Document: leaflet MAH GENERIC_PL 20346-0002 change

• leaflet MAH GENERIC_PL 20346-0002
• leaflet MARTINDALE PHARMACEUTICALS_PL 20346-0002

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TECHNICAL PRESCRIBING INFORMATION

Caffeine Citrate 10mg/ml Solution for Injection

Equivalent to Caffeine 5mg/ml

1.    Composition

Each 1ml contains 10mg of caffeine citrate, equivalent to 5mg of caffeine.

Each 2ml contains 20mg of caffeine citrate, equivalent to 10mg of caffeine.

It also contains Water for Injections, Sodium Hydroxide, Dilute Hydrochloric Acid, Sodium Chloride and Citric Acid

2.    Clinical Particulars

2.1    Therapeutic Indications

Treatment of apnoea of prematurity.

2.2    Posology and Method of Administration

The recommended doses of Caffeine Citrate 10mg/ml Solution for Injection are expressed below. Please note:

(a)    the dose expressed as caffeine citrate is twice the dose expressed as caffeine base.

(b)    given orally or intravenously, caffeine is clinically effective within 4 hours. If the patient fails to respond within this time, a second loading dose may be given. If there is no clinical response to the second loading dose, caffeine blood levels should be measured (see 'special warnings and precautions for use' Section 2.3 below).

(c)    Caffeine Citrate 10mg/ml Solution for Injection is also effective when administered orally, and this route may be used alternatively without adjusting the dose.

(d)    because of the slow elimination of caffeine in this patient population, there is no requirement for dose tapering on cessation of treatment.

(e)    infants must be of sufficient respiratory maturity not to require positive pressure ventilation.

	Dose of Caffeine Citrate 10mg/ml Solution for Injection	Dose Expressed as Caffeine Citrate	Dose Expressed as Caffeine Base	Route	Frequency
Loading Dose See (b) above	2ml/kg	20mg/kg	10mg/kg	Intravenous Infusion (over 30 min) or by oral administration	Once
Maintenance Dose	0.5-1ml/kg*	5-10mg/kg*	2.5-5.0mg/kg*	Intravenous Infusion (over 10 min) or by oral administration	Every 24 hours**

* In some cases maintenance doses higher than 10mg/kg/day (expressed as caffeine citrate) may be required to achieve maximal efficacy (eg in continuing apnoeic episodes where plasma levels indicate the dose may be safely increased)

** Beginning 24 hours after the loading dose(s)

Treatment should be continued until the child has reached a gestational age of 37 weeks, by which time apnoea of prematurity usually resolves spontaneously. This limit may however be revised according to clinical judgement in individual cases, depending on response to treatment, the continuing presence of apnoeic episodes despite treatment, or other clinical considerations.

Caffeine Citrate 10mg/ml Solution for Injection should not be given intramuscularly; being acidic, i.m. injection is likely to be painful. When given intravenously, it should be given as a slow infusion rather than a bolus injection; there is evidence that bolus administration may cause sudden changes in blood pressure.

Please see Section 2.3 below regarding use of filter straws.

Hepatic and Renal Impairment:

In the presence of renal impairment, a reduced daily maintenance dose of caffeine is required and the dose should be guided by blood caffeine measurements. There is increased potential for accumulation.

In very premature infants, clearance of caffeine does not depend on hepatic function. Hepatic caffeine metabolism develops progressively in the weeks following birth and for the older infant, hepatic disease may reduce maintenance caffeine dose requirements.

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PATIENT INFORMATION LEAFLET

Caffeine Citrate 10mg/ml Solution for Injection

Equivalent to Caffeine 5mg/ml

In this leaflet:

1.    What Caffeine Citrate 10mg/ml Solution for Injection is and what it is used for

2.    What you need to know before your baby is given Caffeine Citrate 10mg/ml Solution for Injection

3.    How Caffeine Citrate 10mg/ml Solution for Injection is given

4.    Possible side effects

5.    How Caffeine Citrate 10mg/ml Solution for Injection is stored

6.    Contents of the pack and other information

1.    What Caffeine Citrate 10mg/ml Solution for Injection is and what it is used for

•    Caffeine belongs to a group of medicines known as methylxanthines

•    It stimulates breathing, and is used to treat apnoea of prematurity (breathing difficulties as a result of being born prematurely).

2.    What you need to know before your baby is given Caffeine Citrate 10mg/ml Solution for Injection

Your baby should not be given Caffeine Citrate 10mg/ml Solution for Injection if there is known hypersensitivity (allergy) to any of the ingredients listed in Section 6 below.

