co-administration with nifedipine in vitro, have shown increases in nifedipine plasma concentrations. Therefore, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.

Similarly, the potential interaction between nifedipine and nefazodone has not been clinically investigated. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore, co-administration with nifedipine may increase the plasma concentrations of nifedipine. Again, monitoring of the blood pressure is advised when both drugs are simultaneously administrated with, if necessary, a reduction in the nifedipine dose.

Tacrolimus is metabolised via the cytochrome P450 3A4 system. Upon co-administration with nifedipine, the plasma levels of tacrolimus should be monitored and, if necessary, consideration should be given to reducing the tacrolimus dose.

Carbamazepine, phenobarbital or valproic acid have been shown to alter the plasma levels of a structurally similar calcium channel blocker, however, no interactive studies have been carried out with these drugs and nifedipine. A decrease (with carbamazepine or phenobarbital) or an increase (with valproic acid) in nifedipine plasma concentrations, leading to a change in efficacy, can therefore not be ruled out.

Drugs Shown Not to Interact With Nifedipine

Aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide are drugs known not to affect the pharmacokinetics of nifedipine when they are administered concomitantly with nifedipine.

4.6 Pregnancy And Lactation

Nifedipine is contraindicated in woman capable of child-bearing.

Safe use of nifedipine during human pregnancy has not been established. Animal studies have shown reproductive toxicity (embryotoxic and teratogenic effects) at maternally toxic doses.

Nifedipine may be present in breast milk and therefore, Nifedipine XL Tablets are contraindicated for use in nursing mothers.

In single reports of in vitro fertilisation, calcium antagonists like nifedipine have been associated with biochemical alterations in the head of the spermatozoa that may impair sperm function. Calcium antagonists like nifedipine should be considered as possible causes in those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found.

4.7 Effects On Ability To Drive And Use Machines

Reactions to nifedipine may vary in intensity in patients, especially at the onset of therapy, on changing medication or when combined with alcohol. Therefore, the patient should be warned of the possible effects and advised not to drive or operate machinery, if affected.

4.8 Undesirable Effects

Most undesirable effects are due to vasodilatory action of nifedipine and usually regress upon withdrawal of treatment.

Those commonly reported (at an incidence of> 1% < 10%) in clinical studies include headache, palpitations, vasodilatation (especially at the start of therapy), lethargy, constipation, dizziness and oedema particularly peripheral oedema not connected with weight gain or heart failure.

Other side effects associated with nifedipine therapy are named below:

	Uncommon Side Effects (> 0.1 % < 1 % )	Rare Side Effects (> 0.01 % < 0.1 % )	Spontaneous Reports ( < 0.01 % )
Body as a Whole	abdominal pain, chest pain, leg pain, malaise	allergic reaction, chest pain substernal, chills, hypersensitivity-type jaundice, facial oedema fever	anaphylactic reaction, weight loss
Cardiovascular	hypotension, postural hypotension, syncope, tachycardia	cardiovascular disorder
Digestive	diarrhoea, dry mouth, dyspepsia, flatulence, nausea	anorexia, eructation, gastrointestinal disorder, gingivitis, gingival hyperplasia, vomiting	bezoar, dysphagia, oesophagitis, gum disorder, intestinal obstruction, intestinal ulcer
Haematological			leucopenia, hyperglycaemia
Hepatic		liver function test abnormalities, increase in GGT	increase in ALT, jaundice
Musculoskeletal	leg cramps	arthralgia, joint disorder, myalgia	muscle cramps
Neurological	insomnia, nervousness, paraesthesia, somnolence, vertigo	hyperaesthesia, sleep disorder, tremor, mood changes
Respiratory	dyspnoea	epistaxis
Dermatological	pruritus, rash	angioedema, maculopapular, pustular and vesiculobullous rash, sweating, urticaria	purpura, exfoliative dermatitis, photosensitive dermatitis
Special Senses		abnormal vision, eye disorder, eye pain	blurred vision
Urogenital	nocturia, polyuria	dysuria, impotence

There have also been reports of gynaecomastia in older men on long-term therapy, but this usually regresses when treatment is withdrawn.

Exacerbation of angina pectoris has been observed at the start of treatment with modified-release preparations of dihydropyridines, including nifedipine. Myocardial infarction is also known to occur although it is not possible to distinguish it from the natural course of ischaemic heart disease.

4.9 Overdose

Symptoms

There are few reports of nifedipine overdose and the symptoms are not necessarily dose-related. The most likely manifestations of overdose are severe hypotension due to vasodilatation, tachycardia or bradycardia.

The metabolic disturbances may include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia. The cardiac effects, which may occur, include heart block, AV dissociation and asystole and cardiogenic shock with pulmonary oedema.

Other toxic effects include drowsiness, dizziness, confusion, nausea, vomiting, lethargy, flushing, hypoxia, unconsciousness and coma.

Management

In the treatment of overdose it is important to restore stable cardiovascular conditions as soon as possible and achieve total elimination of nifedipine.

Gastric lavage and charcoal instillation may be of assistance if the patient is found early after the overdose. Gastric lavage may be necessary in combination with irrigation of the small intestine. Ipecacuanha should be given to children.

To prevent the subsequent absorption of nifedipine, elimination must be complete, including from the small intestine.

Activated charcoal should be given in 4 hourly doses of 25g for adults and 10g for children. The blood pressure, central arterial pressure, ECG, electrolytes, pulmonary wedge pressure and urea should be carefully monitored.

Placing the patient in the supine position with the feet raised and the use of plasma expanders, as appropriate, should treat the hypotension resulting from cardiogenic shock and arterial vasodilatation. If these measures are ineffective, hypotension may be treated with 10ml to 20ml of 10% calcium gluconate, administered intravenously over a period of 5 to 10 minutes. If ineffective, the therapy can be continued, with ECG monitoring.

