1. NAME OF THE MEDICINAL PRODUCT
    Caffeine Citrate 10mg/ml Solution for Injection Taj Pharma
    Caffeine Citrate 20mg/ml Solution for Injection Taj Pharma
  2. QUALITATIVE AND QUANTITATIVE COMPOSITION
    Caffeine Citrate 10mg/ml Solution for Injection Taj Pharma
    Each 1ml Ampoule Contains:
    Caffeine Citrate                 10mg
    Equivalent to Caffiene       5mg
    Water for Injection             q.s.Caffeine Citrate 20mg/ml Solution for Injection Taj Pharma
    Each 1ml Ampoule Contains:
    Caffeine Citrate                 20mg
    Equivalent to Caffiene       10mg
    Water for Injection             q.s.
  3. For the full list of excipients, see section 6.1.
    1. PHARMACEUTICAL FORM

    Solution for Injection

    1. CLINICAL PARTICULARS

    4.1 Therapeutic indications

    Treatment of apnoea of prematurity.

    4.2 Posology and method of administration

    Treatment with caffeine citrate should be initiated under the supervision of a physician experienced in neonatal intensive care. Treatment should be administered only in a neonatal intensive care unit in which adequate facilities are available for patient surveillance and monitoring.

    Posology

    The recommended doses of Caffeine Citrate 10mg/ml, 20mg/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 4.4 below)

    (c) Caffeine Citrate 10mg/ml, 20mg/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 InjectionDose Expressed as Caffeine CitrateDose Expressed as Caffeine BaseRouteFrequency
    Loading Dose

    See (b) above

    2ml/kg20 mg/kg10mg/kgIntravenous** (over 30 min) or oralOnce
    Maintenance Dose0.5-1ml/kg*5-10mg/kg*2.5-5.0mg/kg*Intravenous** (over 10 min) or oralEvery 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)

    ** By intravenous infusion

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

    Dosage, adjustments and monitoring

    Plasma concentrations of caffeine may need to be monitored periodically throughout treatment in cases of incomplete clinical response or signs of toxicity.

    Additionally, doses may need to be adjusted according to medical judgment following routine monitoring of caffeine plasma concentrations in at risk situations such as:

    – very premature infants (< 28 weeks gestational age and/or body weight <1000 g) particularly when receiving parenteral nutrition

    – infants with hepatic and renal impairment (see sections 4.4 and 5.2)

    – infants with seizure disorders

    – infants with known and clinically significant cardiac disease

    – infants receiving co-administration of medicinal products known to interfere with caffeine metabolism (see section 4.5)

    – infants whose mothers consume caffeine while providing breast milk for feeding.

    It is advisable to measure baseline caffeine levels in:

    – infants whose mothers may have ingested large quantities of caffeine prior to delivery (see section 4.4)

    – infants who have previously been treated with theophylline, which is metabolized to caffeine.

    Caffeine has a prolonged half-life in premature newborn infants and there is potential for accumulation which may necessitate monitoring infants treated for an extended period (see section 5.2). Blood samples for monitoring should be taken just before the next dose in the case of therapeutic failure and 2 to 4 hours after the previous dose when suspecting toxicity.

    Although a therapeutic plasma concentration range of caffeine has not been determined in the literature, caffeine levels in studies associated with clinical benefit ranged from 8 to 30 mg/l and no safety concerns have normally been raised with plasma levels below 50 mg/l.

    Duration of treatment

    The optimal duration of treatment has not been established. In a recent large multicentre study on preterm newborn infants a median treatment period of 37 days was reported.

    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.

    Please see Section 4.4 below regarding use of the filter straws.

    It is recommended that caffeine citrate administration should be stopped when the patient has 5-7 days without a significant apnoeic attack. If the patient has recurrent apnoea, caffeine citrate administration can be restarted with either a maintenance dose or a half loading dose, depending upon the time interval from stopping caffeine citrate to recurrence of apnoea.

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

    As there is a risk for recurrence of apnoeas after cessation of caffeine citrate treatment monitoring of the patient should be continued for approximately one week.

    Hepatic and renal impairment

    There is limited experience in patients with renal and hepatic impairment. In a post authorisation safety study, the frequency of adverse reactions in a small number of very premature infants with renal/hepatic impairment appeared to be higher as compared to premature infants without organ impairment (see sections 4.4 and 4.8).

    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 indicate a need for monitoring plasma levels and may require dose adjustments (see sections 4.4 and 5.2).