Warnings and precautions

Talk to your doctor before Caffeine Citrate 10mg/ml Solution for Injection is given, if:

•    Your baby has liver or kidney disease

•    Your baby has had any unusual heart rhythms detected.

Other medicines and Caffeine Citrate 10mg/ml Solution for Injection

As with most medicines, Caffeine Citrate 10mg/ml Solution for Injection may interact with other medicines given at the same time.

A premature baby may need many medicines, and any problems with caffeine are likely to be minor, but tell the doctor about any other medication they may not know about, particularly any other medicine (for example theophylline) given to your baby to help it breathe.

If you, as the mother, drank a lot of coffee, or took any other high caffeine-containing product just before your baby was born, some caffeine may still be present in your baby's circulation. Tell the doctor about this.

Medications containing phenobarbitone or phenytoin, taken by the mother herself to treat epilepsy, may also have an effect on the way the baby reacts to caffeine therapy. If you have been taking treatment for epilepsy during pregnancy, please tell your baby's doctor about it. Caffeine Citrate 10mg/ml Solution for Injection contains sodium Caffeine Citrate 10mg/ml Solution for Injection contains 3.04mg sodium per 1 ml of the solution, which the doctor will need to consider if your baby is on a controlled sodium diet.

3.    How Caffeine Citrate 10mg/ml Solution for Injection is given

The doctor or nurse will administer Caffeine Citrate 10mg/ml Solution for Injection into a venous infusion (drip). It can also be equally effective when given by mouth, and all or some of the doses may be given this way when possible. This medicine should not be given by intramuscular injection.

Opening the ampoules may introduce glass particles into this solution. It is recommended that Caffeine Citrate 10mg/ml Solution for Injection be filtered before administration.

Filters should not then be used to administer the dose from the syringe.

2.3    Special Warnings and Precautions for Use

Care should be taken to exclude other causes of apnoea before initiation of treatment.

It is advisable to monitor plasma levels of caffeine periodically. However, at the recommended doses, frequent (more than weekly) monitoring of plasma levels is not normally necessary unless there are concerns regarding lack of efficacy or possible toxicity. In premature neonates, caffeine has a prolonged half-life. If higher maintenance dosages are used, the clinician should recognise this potential for accumulation and monitor plasma caffeine levels (see SmPC for a full list of Pharmacological Properties).

If there is inadequate clinical response to the first loading dose, a second dose may be given, but if there is continued inadequate response, the plasma levels should be confirmed before further doses are given, as the failure to respond could be an indication of another cause of apnoea. Plasma levels should not normally exceed 50 micrograms/ml (optimally 10-30 micrograms/ml).

There may be pre-existing caffeine in the blood of neonates

(a)    whose mothers may have ingested large quantities of caffeine prior to delivery.

(b)    who have previously been treated with theophylline, which is metabolised to caffeine.

There is evidence that caffeine causes tachyarrhythmias in susceptible individuals. In newborn babies this is usually a simple sinus tachycardia. If there have been any unusual rhythm disturbances on a CTG trace before the baby is born, caffeine should be administered with caution. Caffeine should be used with caution in infants suffering gastro-oesophageal reflux, as the drug may exacerbate this condition.

Caffeine may increase cardiac output and heart rate in therapeutic doses. Caffeine should be used with caution in infants with cardiac disease.

Caffeine causes a generalised increase in metabolism, which may result in higher energy and nutrition requirements during therapy. The diuresis and electrolyte loss induced by caffeine may necessitate correction of fluid and electrolyte disturbances.

This medicinal product contains 3.04mg sodium per 1ml of the solution. To be taken into consideration by patients on a controlled sodium diet.

Opening the ampoules may introduce glass particles into this solution. It is recommended that the solution be filtered prior to use by means of a suitable filter device.

2.4    Overdose

Caffeine overdose has been reported in a few cases in newborns and premature infants. There should normally be no concern with blood levels below 50 micrograms/ml; based on limited data, toxicity seems to occur when levels over 100 micrograms/ml are reached. Symptoms of overdosage from these reports include jitteriness, tachycardia, tachypnoea, tremor, opisthotonos, rigidity and tonic-clonic movements. In one case of overdose the patient developed compromised circulation, vomiting and seizures. Other reported effects of gross overdose include fever, agitation, hyperexcitability, hypertonia, gastric residues, distended abdomen, metabolic acidosis, hyperglycaemia and elevated urea levels.

