UNIPHYLLIN^® CONTINUS^® 200, 300 and 400 mg prolonged release tablets

Tablets containing 200, 300 or 400 mg of Theophylline.

For excipients, see 6.1

Prolonged release tablets

For the treatment and prophylaxis of bronchospasm associated with asthma, chronic obstructive pulmonary disease and chronic bronchitis. Also indicated for the treatment of left ventricular and congestive cardiac failure.

Route of Administration

Oral

The tablets should be swallowed whole and not crushed or chewed. Crushing or chewing the tablets may lead to a rapid release of theophylline with the potential for toxicity. Patients vary in their response to xanthines and it may be necessary to titrate the dose on an individual basis.

The usual maintenance dose for adults and elderly patients is 200 mg 12 hourly. This may be titrated to either 300 mg or 400 mg dependent on the therapeutic response. Plasma theophylline concentrations should ideally be maintained between 5 and 15 mg/l. A plasma level of 5 mg/l probably represents the lower level of clinical effectiveness. Significant adverse reactions are usually seen at plasma theophylline levels greater than 20 mg/l. Patients may require monitoring of plasma theophylline levels when higher dosages are prescribed or when co-administered with medication that reduces theophylline clearance.

Children: The maintenance dose is 9 mg/kg twice daily. Some children with chronic asthma require and tolerate much higher doses (10-16 mg/kg twice daily). Lower dosages (based on usual adult dose) may be required for adolescents.

It may be appropriate to administer a larger evening or morning dose in some patients, in order to achieve optimum therapeutic effect when symptoms are most severe e.g. at the time of the 'morning dip' in lung function.

In patients whose night time or day time symptoms persist despite other therapy and who are not currently receiving theophylline, then the total daily requirement of UNIPHYLLIN CONTINUS tablets (as specified above) may be added to their treatment regimen as either a single evening or morning dose.

Porphyria; hypersensitivity to xanthines or any of the tablet constituents; concomitant administration with ephedrine in children.

The patient's response to therapy should be carefully monitored – worsening of asthma symptoms requires medical attention.

Use with caution in patients with cardiac disease, peptic ulcer, hyperthyroidism, severe hypertension, hepatic dysfunction, chronic alcoholism or acute febrile illness.

Caution should be exercised in elderly males with pre-existing partial outflow obstruction, such as prostatic enlargement, due to risk of urinary retention.

The half-life of theophylline may be prolonged in the elderly and in patients with heart failure, hepatic impairment or viral infections. Toxic accumulation may occur (see Section 4.9 Overdose). A reduction of dosage may be necessary in the elderly patient.

The hypokalaemia resulting from beta agonist therapy, steroids, diuretics and hypoxia may be potentiated by xanthines. Particular care is advised in patients suffering from severe asthma who require hospitalisation. It is recommended that serum potassium levels are monitored in such situations.

Severe side effects (hypertonia, convulsions, supraventricular tachycardia) may indicate serum concentrations of theophylline above therapeutic levels. Serum concentrations should be checked urgently and a decrease in the dose of theophylline may be required.

Alternative treatment is advised for patients with a history of seizure activity.

It is not possible to ensure bioequivalence between different prolonged release theophylline products. Therefore patients, once titrated to an effective dose, should not be changed from one prolonged release theophylline preparation to a different prolonged release preparation without re-titration and clinical assessment.

The following increase clearance and it may therefore be necessary to increase dosage to ensure a therapeutic effect: aminoglutethimide, carbamazepine, isoprenaline, moracizine, phenytoin, rifampicin, ritonavir, sulphinpyrazone, barbiturates and hypericum perforatum. Plasma concentrations of theophylline can be reduced by concomitant use of the herbal remedy St John's Wort (hypericum perforatum). Smoking and alcohol consumption can also increase clearance of theophylline.

The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-effects: allopurinol, carbimazole, cimetidine, ciprofloxacin, clarithromycin, diltiazem, disulfiram, erythromycin, fluconazole, interferon, isoniazid, methotrexate, mexiletine, nizatidine, norfloxacin, oxpentifylline, propafenone, propranolol, ofloxacin, thiabendazole, verapamil, viloxazine hydrochloride and oral contraceptives (see Section 4.9 Overdose). The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline dose halved and plasma theophylline should be monitored closely.

Factors such as viral infections, liver disease and heart failure also reduce theophylline clearance (see Section 4.9 Overdose). There are conflicting reports concerning the potentiation of theophylline by influenza vaccine and physicians should be aware that interaction may occur. A reduction in dosage may be necessary in elderly patients. Thyroid disease or associated treatment may alter theophylline plasma levels. There is also a pharmacological interaction with adenosine, benzodiazepines, halothane, lomustine and lithium and these drugs should be used with caution.

