Caffeine Citrate 10mg/Ml Solution For Injection
PATIENT INFORMATION LEAFLET
Equivalent to Caffeine 5mg/ml
Please read all of this leaflet carefully before your baby is given this medicine.
• Keep this leaflet. You may need to read it again.
• If you have further questions, please ask the hospital doctor who is looking after your baby.
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In this leaflet:
What Caffeine Citrate 10mg/ml Solution for Injection is and what it is used for
2. Before your baby is given Caffeine Citrate 10mg/ml Solution for Injection
3. How Caffeine Citrate 10mg/ml Solution for Injection is used
4. Possible side effects
5. Storing Caffeine Citrate 10mg/ml Solution for Injection Further 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. Before your baby is given Caffeine Citrate 10mg/ml Solution for Injection
Your baby should not be given Caffeine Citrate 10mg/ml Solution for Inj'ection if there is known hypersensitivity (allergy) to any of the ingredients listed in section 6 below.
Special care is needed with Caffeine Citrate 10mg/ml Solution for Inj'ection when your baby:
has liver or kidney disease has had any unusual heart rhythms detected.
Please tell the doctor looking after your baby of any of such problems.
■ 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 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.
■ 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.
3. How Caffeine Citrate 10mg/ml Solution for Injection is used
The doctor or nurse will administer Caffeine Citrate 10mg/ml Solution for Injection into a venous nfusion (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.
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 body weight calculated as caffeine citrate (equivalent to caffeine 10mg/kg or 2ml/kg of this solution) if by injection then infused over 30 minutes
■ Followed after 24 hours by a lower daily maintenance dose of 5 to 10mg/kg of the baby's body weight calculated as caffeine citrate (equivalent to caffeine 2.5 to 5mg/kg or 0.5 to 1ml/kg of this solution) if by injection then infused over 10 minutes
f 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.
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TECHNICAL PRESCRIBING INFORMATION
Composition
1. Each 1ml contains 10mg of ca%eine 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
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 2.4 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.
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Dose of Caffeine Ciitrate 10mg/ml
Solution for Injection
Equivalent to Caffeine 5mg/ml
2.2 Posology and Method of Administration (Continued)
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.
Ca%eine Citrate 10mg/ml Solution for Injection should not be given intramuscularly; being acidic, i.m. injection s likely to be painful. When given intravenously, it should be given as a slow infusion rather than a bolus njection; there is evidence that bolus administration may cause sudden changes in blood pressure.
Please see Section 2.4 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.
n 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.
Adults and Children
Not applicable
Elderly
Not applicable
Dose Expressed as
Ca%eine Citrate
Dose Expressed as
Ca%eine Base
Route
Frequency
Loading Dose See (b) above
Maintenance
Dose
2ml/kg
20 mg/kg
10mg/kg
Intravenous** (over 30 min) or oral
Once
0.5-1 ml/kg*
5-10mg/kg*
.5-5mg/kg*
Intravenous** (over 10 min) or oral
Every 24 hours***
In some cases maintenance doses higher than 10mg/k to achieve maximal efficacy (eg in continuing apno be safely increased)
By intravenous infusion * Beginning 24 hours after the loading dose(s)
g/day (expressed as caffeine citrate) may be required episodes where plasma levels indicate the dose may
2.3 Contraindications
Caffeine Citrate 10mg/ml Solution for Injection is contraindicated in patients who have demonstrated hypersensitivity to any of its components.
2.4 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 also section 3.2).
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.
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2.5 Interactions with other Medicinal Products and other forms of Interaction
No clinically significant interactions between caffeine and other medications have been reported in premature infants. Nevertheless, certain clinical situations have a theoretical potential for interaction. If the child's mother has been treated with phenytoin or phenobarbitone during pregnancy, the child might have enhanced hepatic enzyme induction and thus require higher doses of caffeine to compensate for increased caffeine metabolism. Plasma caffeine levels should be monitored during treatment in such situations, to ensure that adequate caffeine has been administered.
Interconversion between caffeine and other xanthines such as theophylline has been reported in premature neonates. Therefore the concurrent use of these drugs should be avoided. Baseline serum levels of caffeine should be measured in patients previously treated with theophylline.
2.6 Pregnancy and Lactation
Not applicable.
2.7 Effects on Ability to Drive and Use Machines
Not applicable.
2.8 Undesirable Effects
Caffeine has been reported to cause a number of adverse effects in premature neonates. Effects described include CNS stimulation such as irritability, restlessness and jitteriness and cardiac effects such as tachycardia, hypertension and increased stroke volume. These effects are dose related and may necessitate dose reduction and measurement of plasma levels. They are generally, although not exclusively, associated with serum caffeine concentrations >50 micrograms/ml.
On the available evidence, caffeine does not appear to aggravate cerebral hypoxia or to exacerbate any resulting damage, although the possibility cannot be ruled out.
Caffeine treatment may increase gastro-oesophageal reflux, induce intestinal stasis and increase enteral secretion and gastric aspirations. Caffeine treatment may also reduce splanchnic blood flow. These factors may increase the risk of necrotising enterocolitis, although the prevention of systemic hypoxia may offset this theoretical increased risk. No significantly increased incidence of necrotising enterocolitis has been reported in clinical trials.