    Adults and Children

    Not applicable

    Elderly

    Not applicable

    Method of administration

    Caffeine Citrate 10mg/ml 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.

    4.3 Contraindications

    Hypersensitivity to caffeine citrate or to any of the excipients listed in section 6.1

    4.4 Special warnings and precautions for use

    Apnoea

    Apnoea of prematurity is a diagnosis of exclusion. Other causes of apnoea (e.g., central nervous system disorders, primary lung disease, anaemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnoea) should be ruled out or properly treated prior to initiation of treatment with caffeine citrate.

    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 5.2).

    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 50micrograms/ml (optimally 10-30micrograms/ml).

    Caffeine consumption

    In newborn infants born to mothers who consumed large quantities of caffeine prior to delivery, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate, since caffeine readily crosses the placenta into the foetal circulation (see sections 4.2 and 5.2).

    Breast-feeding mothers of newborn infants treated with caffeine citrate should not ingest caffeine-containing foods and beverages or medicinal products containing caffeine (see section 4.6), since caffeine is excreted into breast milk (see section 5.2).

    Theophylline

    In newborns previously treated with theophylline, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate because preterm infants metabolise theophylline to caffeine.

    Seizures

    Caffeine is a central nervous system stimulant and seizures have been reported in cases of caffeine overdose. Extreme caution must be exercised if caffeine citrate is used in newborns with seizure disorders.

    Cardiovascular reactions

    Caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, caffeine citrate should be used with caution in newborns with known cardiovascular disease. There is evidence that caffeine causes tachyarrhythmias in susceptible individuals. In newborns this is usually a simple sinus tachycardia. If there have been any unusual rhythm disturbances on a cardiotocograph (CTG) trace before the baby is born, caffeine citrate should be administered with caution.

    Renal and hepatic impairment

    Caffeine citrate should be administered with caution in preterm newborn infants with impaired renal or hepatic function. In a post-authorisation safety study, the frequency of adverse reactions in a small number of very premature infants with renal/hepatic impairment appeared to be higher as compared to premature infants without organ impairment (see sections 4.2, 4.8 and 5.2). Doses should be adjusted by monitoring of caffeine plasma concentrations to avoid toxicity in this population.

    Necrotising enterocolitis

    Necrotising enterocolitis is a common cause of morbidity and mortality in premature newborn infants. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.8).

    Caffeine citrate should be used with caution in infants suffering gastro-oesophageal reflux, as the treatment may exacerbate this condition.

    Caffeine citrate 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 citrate may necessitate correction of fluid and electrolyte disturbances.

    Use of filter straws

    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.

    Caffeine Citrate 10mg/ml Injection contains sodium

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

    4.5 Interaction with other medicinal products and other forms of interaction

    Cytochrome P450 1A2 (CYP1A2) is the major enzyme involved in the metabolism of caffeine in humans. Therefore, caffeine has the potential to interact with active substances that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. However, caffeine metabolism in preterm newborn infants is limited due to their immature hepatic enzyme systems.

    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.

    Although few data exist on interactions of caffeine with other active substances in preterm newborn infants, lower doses of caffeine citrate may be needed following co-administration of active substances which are reported to decrease caffeine elimination in adults (e.g., cimetidine and ketoconazole) and higher caffeine citrate doses may be needed following co-administration of active substances that increase caffeine elimination (e.g., phenobarbital and phenytoin). Where doubt exists about possible interactions, plasma caffeine concentrations should be measured.

    As bacterial overgrowth in the gut is associated with the development of necrotising enterocolitis, co-administration of caffeine citrate with medicinal products that suppress gastric acid secretion (antihistamine H2 receptor blockers or proton-pump inhibitors) may in theory increase the risk of necrotising enterocolitis (see section 4.4 and 4.8).

    Concurrent use of caffeine and doxapram might potentiate their stimulatory effects on the cardio-respiratory and central nervous system. If concurrent use is indicated, cardiac rhythm and blood pressure must be carefully monitored.

    4.6 Fertility, pregnancy and lactation

    Fertility

    Effects on reproductive performance observed in animals are not relevant to its indication in the preterm newborn infants (see section 5.3).

    Pregnancy

    Caffeine in animal studies, at high doses, was shown to be embryotoxic and teratogenic. These effects are not relevant with regard to short term administration in the preterm infant population (see section 5.3).