Theophylline may decrease steady state phenytoin levels.

Xanthines can potentiate hypokalaemia resulting from beta₂ agonist therapy, steroids, diuretics and hypoxia. Particular caution is advised in severe asthma. It is recommended that serum potassium levels are monitored in such situations.

Co-administration with β-blockers may cause antagonism of bronchodilation; with ketamine may cause reduced convulsive threshold; with doxapram may cause increased CNS stimulation.

There are no adequate data from well controlled studies of the use of theophylline in pregnant women. Theophylline has been reported to give rise to teratogenic effects in mice, rats and rabbits (See section 5.3). The potential risk for humans is unknown. Theophylline should not be administered during pregnancy unless clearly necessary. Theophylline is secreted in breast milk, and may be associated with irritability in the infant, therefore it should only be given to breast feeding women when the anticipated benefits outweigh the risk to the child.

No known effects.

The following adverse drug reactions have been reported in the post-marketing setting for theophylline. Frequencies of “not known” have been assigned as accurate frequencies cannot be estimated from the available clinical trial data.

* Please refer to section 4.4 as theophylline may induce urinary retention in elderly males with pre-existing partial outflow obstruction.

Over 3 g could be serious in an adult (40 mg/kg in a child). The fatal dose may be as little as 4.5 g in an adult (60 mg/kg in a child), but is generally higher.

Symptoms

Warning: Serious features may develop as long as 12 hours after overdosage with prolonged release formulations.

Alimentary features: Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Consider pancreatitis if abdominal pain persists.

Neurological features: Restlessness, hypertonia, exaggerated limb reflexes and convulsions. Coma may develop in very severe cases.

Cardiovascular features: Sinus tachycardia is common. Ectopic beats and supraventricular and ventricular tachycardia may follow.

Metabolic features: Hypokalaemia due to shift of potassium from plasma into cells is common, can develop rapidly and may be severe. Hyperglycaemia, hypomagnesaemia and metabolic acidosis may also occur. Rhabdomyolysis may also occur.

Management

Activated charcoal or gastric lavage should be considered if a significant overdose has been ingested within 1-2 hours. Repeated doses of activated charcoal given by mouth can enhance theophylline elimination. Measure the plasma potassium concentration urgently, repeat frequently and correct hypokalaemia. BEWARE! If large amounts of potassium have been given, serious hyperkalaemia may develop during recovery. If plasma potassium is low, then the plasma magnesium concentration should be measured as soon as possible.

In the treatment of ventricular arrhythmias, proconvulsant antiarrhythmic agents such as lignocaine (lidocaine) should be avoided because of the risk of causing or exacerbating seizures.

Measure the plasma theophylline concentration regularly when severe poisoning is suspected, until concentrations are falling. Vomiting should be treated with an antiemetic such as metoclopramide or ondansetron.

Tachycardia with an adequate cardiac output is best left untreated. Beta-blockers may be given in extreme cases but not if the patient is asthmatic. Control isolated convulsions with intravenous diazepam. Exclude hypokalaemia as a cause.

Theophylline is a bronchodilator. In addition it affects the function of a number of cells involved in the inflammatory processes associated with asthma and chronic obstructive airways disease. Of most importance may be enhanced suppressor, T-lymphocyte activity and reduction of eosinophil and neutrophil function. These actions may contribute to an anti-inflammatory prophylactic activity in asthma and chronic obstructive airways disease. Theophylline stimulates the myocardium and produces a diminution of venous pressure in congestive heart failure leading to marked increase in cardiac output.

Theophylline is well absorbed from UNIPHYLLIN CONTINUS tablets and at least 60% may be bound to plasma proteins. The main urinary metabolites are 1,3-dimethyl uric acid and 3-methylxanthine. About 10% is excreted unchanged.

In studies in which mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.

Hydroxyethylcellulose

Povidone (K25)

Cetostearyl Alcohol

Macrogol 6000

Talc

Magnesium Stearate

Not applicable.

Three years.

Do not store above 25°C.

Blister packs consisting of aluminium foil sealed to 250 μm PVC with a PVdC coating of at least 40 gsm thickness, containing 56 tablets.

None.

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

PL 16950/0066-0068

200 mg - 23 August 1979/15 May 2003

300 mg – 22 February 1988/15 May 2003

400 mg – 29 October 1982/15 May 2003

22 March 2011

P

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