Section 4.2:
This section has been sunstantially revised to include additional detail and instructions on the method of administration, inclusion of a dosage table with revised dosage instructions and further information on treating special populations.

Section 4.8:
Addition of the following adverse drug reactions to the section for nervous system disorders with frequency uncommon: Anxiety
and with frequency not known: Agitation, Restlessness, Insomnia

Section 10:
Date of revision changed to 22 August 2016

4.1 Therapeutic Indications

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

4.2 Posology and method of administration

Children:
Children under 6 months:
Zepholin should not be used in children under 6 months of age.

Children under 6 years:
Zepholin capsules should not be used in children under 6 years of age. Other dosage forms are available that are more suitable for children aged less than 6 years.

4.3 Contraindications

• Use in patients with known hypersensitivity to the xanthine group of drug or to any of the excipients listed in section 6.1
• Recent myocardial infarction
• Acute tachycardiac arrhythmia
• Children under 6 months of age.

4.4 Special warnings and precautions for use

Zepholin should be used only when strictly indicated and cautiously in patients with:

• unstable angina pectoris
• tendency to suffer from tachycardiac arrhythmia
• severe hypertension
• hypertrophic obstructive cardiac myopathy
• hyperthyroidism
• seizure
• gastric and/or duodenal ulcer
• porphyria
• severe hepatic or renal impairment
• alcohol consumption


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

The use of Zepholin in old, polymorbid, critically ill and / or intensive medically treated patients is associated with an increased risk for intoxication and should therefore be controlled by therapeutic drug monitoring (TDM).
In patients receiving electroconvulsive therapy, caution should be exercised as Zepholin may prolong seizures. The occurrence of a status epilepticus is possible.


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

Acute febrile illness:
Fever decreases the clearance of Zepholin. It may be necessary to decrease the dose to avoid intoxication.


4.5 Interaction with other medicinal products and other forms of interaction

Zepholin is metabolized in the liver by the enzyme CYP1A2. The concomitant use of drugs that affect this enzyme may lead to changes in theophylline clearance.
Zepholin acts synergistically with other medicines containing xanthines, beta-sympathomimetics, caffeine and similar substances.
An accelerated degradation of theophylline and / or decreased bioavailability as well as reduced efficacy can be found:
• in smokers
• during concomitant treatment with barbiturates (particularly phenols, or pentobarbital), carbamazepine, phenytoin, rifampicin, primidone, sulfinpyrazone, ritonavir, hypericum perforatum and aminoglutethimide.
Theophylline levels should be monitored in case of concomitant treatment with these drugs and dose adjustment should be performed if necessary, even after the discontinuation of these medications.

Delayed degradation and / or increased theophylline blood levels with an increased risk of overdose and increased risk of side effects may occur during concomitant treatment with the following drugs: oral contraceptives, macrolide antibiotics (eg: erythromycin, clarithromycin, josamycin, spiramycin), quinolones (gyrase inhibitors), isonicotinic acid hydrazide, thiabendazole, calcium-channel blockers (eg diltiazem or verapamil), propranolol, propafenone, mexiletine, ticlopidine, cimetidine, allopurinol, α-interferon, rofecoxib, pentoxifylline, fluvoxamine, viloxazine, disulfiram, zileuton, phenylpropanolamine, influenza- and BCG-vaccines. A dose reduction of Zepholin may be indicated.

According to single reports, symptoms of theophylline overdose were observed during concomitant treatment with ranitidine, aciclovir or zafirlukast. When used concomitantly, the required individual theophylline dose should be determined carefully.

The dose of Zepholin should be reduced during concomitant treatment with
• ciprofloxacin to a maximum of 60%,
• enoxacin to a maximum of 30% and
• grepafloxacin or clinafloxacin to 50% of the recommended dose.
Other quinolones (eg, pefloxacin, pipemidic acid) can increase the effect of Zepholin. It is strongly recommended to monitor the theophylline concentration during concomitant treatment with quinolones closely.

The theophylline concentration may rise or fall during concomitant treatment with isoniazid. Monitoring of the plasma theophylline level is indicated.

During concomitant treatment with lithium, decrease in serum lithium level should be expected, but its magnitude cannot be predicted. Monitoring of lithium levels at 3 or 4 days after adding theophylline to assess initial degree and direction of serum level change and again at steady state (time will vary with lithium clearance) will allow adjustment of lithium dose. Even when theophylline is discontinued, close monitoring of lithium levels is again important. Here, one would predict a rise in serum lithium levels due to decreased lithium clearance.