Treatment of overdosage should include monitoring of blood levels of caffeine and supportive measures. Previous cases reported resolved satisfactorily.

In severe cases of overdose, exchange transfusion should be considered. In one case, this was found to reduce plasma caffeine levels by 40mg/L per transfusion.

3. Pharmaceutical Particulars

3.1    Incompatibilities

This medical product must not be mixed with other medicinal products except those mentioned in Section 3.2.

3.2    Special Precautions for disposal and other handling

Only clear solution without particulate matter should be used. For single use only. Any unused solution should be discarded.

There was no detectable degradation of the solution when diluted 50/50 with commercial glucose 5%, glucose 4% saline 0.18%, and sodium chloride 0.9% infusions, when stored in disposable plastic syringes at room temperature for 4 hours.

Marketing Authorisation Number: 20346/0002 Marketing Authorisation Holder: Viridian Pharma Ltd, Newport NP18 2AB

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The exact dose, to be determined by the doctor, depends on each baby's needs and response to the treatment, but will usually be:

•    A starting dose of 20mg/kg of the baby's bodyweight calculated as caffeine citrate (equivalent to caffeine 10mg/kg or 2ml/kg of this solution). If given by injection this dose should be infused over 30 minutes

•    Followed after 24 hours by a lower daily maintenance dose of 5 to 10mg/kg of the baby's bodyweight calculated as caffeine citrate (equivalent to caffeine 2.5 to 5mg/kg or 0.5 to 1ml/kg of this solution). If given by injection this dose should be infused over 10 minutes.

If your baby fails to respond to the starting dose (after at least 4 hours), the doctor or nurse may give one more additional starter dose, before continuing to the lower maintenance doses.

If your baby is given too much

Accidental overdosage: If too much caffeine solution is accidentally given to your baby, the side effects described below may become more noticeable. In cases of very high overdosage, fits can also occur. If signs of overdosage are noticed, please tell the baby's doctor immediately.

4.    Possible side effects

Caffeine acts as a stimulant to the nervous system. Side effects from this action may include restlessness or jitteriness. Caffeine may also aggravate any tendency to vomiting.

If you think your baby is showing any of these side effects, or you notice any other effects after caffeine treatment, please tell the doctor immediately.

Other side effects are not visible, but will be detected by the monitoring equipment used in the special care baby unit:

•    your baby may produce more urine than usual, and as a consequence blood levels of certain chemicals (sodium, calcium and glucose) may be affected.

•    Increased blood pressure or heart rate.

The doctor may decide to check the levels of caffeine in a blood sample as a precaution, or if your baby is not responding to treatment as expected.

Reporting of side effects

If you notice any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme,

Website: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

5.    How Caffeine Citrate 10mg/ml Solution for Injection is stored

Caffeine Citrate 10mg/ml Solution for Injection needs to be kept out of the reach and sight of children. There are no other special conditions of storage.

Use by date: Do not use Caffeine Citrate 10mg/ml Solution for Injection after the expiry date on the label, or if there are any signs of discolouration or clouding of the solution.

6.    Contents of the pack and other information

What Caffeine Citrate 10mg/ml Solution for Injection contains

The active ingredient is Caffeine Citrate 10mg/ml, equivalent Caffeine 5mg/ml.

Other ingredients are:

•    water for injections

•    citric acid

•    sodium chloride

•    sodium hydroxide

•    dilute hydrochloric acid

Caffeine Citrate 10mg/ml Solution for Injection contains 3.04mg sodium per 1ml of the solution What Caffeine Citrate 10mg/ml Solution for Injection looks like and contents of the pack

•    Each 1ml ampoule of Caffeine Citrate 10mg/ml Solution for Injection contains 10mg of caffeine citrate, equivalent to 5mg of caffeine

•    Each 2ml ampoule of Caffeine Citrate 10mg/ml Solution for Injection contains 20mg of caffeine citrate, equivalent to 10mg of caffeine

•    Caffeine Citrate 10mg/ml Solution for Injection is available in ampoules of 1ml or 2ml, in packs of 10 ampoules.

Marketing Authorisation Holder

Viridian Pharma Ltd, Yew Tree House, Hendrew Lane, Llandevaud, Newport, Gwent NP18 2AB Manufacturer

Sterop, Avenue de Scheut 42-50, B - 1070 Brussels - BELGIUM

This leaflet was last revised in May 2014    4/ridian Pharma Ltd