Caffeine may suppress erythropoietin synthesis and hence reduce haemoglobin concentration with prolonged treatment.
Other adverse effects associated with caffeine are effects on blood glucose levels such as hypoglycaemia and hyperglycaemia, and renal effects including increased urine flow rate, increased sodium and calcium excretion.
Available evidence does not indicate any adverse long-term effects of neonatal caffeine therapy on neurodevelopmental outcome, failure to thrive, or on the cardiovascular, gastrointestinal or endocrine systems. However, the possibility of long-term adverse effects cannot be ruled out.
A withdrawal syndrome after discontinuation of caffeine treatment has not been reported in this age group.
2.9 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.
Pharmacological Properties
3.1 Pharmacodynamic Properties
The pharmacological actions of caffeine result from its effect as a nonspecific adenosine receptor antagonist. The desired respirogenic activity of caffeine is an expression of its central nervous system stimulation, although it may also increase the sensitivity of respiratory response to carbon dioxide levels. Caffeine increases both tidal volume and frequency of ventilation.
In the premature infant, caffeine produced increased minute ventilation, mainly due to an increase in inspiratory drive as shown by an increased mean respiratory flow (Vt/T1).
Caffeine regularises the breathing pattern, indicating that it stabilises the oscillation of the respiratory control system.
Caffeine also inhibits phosphodiesterase, but this effect only occurs at concentrations associated with toxicity, and not at therapeutic concentrations.
Caffeine increases metabolic rate, heart rate, cardiac contractility and output. It also increases blood flow to the kidneys, and prevents sodium and chloride from reabsorbing at the proximal tubules, so mild diuresis can occur.
Adenosine is a vasodilator and therefore caffeine, as its antagonist, can cause vasoconstriction. Hence it is a vasoconstrictor in the cerebral and splanchnic circulations. Elsewhere, it has a vasodilator effect due to an effect on vascular smooth muscle.
The stimulant effect may affect sleep patterns.
3.2 Pharmacokinetic Properties
In neonates, orally administered caffeine has been shown to be rapidly and completely absorbed. Peak plasma levels and extent of absorption are comparable for oral administration and intravenous infusion. In premature infants, the volume of distribution is reported to be 0.8 to 0.9 L/kg. It is widely distributed throughout the body and passes readily into the central nervous system and into saliva.
Neonates, especially premature neonates,
have a greatly reduced capacity to metabolise caffeine and it is largely excreted unchanged in the urine until hepatic metabolism becomes significantly developed, a process which is completed by about 6 months of age. Elimination half-lives may be in excess of 52-96 hours in premature neonates.
Interconversion between caffeine and theophylline has been observed in premature infants. Approximately 3% to 8% of caffeine administered is expected to be converted to theophylline. After theophylline administration, caffeine concentrations are approximately 25% of theophylline concentrations.
The predominant caffeine metabolic process in premature infants appears to be via N7-demethylation.
Low concentrations of caffeine may be present in breast milk of the mother, and it crosses the placenta.
3.3 Preclinical Safety Data
There is no preclinical data of relevance to the prescriber.
Pharmaceutical Particulars
4.1 Incompatibilities
This medical product must not be mixed with other medicinal products except those mentioned in section. 4.4
4.2 Shelf Life
3 years
4.3 Special Precautions for Storage
No special precautions for storage.
4.4 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 Distributed in the UK by:
Martindale Pharmaceuticals, Romford RM3 8UG
MARTINDALE PHARMA
Bampton Road, Harold Hill, Romford, RM3 8UG, UK
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.
f 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.
Accidental overdosage: If too much caffeine solution is accidentally given to your baby, the side effects described above may become more noticeable. In cases of very high overdosage, fits can also occur. If signs of over dosage are noticed, please tell the baby's doctor immediately.
. Storing Caffeine Citrate 10mg/ml Solution for Injection
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 abel, or if there are any signs of discolouration or clouding of the solution.
. Further Information
What Caffeine Citrate 10mg/ml Solution for Injection contains
The active ingredient is caffeine citrate 10mg/ml, equivalent to 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 1 ml 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 caffeine.
Each 2ml ampoule of Caffeine Citrate 10mg/ml Solution for Injection contains 20mg of caffeine citrate, equivalent to 10mg caffeine.
Caffeine Citrate 10mg/ml Solution for Injection is available in ampoules of 1 ml or 2ml, in packs of 10 ampoules Marketing authorisation holder Viridian Pharma Ltd,
Yew Tree House,
Hendrew Lane,
Llandevaud,
Newport,
Gwent NP18 2AB Manufacturer
Martindale Pharmaceuticals, Bampton Road, Harold Hill, Romford, Essex RM3 8UG This leaflet was last revised in July 2013 Marketing Authorisation Number: 20346/0002
Distributed in the UK by:
Martindale Pharmaceuticals, Romford RM3 8UG
M
MARTINDALE PHARMA
Bampton Road, Harold Hill, Romford, RM3 8UG, UK
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