This information is intended for use by health professionals

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

3. Pharmaceutical form

Prolonged release tablet

4. Clinical particulars
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.

Drug

Type of interaction

Allopurinol

Decreases theophylline clearance at allopurinol doses ≥600 mg/day

Aminoglutethimide

Increases theophylline clearance by induction of microsomal enzyme activity

Barbiturates (especially pentobarbital)

Shorter half-life and/or diminished bioavailability

Carbamazepine

Similar to aminoglutethimide

Carbimazole

Carbimazole may increase serum theophylline levels

Cimetidine, Ranitidine

Decreases theophylline clearance by inhibiting cytochrome P450 1A2

Clarithromycin

Similar to erythromycin

Doxapram

Increases CNS stimulation

Diazepam

Decreases the effect of benzodiazepine. Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors

Digoxin

Digoxin may increase theophylline serum levels

Diltiazem and other calcium channel blockers

May decrease theophylline clearance and elevate theophylline plasma levels

Disulfiram

Decreases theophylline clearance by inhibiting hydroxylation and demethylation

Diuretics

Increases diuretics' activity

Erythromycin

Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3

Estrogen (oral contraceptives)

Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.

Fluconazole

Fluconazole may increase serum theophylline levels

Fluvoxamine

Similar to cimetidine

Careful monitoring of theophylline serum concentration is required.

Furosemide

Furosemide may increase serum theophylline levels

Halothane

Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines

Imipenem

May decrease clearance and elevate theophylline plasma levels

Influenza vaccines

May decrease theophylline clearance and elevate theophylline plasma levels

Isoniazid

May decrease theophylline clearance and elevate theophylline plasma levels

Interferon, human recombinant alpha-A

Decreases theophylline clearance

Ketamine

Reduces convulsive threshold

Lithium

Theophylline increases renal lithium clearance

Macrolides (josamycin, spiramycin)

May decrease theophylline clearance and elevate theophylline plasma levels

Methotrexate (MTX)

Decreases theophylline clearance

Mexiletine

Similar to disulfiram

Nizatidine

Nizatidine may increase serum theophylline levels

Norfloxacin

Norfloxacin may increase serum theophylline levels

Pentoxifylline

Decreases theophylline clearance

Phenobarbital

Similar to aminoglutethimide

Phenytoin

Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption

Primidone

Shorter half-life and/or diminished bioavailability

Propafenone

Decreases theophylline clearance and pharmacologic interaction

Propranolol

Similar to cimetidine and pharmacologic interaction

In general, however, beta blockers should be avoided in patients taking theophylline as they can dangerously exacerbate bronchospasm in patients with a history of asthma or chronic obstructive pulmonary disease

Quinolones (e.g Ciprofloxacin**, Pefloxacin, Pipemidic acid, Enoxacin)

Similar to cimetidine

Rifampin

Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity

Ritonavir

Ritonavir may decrease serum theophylline levels

Saint John's wort

Concurrent use of theophylline with Saint John's wort may result in reduced theophylline efficacy

Sulfinpyrazone

Increases theophylline clearance by

increasing demethylation and hydroxylation. Decreases renal clearance of theophylline

Thiabendazole

Decreases theophylline clearance

Ticlopidine

Decreases theophylline clearance

Verapamil

Similar to disulfiram

Viloxazine

Viloxazine may increase serum theophylline levels

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

Symptoms of intoxication

When serum theophylline levels are between 20 and 25 μg/ml, the known adverse effects of theophylline are generally observed with greater intensity.

Toxic effects such as seizures, a sudden drop in blood pressure, ventricular arrhythmia, cardiovascular collapse, rhabdomyolysis and severe gastrointestinal symptoms (such as gastrointestinal bleeding) can occur mainly when serum theophylline levels are higher than 25 μg/ml.

These reactions can also occur without the precursors of milder adverse effects. Children in particular can have sensitivity reactions to theophylline overdose. When overdose is caused by prolonged-release theophylline preparations, the onset of symptoms can be delayed.

In patients with high individual sensitivity to theophylline, severe symptoms of overdose are possible with serum concentrations lower than those mentioned above.

Treatment of overdose

In patients with mild symptoms of overdose:

The preparation in question should be discontinued and serum theophylline levels assayed. If treatment is resumed, the dose in question should be reduced.

Treatment of all theophylline overdoses

Gastric lavage can be considered for up to 2 hours after oral administration.

For further removal of theophylline as well as after overdose with intravenously-administered theophylline, activated charcoal should be administered repeatedly, if necessary in combination with a fast-acting laxative (e.g. sodium sulfate).

In patients with central nervous system reactions (e.g. restlessness and seizures):

IV diazepam, 0.1-0.3 mg/kg body weight, up to 15 mg.

In life-threatening cases:

- Monitoring of vital functions,

- Airways kept open (intubation),

- Supply of oxygen,

- if necessary, IV volume replacement with plasma expanders,

- monitoring and possible correction of water and electrolyte balance,

- Hemoperfusion (see below).

In patients with life-threatening heart rhythm disturbances:

IV administration of propranolol in non-asthmatic patients (1 mg in adults, 0.02 mg/kg body weight in children): this dose can be repeated every 5 to 10 minutes until heart rhythm normalizes or up to the maximum dose of 0.1 mg/kg body weight.

Warning:

Propranolol can trigger severe bronchospasm in asthmatic patients. Verapamil should therefore be used in asthmatic patients.

In particularly severe cases of overdose where response to the measures listed above is insufficient, as well as in patients with very high serum theophylline levels, rapid and complete removal of the drug can be achieved with hemoperfusion or hemodialysis. However, this is generally not necessary, as theophylline is metabolized relatively quickly.

Further treatment overdose is based on the extent and course of the intoxication as well as existing symptoms.

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 and other handling

No special requirements for disposal.

7. Marketing authorisation holder

Mylan Products Ltd

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 46302/0188

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 22 January 1980

Date of latest renewal: 21 August 2004

10. Date of revision of the text

September 2018