    Breast-feeding

    Caffeine is excreted into breast milk and readily crosses the placenta into the foetal circulation (see section 5.2).

    Breast-feeding mothers of newborn infants treated with caffeine citrate should not ingest caffeine-containing foods, beverages or medicinal products containing caffeine.

    In newborn infants born to mothers who consumed large quantities of caffeine prior to delivery, baseline plasma caffeine concentrations should be measured prior to initiation of treatment with caffeine citrate (see section 4.4).

    4.7 Effects on ability to drive and use machines

    Not applicable

    4.8 Undesirable effects

    Summary of the safety profile

    The known pharmacology and toxicology of caffeine and other methylxanthines predict the likely adverse reactions to caffeine citrate. Effects described include central nervous system (CNS) stimulation such as convulsion, irritability, restlessness and jitteriness, cardiac effects such as tachycardia, arrhythmia, hypertension and increased stroke volume, metabolism and nutrition disorders such as hyperglycaemia. These effects are dose related and may necessitate measurement of plasma levels and dose reduction.

    They are generally, although not exclusively, associated with serum caffeine concentrations ≥50micrograms/ml.

    Tabulated list of adverse reactions

    The adverse reactions described in the short- and long-term published literature and obtained from a post-authorisation safety study that can be associated with caffeine citrate are listed below by System Organ Class and Preferred Term (MedDRA).

    Frequency is defined as: 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) and not known (cannot be estimated from the available data).

    System Organ ClassAdverse ReactionFrequency
    Infections and infestationsSepsisNot known
    Immune system disordersHypersensitivity reactionRare
    Metabolism and nutrition disordersHyperglycaemiaCommon
    Hypoglycaemia, failure to thrive, feeding intoleranceNot known
    Nervous system disordersConvulsionUncommon
    Irritability, jitteriness, restlessness, brain injuryNot known
    Ear and labyrinth disordersDeafnessNot known
    Cardiac disordersTachycardiaCommon
    ArrhythmiaUncommon
    Increased left ventricular output and increased stroke volumeNot known
    Gastrointestinal disordersRegurgitation, increased gastric aspirate, necrotising enterocolitisNot known
    General disorders and administration site conditionsInfusion site phlebitis, infusion site inflammationCommon
    InvestigationsUrine output increased, urine sodium and calcium increased, haemoglobin decreased, thyroxine decreasedNot known

    Description of selected adverse reactions

    Necrotising enterocolitis is a common cause of morbidity and mortality in premature newborn infants. There are reports of a possible association between the use of methylxanthines and development of necrotising enterocolitis. However, a causal relationship between caffeine or other methylxanthine use and necrotising enterocolitis has not been established.

    In a double-blind placebo-controlled study of caffeine citrate in 85 preterm infants (see section 5.1), necrotising enterocolitis was diagnosed in the blinded phase of the study in two infants on active treatment and one on placebo, and in three infants on caffeine during the open-label phase of the study. Three of the infants who developed necrotising enterocolitis during the study died. A large multicentre study (n=2006) investigating long-term outcome of premature infants treated with caffeine citrate (see section 5.1) did not show an increased frequency of necrotising enterocolitis in the caffeine group when compared to placebo. As for all preterm infants, those treated with caffeine citrate should be carefully monitored for the development of necrotising enterocolitis (see section 4.4). Brain injury, convulsion and deafness were observed but they were more frequent in the placebo group.

    Caffeine may suppress erythropoietin synthesis and hence reduce haemoglobin concentration with prolonged treatment.

    Transient falls in thyroxine (T4) have been recorded in infants at the start of therapy but these are not sustained with maintained therapy.

    Available evidence does not indicate any adverse long-term reactions of neonatal caffeine therapy as regards neurodevelopmental outcome, failure to thrive or on the cardiovascular, gastrointestinal or endocrine systems. Caffeine does not appear to aggravate cerebral hypoxia or to exacerbate any resulting damage, although the possibility cannot be ruled out.

    Other special populations

    In a post-authorisation safety study on 506 preterm infants treated with Peyona, safety data have been collected in 31 very premature infants with renal/hepatic impairment. Adverse reactions appeared to be more frequent in this subgroup with organ impairment than in other observed infants without organ impairment. Cardiac disorders (tachycardia, including one single case of arrhythmia) were mostly reported.

    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.

    4.9 Overdose

    Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to 350 mg/l.

