This information is intended for use by health professionals

1. Name of the medicinal product

PHYLLOCONTIN® CONTINUS® 225 mg prolonged release tablets

PHYLLOCONTIN® Forte CONTINUS® 350 mg prolonged release tablets

2. Qualitative and quantitative composition

Aminophylline hydrate 225 mg and 350 mg

For a full list of excipients, see 6.1.

3. Pharmaceutical form

Prolonged release tablets

PHYLLOCONTIN CONTINUS tablets 225 mg are pale yellow, film-coated, prolonged release tablets with the Napp logo on one side and SA on the other.

PHYLLOCONTIN Forte CONTINUS tablets 350 mg are pale yellow, film-coated, prolonged release tablets with the Napp logo on one side and SA 350 on the other.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Route of Administration

Oral

Tablets should be swallowed and not chewed.

Children: The maintenance dose (expressed as mg aminophylline) is 12 mg/kg twice daily adjusted to the nearest 225 mg. It is recommended that half the maintenance dose be given for the first week of therapy if the patient has not previously been receiving xanthine preparations. PHYLLOCONTIN CONTINUS tablets 225 mg are, therefore, not suitable as a starting dose for children weighing under 40 kg.

Some children with chronic asthma require and tolerate much higher doses (13-20 mg/kg twice daily). Lower doses (based on the usual adult dose) may be required by adolescents.

Adults: The usual dose is two PHYLLOCONTIN CONTINUS tablets 225 mg, or one or two PHYLLOCONTIN Forte CONTINUS tablets 350 mg twice-daily following an initial week of therapy on one tablet twice-daily.

The Elderly: The dose should be adjusted following the response to the initial week of therapy on one tablet twice-daily.

Dose Titration: Patients vary in their response to xanthines and it may be necessary to titrate dosage individually. Steady state theophylline levels are generally attained 3-4 days after dose adjustment. If a satisfactory clinical response is not achieved, serum theophylline should be measured 4-6 hours after the last dose. Based on serum theophylline assay results dosage should be titrated using the following as a guide:

Peak serum theophylline level

Dosage adjustment to nearest 125mg

< 10 micrograms/ml

Increase total daily dose by half

10-15 micrograms/ml

Increase total daily dose by one quarter if symptoms persist

16-20 micrograms/ml

No adjustment required

21-25 micrograms/ml

Decrease dose by one quarter

26-30 micrograms/ml

Miss next dose and decrease maintenance dose by one half.

4.3 Contraindications

Should not be given concomitantly with ephedrine in children.

Hypersensitivity to xanthines or any of the tablet constituents.

Porphyria.

4.4 Special warnings and precautions for use

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

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

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.

Avoid concomitant use with other xanthine-containing products.

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.

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

4.5 Interaction with other medicinal products and other forms of interaction

The following increase clearance and it may therefore be necessary to increase dosage to ensure a therapeutic effect: aminoglutethimide, carbamazepine, moracizine, phenytoin, rifampicin, 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, isoprenaline, methotrexate, mexiletine, nizatidine, norfloxacin, oxpentifylline, propafenone, propranolol, ofloxacin, thiabendazole, verapamil, viloxazine hydrochloride and oral contraceptives. 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. There are conflicting reports concerning the potentiation of theophylline by influenza vaccine and physicians should be aware that interaction may occur. A reduction of 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.

4.6 Pregnancy and lactation

There are no adequate data from well controlled studies from 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.

4.7 Effects on ability to drive and use machines

No known effects.

4.8 Undesirable effects

The side-effects usually associated with theophylline and xanthine derivatives are nausea, gastric irritation, headache, CNS stimulation, tachycardia, palpitations, arrhythmias and convulsions.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other systemic drugs for obstructive airways diseases.

ATC code: R03D A05

Aminophylline (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.

5.2 Pharmacokinetic properties

Aminophylline (theophylline) is well absorbed from PHYLLOCONTIN 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.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Hydroxyethylcellulose

Povidone [K25]

Cetostearyl Alcohol

Purified Talc

Magnesium Stearate

Film coat

225 mg: Opadry 06B220001 (containing Macrogol 400,Hypromellose [E464], Titanium Dioxide [E171], Iron Oxide [E172])

350 mg: Opadry 06B220000 (containing Macrogol 400,Hypromellose [E464], Titanium Dioxide [E171], Iron Oxide [E172])

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Three years

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package.

6.5 Nature and contents of container

225 mg: PVC blister packs containing 56 tablets.

350 mg: Polypropylene containers containing 56 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing authorisation number(s)

PL 16950/0057-58

9. Date of first authorisation/renewal of the authorisation

225 mg: 7 July 1989 / 28 July 2006

350 mg: 17 August 1983 / 28 July 2006

10. Date of revision of the text

28 January 2014

® PHYLLOCONTIN, CONTINUS, NAPP and the Napp device (logo) are registered Trade Marks.

© 2006-2014 Napp Pharmaceuticals Ltd.