The effect of β-blockers, adenosine and benzodiazepines can be reduced by the simultaneous administration of theophylline.

Zepholin enhances the diuretic effect of diuretics.

There is evidence that lowering the seizure threshold may occur in the brain during concomitant administration of certain fluoroquinolones or imipenem.

The use of halothane may lead to serious cardiac arrhythmia in patients who receive Zepholin.
The effect of corticosteroids on the theophylline kinetics is not yet conclusive.
Due to the various interactions of theophylline, serum level controls are generally advisable on long-term use of theophylline together with other drugs.

4.6 Fertility, pregnancy and lactation

Pregnancy
Currently, there are insufficient data for an application of Zepholin during the first trimester of pregnancy. Therefore, a treatment with Zepholin should be avoided during this time.
During the second and third trimester, Zepholin should be used only after a strict benefit-risk assessment, as it crosses the placenta and can have a sympathomimetic effect on the foetus.
With increasing duration of pregnancy the plasma protein binding and clearance of theophylline may decrease. A dose reduction may be necessary to avoid adverse effects.
A treatment with Zepholin at the end of pregnancy may lead to the inhibition of uterine contractions. Prenatally exposed newborns need to be carefully monitored for theophylline effects.

Lactation
Theophylline is excreted in breast milk; therapeutic serum concentrations can be achieved in the child. For this reason, the therapeutic dose of Zepholin to a nursing woman should be kept as low as possible. Breast-feeding should take place immediately prior to administration of the drug.
The breastfed baby needs to be monitored carefully for the possible occurrence of theophylline -effects. If higher therapeutic doses should be required, breastfeeding should be discontinued.

4.7 Effects on ability to drive and use machines

Zepholin has moderate influence on the ability to drive and use machines as it may change the ability to react. The ability to actively participate in road traffic, using machines or to work at height and without a firm grip may be impaired. This applies even more in combination with alcohol or medicinal products, which affect the ability to react.

4.8 Undesirable effects

The following categories are used as a basis for evaluating undesirable effects:
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). 

	Common	Uncommon	Not known
Immune system disorders		Hypersensitivity reactions to theophylline ( e.g. rash, pruritus, urticaria, bronchospasm) including anaphylactic and anaphylactoid reactions.
Metabolism and nutrition disorders		Hyperuricaemia	Changes in serum electrolytes, especially hypokalaemia increase of serum calcium and creatinine hyperglycaemia
Psychiatric disorders		Agitation Anxiety Insomnia
Nervous system disorders	Headache	Convulsion Tremor Seizures Dizziness
Cardiac disorders		Atrial tachycardia Palpitations Sinus tachycardia Tachycardia Palpitations	Arrhythmia Drop in blood pressure
Gastrointestinal disorders	Nausea	Abdominal pain Diarrhoea Gastric irritation Gastro-oesophageal reflux Vomiting	Gastrointestinal discomfort stimulation of the secretion of gastric acid
Skin and subcutaneous tissue		Pruritus Rash
Renal and urinary disorders		Diuresis  Urinary retention