Also, beta-sympathomimetics may be given e.g. 0.2mg of isoprenaline by slow intravenous or 5μg per minute as a continuous infusion. If the blood pressure response is inadequate with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The patient's response should determine the dosage of these drugs.

Bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker.

Additional fluid should be administered with caution to avoid cardiac overload.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Anatomical Therapeutic Chemical (ATC) code: C08C A05

Selective calcium channel blocker

(dihydropyridine derivative), with mainly vascular effects

Nifedipine is a dihydropyridine and is a specific and potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells, both in coronary and peripheral circulation.

The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance. Nifedipine administered once daily provides twenty-four hours control of elevated blood pressure. Nifedipine reduces blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect.

Nifedipine produces its effects in the treatment of angina by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume and causing a decrease in after-load. Also, nifedipine submaximally dilates clear and atherosclerosis coronary arteries to protect the heart against coronary artery spasm and improve perfusion to the ischaemic myocardium. Nifedipine decreases the frequency of painful attacks and the ischaemic ECG changes regardless of the relative contribution from coronary artery spasm or atheroschlerosis.

5.2 Pharmacokinetic Properties

General Characteristics

Nifedipine XL Tablets are formulated as prolonged release products. They are designed to control the release of nifedipine over twenty-four hours so that a clinical effect is achieved when the tablets are swallowed, once a day.

The pharmacokinetic profile is characterised by low peak-trough fluctuation. Over twenty-four hours plasma concentration versus time profiles at steady state are plateau-like, rendering the Nifedipine XL Tablets suitable for once daily administration.

Absorption

Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. However, due to extensive hepatic first pass metabolism in the liver, the resultant bioavailability lies between 45% and 68%. The absorption rate is slightly changed when the tablets are taken after ingesting food but the extent of drug availability is not affected.

Distribution

Nifedipine is about 95% bound to plasma proteins.

Metabolism

Nifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes.

Elimination

The elimination half-life is 2 to 5 hours. About 70% to 80% of the administered dose of nifedipine is excreted via the kidneys, mostly as its active metabolites. The rest (5% to 15%) is excreted via the bile in the faeces. The non-metabolised drug substance is only found in traces (less than 1.0%) in the urine.

Characteristics in Patients

Patients with Renal Impairment

There are no significant differences in the pharmacokinetics of nifedipine in patients with renal impairment and in healthy subjects. Therefore, dosage adjustments should not be required for patients with impaired renal function.

Patients with Hepatic Impairment

Nifedipine is primarily metabolised in the liver. The elimination half-life is markedly prolonged and there is a reduction in total clearance. Therefore, owing to the duration of action, nifedipine should not be administered to patients with reduced hepatic function.

5.3 Preclinical Safety Data

The LD₅₀ values (in mg per kg) determined when nifedipine was given orally and intravenously to different animal species, are reported below:

Animal Species	Oral	Intravenous
Mouse	454 (401 - 572) *	4.2 (3.8 - 4.6) *
Rat	1022 (950 - 1087) *	15.5 (13.7 - 17.5) *
Rabbit	250 - 500	2 - 3
Cat	~ 100	0.5 - 8
Dog	> 250	2 - 3

* 95% confidence interval

Subacute & Subchronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to 50mg per kg in rats and 100mg per kg in dogs p.o were tolerated without any damage when administered orally over periods of thirteen and four weeks, respectively.

Nifedipine doses of 2.5mg per kg in rats and 0.1mg per kg in dogs were tolerated without any damage when administered intravenously over periods of three weeks and six days, respectively.

Chronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to and including 100 mg per kg in dogs p.o were tolerated without any damage when administered orally up to one year.

In rats, toxic effect occurred at nifedipine concentrations above 100 ppm in the feed (about 5mg to 7mg per kg body weight).

Carcinogenic Studies (in Rats)

Studies in rats over two years produced no evidence of carcinogenic effects caused by nifedipine.

Reproductive Studies (in Rats, Mice & Rabbits)

Studies in rats, mice and rabbits maternally toxic doses of nifedipine induced some teratogenic and embryotoxic effects.

Mutagenic Studies

In vivo and in vitro studies showed that nifedipine has no mutagenic properties.

6. Pharmaceutical Particulars

6.1 List Of Excipients

In Tablet Core

Povidone K30

Lactose monohydrate

Carbomer 974P

Silica, colloidal anhydrous

In Tablet Core & Coat

Talc

Hypromellose (E 464)

Magnesium stearate

In Tablet Coat

Dimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate copolymer

Macrogol 4000

Red iron oxide (E 172)

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

Shelf Life of the Medicinal Product as Packaged for Sale

24 months

Shelf Life after Dilution or Reconstitution

Not applicable

Shelf Life after First Opening the Container

Not applicable

6.4 Special Precautions For Storage

Do not store above 25 ºC. Keep blister in the outer carton.

6.5 Nature And Contents Of Container

The tablets are enclosed in blisters composed of 25µm aluminium foil coated with 20gm^-2 PVDC film/250µm PVC foil coated with 40gm^-2 PVDC film

The blisters are boxed in cardboard cartons containing 28 tablets and a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

8. Marketing Authorisation Number(S)

Adipine XL 30 mg Tablets - PL 08829/0147

Adipine XL 60 mg Tablets - PL 08829/0148

9. Date Of First Authorisation/Renewal Of The Authorisation

28^th October 2004

10. Date Of Revision Of The Text

22/12/2008

11. LEGAL CATEGORY

POM