NUELIN SA 175 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Nuelin SA 175 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Theophylline 175mg

Excipients with known effect:

Each tablet contains Lactose Ph Eur

For the full list of excipients, see section 6.1

Prolonged release tablet

The tablets are white, round, biconvex, uncoated tablets with “T” on one face and “175” on the other face.

4.1 Therapeutic indications

Nuelin SA are indicated for the prophylaxis and treatment of reversible bronchospasm associated with asthma and chronic obstructive pulmonary disease.

Because effective plasma levels are maintained for up to twelve hours from a single dose, less frequent dosing is required than with conventional theophylline preparations.

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

One tablet twice daily, preferably after food, increasing to two tablets twice daily, if necessary.

Paediatric population

Below 6 months: Nuelin should not be used in children below 6 months of age.

Below 6 years: Nuelin 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.

6 to 12 years: One tablet twice daily, preferably after food.

Elderly

Elderly patients may require lower doses due to reduced theophylline clearance.

Method of administration

Nuelin SA tablets should be swallowed whole and not crushed or chewed.

The dosage should be titrated for each individual and adjusted with caution. Serum theophylline levels should be monitored to ensure that they remain within the therapeutic range.

4.3 Contraindications

Hypersensitivity to the active substance, xanthines or any of the excipients listed in section 6.1

Recent myocardial infarction

Acute tachyarrhythmia

Concomitant use with ephedrine in children.

Children under 6 months of age.

4.4 Special warnings and precautions for use

The patients response to therapy should be carefully monitored. Worsening of asthma symptoms requires urgent medical attention.

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

Use with caution in patients with cardiac diseases (e.g. cardiac arrhythmias, severe hypertension), peptic ulcer, hyperthyroidism, acute porphyria, hepatic dysfunction, renal dysfunction, chronic alcoholism, and chronic lung disease.

Use with caution in patients with acute febrile illness, as fever decreases the clearance of theophylline. It may be necessary to decrease the dose to avoid intoxication.

Smoking and alcohol consumption may increase theophylline clearance and increased doses of theophylline are therefore required. In patients with cardiac failure, hepatic dysfunction/disease and fever the reverse is true and these patients may require a reduced dosage.

Alternative bronchodilator therapy should be used in patients with a history of

seizures.

It is not recommended that the product be used concurrently with other preparations containing xanthine derivatives.

WARNINGS: Xanthines can potentiate hypokalaemia resulting from beta-2-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.

PRECAUTIONS: In the case of an acute asthmatic attack in a patient receiving a sustained action theophylline preparation, great caution should be taken when administering intravenous aminophylline.

Half the recommended loading dose of aminophylline (generally 6 mg/kg) should be given, i.e. 3 mg/kg, cautiously.

4.5 Interaction with other medicinal products and other forms of interaction Interactions with other xanthines, beta-sympathomimetics, caffeine and similar substances have been reported with theophylline. Theophylline may have a shorter half-life and/or diminished bioavailability and efficacy in smokers and when given with pentobarbital, the theophylline dose may need to be increased.

4.6 Fertility, pregnancy and lactation

Fertility

There are no clinical data on fertility in humans. Nonclinical data on theophylline reveal adverse effects on male and female fertility.

Pregnancy

Administration of theophylline drugs during pregnancy should only be considered if there is no safe alternative and the benefits of treatment outweigh the risks.

Breastfeeding

Theophylline is excreted in breast milk and therapeutic serum concentrations can be reached in children. For this reason, the therapeutic theophylline dose should be kept as low as possible in breast-feeding patients. Breast-feeding should preferably take place immediately before administration of the medicinal product. The breast-fed infant must be carefully monitored for any effects of theophylline. If higher therapeutic doses are required, it must be discontinued.

4.7 Effects on ability to drive and use machines

Even when taken as prescribed, this drug may affect the individual's a­bility to drive a vehicle, operate machinery or work safely under hazardous conditions. This applies particularly when the medication is taken in conjunction with alcohol or other drugs liable to impair judgment and motor skills.

4.8 Undesirable effects

The following side effects are seen in association with treatment with theophylline-containing drugs:

Immune system disorders:

Hypersensitivity (including anaphylactic reaction, rash, pruritus, urticaria and bronchospasm)

Metabolism and nutrition disorders:

Hyperglycaemia, hyperuricaemia, electrolyte imbalance, increase in serum calcium

Psychiatric disorders:

Agitation, restlessness

Nervous system disorders:

Headache, insomnia, tremor, convulsions

Cardiac disorders:

Palpitations, arrhythmia, tachycardia

Vascular disorders:

Hypotension

Gastrointestinal disorders:

Nausea, vomiting, gastric irritation, gastrointestinal disorder including gastrooesophageal reflux disease

Renal and urinary disorders:

Diuresis

Investigations:

Blood creatinine increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Theophylline toxicity is most likely to occur when serum concentration exceed 20 Hg/ml (110 ^mol/l) and becomes progressively more severe at higher concentration.