More severe side effects can occur in individual hypersensitivity or an overdosage (Theophylline serum levels above 20 μg / ml) (please refer to 4.9).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Symptoms
At serum Theophylline levels of 20-25 μg / ml the known adverse effects of Theophylline occur with increased intensity.
Especially in serum Theophylline levels higher than 25 μg / ml, toxic effects such as seizures, sudden drop in blood pressure, ventricular arrhythmias, cardiovascular failure, rhabdomyolysis and severe gastrointestinal symptoms (e.g. gastrointestinal bleeding) may occur.
Such reactions can occur even without former slighter side effects. Children in particular are sensitive to Theophylline overdosage.
Warning: serious features may develop as long as 12 hours after overdosage with sustained release formulationsWith increased individual sensitivity, symptoms of overdosage are possible even below the above mentioned serum concentrations.
Therapeutic measures
• In slight overdose symptoms:
The corresponding drug should be discontinued and the serum Theophylline levels should be measured. For restart of treatment, the dose should be reduced accordingly.
• Treatment of all intoxications with Theophylline:
Up to two hours after ingestion, gastric lavage may be useful. To further poison removal, activated charcoal optionally in combination with a rapidly acting laxative (e.g. Galuber´s salt) should be administered repeatedly. Measure the plasma potassium concentration urgently, repeat frequently and correct hypokalaemia.
• In central nervous system disorders (eg, restlessness, and convulsions):
Diazepam i.v., 0.1 - 0.3 mg / kg body weight, up to 15 mg
• When life threatening:
Monitoring of vital functions,
Maintain the airways (intubation),
Supply of oxygen,
if needed: i.v. fluid substitution with plasma expanders,
Check and possibly correct the water and electrolyte balance,
Hemoperfusion (see below).
• In threatening cardiac rhythm disorders:
i.v. administration of propranolol in non-asthmatics (1 mg in adults, 0.02 mg / kg in children), this dose may be repeated every 5-10 minutes until the rhythm normalization or until the maximum dose of 0.1 mg / kg.
• Caution:
Propranolol may cause severe bronchospasm in asthmatic patients. Verapamil should therefore be administered in patients with asthma.
Particularly in severe intoxications, where a response to the measures mentioned above is not sufficient, as well as at very high serum levels of Theophylline, a rapid and complete detoxification can be achieved by hemoperfusion or hemodialysis. In general this can be refrained, as Theophylline is metabolized quickly enough.
Further treatment of poisoning with Theophylline is dependent on the extent, the course and the present symptoms.
• Extracorporeal methods of reducing the serum Theophylline:
The serum concentrations may rapidly decrease by increasing the clearance of Theophylline with extracorporeal methods. Hemoperfusion with activated charcoal is the most effective method, where the clearance of Theophylline rises to 6-fold, albeit serious complications such as hypotension, hypocalcemia, decreased platelet count and haemorrhage may occur. Hemodialysis is effective as the administration of multiple doses activated charcoal and has a lower risk for serious complications than hemoperfusion with charcoal.
The serum Theophylline may rise again to 5 to 10 µg / ml due to the redistribution of Theophylline from the tissue after completion of hemoperfusion with activated charcoal or hemodialysis.
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.

5.2 Pharmacokinetic properties

Serum half life is about 12 hours. Effective plasma concentrations: 5-12 μg/ml (do not exceed 20 μg/ml). Zepholin is mainly excreted by the kidneys.


10. DATE OF REVISION OF THE TEXT

October 2014

Change Detail

 

7              Marketing Authorisation Holder

 

Astellas Pharma Co Ltd

5 Waterside

Citywest Business Campus

Naas Road

Dublin 24

Ireland

6.1. List of excipients

 

Povidone

Colloidal anhydrous silica

Ammonio Methacrylate Copolymer (Type B)

Ammonio Methacrylate Copolymer (Type A)

Triethylcitrate (TEC)

Talc

 

Capsule Shell:

Gelatin

Indigotine (E132)

Titanium dioxide (E171)

 

Printing ink:

Shellac

Iron oxide black (E172)

Propylene glycol

Ammonium hydroxide

Update underlined

6.1. List of excipients

 

Povidone

Colloidal anhydrous silica

Ammonio Methacrylate Copolymer (Type B)

Ammonio Methacrylate Copolymer (Type A)

Triethylcitrate (TEC)

Talc

6.5. Nature and contents of container

 

Blister (Aluminium/PVC)

 

Pack size: 56 capsules.

14 capsules per strip, 4 strips per pack.

Not all pack sizes may be marketed

 

Change detail

 

Zepholin S.R 100mg PR Capsules
June 2010

 

Changes are in Red

 

 

6.5. Nature and contents of container

 

Blister (Aluminium/PVC)

 

Pack size: 56 capsules.

14 capsules per strip, 4 strips per pack.

Not all pack sizes may be marketed

 

 

10 DATE OF REVISION OF THE TEXT

 

June 2010

Changes in Red

6.5. Nature and contents of container
Not all pack sizes may be marketed

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal:  3 January 2009

10 DATE OF REVISION OF THE TEXT

 

April 2010

Zepholin SR 100mg Prolonged Release Capsules

Section 7: Marketing Authorisation Holder changed to Astellas Pharma Co. Ltd.

 

Section 8: 100mg: Marketing Authorisation Number changed to 1241/15/1

 

Section 10: Date of Revision of Text changed to September 2005