Uniphyllin Continus 400mg Prolonged Release Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

UNIPHYLLIN CONTINUS 400mg prolonged release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tablets containing 400 mg of Theophylline Ph Eur.

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Prolonged release tablets

Capsule shaped, white, tablet with ‘UNIPHYLLIN’ on one side and the ‘U400’ and the Napp logo on the reverse.

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 for the treatment of left ventricular and congestive cardiac failure.

Theophylline should not be used as first drug of choice in the treatment of asthma in children.

4.2 Posology and method of administration

Posology

Adults and the elderly

The usual maintenance dose is 200 mg 12 hourly. This may be titrated to either 300 mg or 400 mg dependent on the therapeutic response.

Paediatric population aged 6 years and above

The usual paediatric 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).

Clearance is increased in children compared to values observed in adult subjects. The rapid clearance observed in children decreases towards adult values in late teens. Therefore, lower dosages (based on usual adult dose) may be required for adolescents.

UNIPHYLLIN CONTINUS tablets should not be used in children below 6 years of age. Other dosage forms are available that are more suitable for children aged less than 6 years.

Theophylline distributes poorly into body fat, therefore mg/kg doses should be calculated on the basis of lean (ideal) bodyweight.

Plasma theophylline concentrations should ideally be maintained between 5 and 12 micrograms/ml. A plasma level of 5 micrograms/ml probably represents the lower level of clinical effectiveness. Significant adverse reactions are usually seen at plasma theophylline levels greater than 20 micrograms/ml. Monitoring of plasma theophylline concentrations may be required when:

• higher dosages are prescribed;

• patients have co-morbidities resulting in impaired clearance;

• theophylline is co-administered with medication that reduces theophylline clearance.

Patients vary in their response to xanthines and it may be necessary to titrate the dose on an individual basis.

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.

Method of administration Oral

These tablets must be swallowed whole and not broken, crushed or chewed as doing so may lead to a rapid release of theophylline with the potential for toxicity.

Missed dose

If a patient forgets to take a dose but remembers within 4 hours of the time the dose was due to be taken, the tablets can be taken straight away. The next dose should be taken at the normal time. Beyond 4 hours the prescriber may need to consider alternative treatment until the next dose is due.

4.3 Contraindications

Hypersensitivity to xanthines or to any of the excipients listed in section 6.1. Patients with porphyria.

Concomitant administration with ephedrine in children less than 6 years of age (or less than 22 kg).

Theophylline is contraindicated in children under 6 months of age.

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 disease, peptic ulcer, hyperthyroidism, severe hypertension, hepatic dysfunction, chronic alcoholism or acute febrile illness.

Fever decreases the clearance of theophylline. It may be necessary to decrease the dose to avoid intoxication.

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.

In case of insufficient effect of the recommended dose and in case of adverse events, theophylline plasma concentration should be monitored. 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.

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, 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 P-blockers may cause antagonism of bronchodilation; with ketamine may cause reduced convulsive threshold; with doxapram may cause increased CNS stimulation.

4.6 Pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

No known effects.

4.8 Undesirable 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.

Immune system disorders	Anaphylactic reaction
	Anaphylactoid reaction
	Hypersensitivity

Metabolism and nutrition disorders	Hyperuricaemia

Psychiatric disorders	Agitation
	Anxiety

	Insomnia

Nervous system disorders	Convulsions
	Dizziness
	Headache
	Tremor

Cardiac disorders	Atrial tachycardia
	Palpitations
	Sinus tachycardia

Gastrointestinal disorders	Abdominal pain
	Diarrhoea
	Gastric irritation
	Gastro-oesophageal reflux
	Nausea
	Vomiting

Skin and subcutaneous tissue disorders	Pruritus
	Rash

Renal and urinary disorders	Diuresis
	Urinary retention*

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

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

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

Absorption

Following oral administration, theophylline is efficiently absorbed and is associated with an absolute bioavailability approximating 100%. Following oral administration of UNIPHYLLIN CONTINUS tablets, the delivery of theophylline is controlled and, at steady state, peak concentrations are typically seen after approximately 5 hours.

An effective plasma concentration is considered to be 5-12 micrograms/ml, although plasma concentrations up to 20 micrograms/ml may be necessary to achieve efficacy in some cases. Do not exceed 20 micrograms/ml.

Distribution and protein binding

Theophylline is distributed through all body compartments; approximately 60% is bound to plasma proteins.

Biotransformation

Theophylline is metabolised in the liver to 1, 3-dimethyl uric acid and 3-methylxanthine.

Elimination

Theophylline and its metabolites are excreted mainlyin the urine. Approximately 10% is excreted unchanged. The mean elimination half life associated with UNIPHYLLIN CONTINUS tablets is approximately 7 hours.

Factors affecting clearance

The predominant factors which alter theophylline clearance are: age, body weight, diet, smoking habits, other drugs and cardiorespiratory or hepatic disease. Clearance is increased in children compared to values observed in adult subjects. Clearance decreases towards adult values in late teens.

Linearity

Studies involving prolonged-release UNIPHYLLIN CONTINUS tablets have demonstrated approximately dose-proportional pharmacokinetics across the 200-600 mg dose range.

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 Macrogol 6000 Talc

Magnesium Stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Three years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVdC coated PVC blister packs with aluminium backing containing 8 or 56 tablets.

Polypropylene containers with polyethylene lids containing 100, 250 or 1000 tablets.

Amber glass bottles containing 50 or 100 tablets

6.6 Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Ltd Cambridge Science Park Milton Road Cambridge CB4 0GW

8 MARKETING AUTHORISATION NUMBER(S)

Pl 16950/0068

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29 October 1982/ 15 May 2003

10 DATE OF REVISION OF THE TEXT

16/03/2016