Symptoms

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

Alimentary features:

Provided plasma theophylline levels remain within the therapeutic range of up to 20 mcg/mL and depending on individual sensitivity, the known side effects include gastrointestinal disorder. Nausea, vomiting (which is often severe), epigastric pain, diarrhoea, haematemesis and rhabdomyolysis. Consider pancreatitis if abdominal pain persists.

Neurological features:

Central nervous system stimulation (restlessness, hypertonia, headache, insomnia). 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. Sudden blood pressure decrease and ventricular arrhythmia may also occur.

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.

Treatment

The product should be discontinued and plasma theophylline concentrations determined.

In very severe cases of overdose that fail to respond to treatment measures, or if plasma theophylline levels are very high, hemoperfusion or hemodialysis may achieve rapid and complete detoxification. Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive.

Oral activated charcoal (0.5 gm/kg up to 20 gm and repeat at least once one to two hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract. Although emetics induce vomiting, they do not reduce the absorption of theophylline unless administered within five minutes of ingestion and even then is less effective than oral activated charcoal.

Electrocardio­graphic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a nontoxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals as indicated by clinical circumstances. Monitoring and treatment should be continued until the serum concentration

Specific Recommendations

Serum Concentration > 20 < 30 mcg/mL

1. Administer a single dose of oral activated charcoal.

2. Monitor the patient and obtain a serum theophylline concentration in two to four hours to ensure that the concentration is not increasing. decreases below 20 mcg/mL.

Serum Concentration > 30 < 100 mcg/mL

1. Administer multiple-dose oral activated charcoal and measures to control emesis.

2. Monitor the patient and obtain serial theophylline concentrations every two to four hours to gauge the effectiveness of therapy and to guide further treatment decisions.

3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled.

Serum Concentration > 100 mcg/mL

1. Consider prophylactic anticonvulsant therapy.

2. Administer multiple-dose oral activated charcoal and measures to control emesis.

3. Consider extracorporeal removal, even if the patient has not experienced a seizure.

4. Monitor the patient and obtain serial theophylline concentrations every two to four hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption, and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Serum theophylline concentrations may rebound 5 to 10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs for obstructive airway diseases, ATC code: R03DA04.

Theophylline's mecha­nisms of action are not yet fully understood. Inhibition of phosphodiesterase and elevation of intracellular c-AMP may only be of significance at concentrations in the upper therapeutic range. Other mechanisms that have been postulated include adenosine receptor antagonism, prostaglandin antagonism and translocation of intracellular calcium. However, these effects also only occur with high doses of theophylline.

5.2 Pharmacokinetic properties

Theophylline is well absorbed after oral dosing. Food intake may affect the absorption rate (delay or acceleration, dose dumping) and the relative bioavailability of sustained release dosage forms.

Peak theophylline slow release (SR) forte concentrations at steady state (CRmax/ssR) were 9.16 mcg/mL (geometric mean) in fasted subjects and 9.42 mcg/mL (geometric mean) in fed subjects.

Theophylline's bron­chodilatory action correlates with the plasma concentration. Optimum therapeutic effects in the presence of a calculable risk of side effects are achieved at plasma levels of 8–20 mcg/mL.

About 60 % of plasma theophylline is protein-bound in the therapeutically effective range (approximately 40 % in neonates and adults with cirrhosis of the liver). The drug distributes from the blood stream into all compartments of the organism with the exception of fatty tissue. Theophylline is eliminated by hepatic biotransformation and renal excretion. Adults excrete about 7 to 13 % of a dose intact in the urine.

Theophylline is mainly excreted by the kidneys in the pediatric population. Neonates excrete about 50 % unchanged drug and substantial portions in the form of caffeine.

The main metabolites are 1.3-dimethyl uric acid (approximately 40 %), 3-methylxanthine (approximately 36 %) and 1-methyl uric acid (approximately 17 %).

Of these, 3-methylxanthine is pharmacologically active, but less so than theophylline. Hepatic first-pass metabolism of theophylline differs substantially between individuals, resulting in great interindividual variations in clearance, serum concentrations and elimination half-lives.

Kidney dysfunction may result in the accumulation of theophylline metabolites, some of which are pharmaceutically active. Clearance is also lowered in the presence of physical stress and severe hypothyroidism and elevated in the presence of severe psoriasis. The elimination rate is initially concentration-dependent, but a saturation effect occurs at serum concentrations in the upper therapeutic range. Accordingly, small dose increases result in a disproportionate increase in theophylline levels. The plasma half-life of theophylline is also subject to great variation. It is seven to nine hours in healthy non-smoking adult asthmatic patients with no other intercurrent diseases, four to five hours in smokers, three to five hours in children and may be more than 24 hours in preterm infants and patients with pulmonary disease, heart failure or liver disease.

5.3 Preclinical safety data

Theophylline is embryotoxic and teratogenic and shows effects on male and female fertility in animals depending on dose. In rabbits the teratogenic effects occur at 5 times the human target therapeutic plasma concentration.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Ph Eur

Cellulose Acetate Phthalate Ph Eur

Magnesium Stearate Ph Eur

6.2 Incompatibilities

None known

6.3 Shelf life

30 months

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Bottle or Blister packs of 60

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Mylan Products Ltd.,

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0188

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 22 January 1980

Date of latest renewal: 21 August 2004