    Symptoms

    Signs and symptoms of overdosage from these reports include jitteriness, tachycardia, tachypnoea, tremor, opisthotonos, rigidity and tonic-clonic movements, hypokalaemia, , restlessness, , gastric irritation, gastro-intestinal haemorrhage, increased white blood cell count, non-purposeful jaw and lip movements. One case of caffeine overdose complicated by development of intraventricular haemorrhage and long-term neurological sequelae has been reported. 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. No deaths associated with caffeine overdose have been reported in preterm infants.

    Management

    Treatment of overdosage should include monitoring of blood levels of caffeine and supportive measures. Plasma potassium and glucose concentrations should be monitored and hypokalaemia and hyperglycaemia corrected.

    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.

    Convulsions may be treated with intravenous administration of anticonvulsants (diazepam or a barbiturate such as pentobarbital sodium or phenobarbital).

    1. PHARMACOLOGICAL PROPERTIES

    5.1 Pharmacodynamic properties

    Pharmacotherapeutic group: Psychoanaleptics xanthine derivatives.

    Mechanism of action

    Caffeine is structurally related to the methylxanthines theophylline and theobromine. Most of its effects have been attributed to antagonism of adenosine receptors, both A1 and A2A subtypes, demonstrated in receptor binding assays and observed at concentrations approximating those achieved therapeutically in this indication.

    Pharmacodynamic effects

    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 (VΤ/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.

    Clinical efficacy and safety

    The clinical efficacy of caffeine citrate was assessed in a multicentre, randomised, double-blind study that compared caffeine citrate to placebo in 85 preterm infants (gestational age 28 to < 33 weeks) with apnoea of prematurity. Infants received 20 mg/kg caffeine citrate loading dose intravenously. A maintenance daily dose of 5 mg/kg caffeine citrate was then administered either intravenously or orally (through a feeding tube) for up to 10-12 days. The protocol allowed infants to be “rescued” with open-label caffeine citrate treatment if their apnoea remained uncontrolled. In that case, infants received a second loading dose of 20 mg/kg caffeine citrate after treatment day 1 and before treatment day 8.

    There were more days without any apnoea under caffeine citrate treatment (3.0 days, versus 1.2 days for placebo; p=0.005); also, there was a higher percentage of patients with no apnoeas for > 8 days (caffeine 22% versus placebo 0%).

    A recent large placebo-controlled multicentre study (n=2006) investigated short-term and long-term (18-21 months) outcomes of premature infants treated with caffeine citrate. Infants randomised to caffeine citrate received an intravenous loading dose of 20 mg/kg, followed by a daily maintenance dose of 5 mg/kg. If apnoeas persisted, the daily maintenance dose could be increased to a maximum of 10 mg/kg of caffeine citrate. The maintenance doses were adjusted weekly for changes in body weight and could be given orally once an infant tolerated full enteral feedings. Caffeine therapy reduced the rate of bronchopulmonary dysplasia [odds ratio (95%CI) 0.63 (0.52 to 0-76)] and improved the rate of survival without neurodevelopmental disability [odds ratio (95%CI) 0.77 (0.64 to 0.93)].

    The size and direction of caffeine effect on death and disability differed depending on the degree of respiratory support infants needed at randomisation, indicating more benefit for the supported infants [odds ratio (95%CI) for death and disability, see table below].

    Death or disability according to subgroup of respiratory support at entry to study

    SubgroupsOdds ratio (95% CI)
    No support1.32 (0.81 to 2.14)
    Non invasive support0.73 (0.52 to 1.03)
    Endotracheal tube0.73 (0.57 to 0.94)

    5.2 Pharmacokinetic properties

    Caffeine citrate readily dissociates in aqueous solution. The citrate moiety is rapidly metabolized on infusion or ingestion.

    Absorption

    The onset of action of caffeine from caffeine citrate is within minutes of commencement of infusion. In neonates, orally administered caffeine has been shown to be rapidly and completely absorbed. After oral administration of 10 mg caffeine base/kg body weight to preterm newborn infants, the peak plasma caffeine concentration (Cmax) ranged from 6 to 10 mg/l and the mean time to reach peak concentration (tmax) ranged from 30 min to 2 h. The extent of absorption is not affected by formula feeding but tmax may be prolonged.

    Distribution

    Caffeine is rapidly distributed into the brain following caffeine citrate administration. Caffeine concentrations in the cerebrospinal fluid of preterm newborn infants approximate to their plasma levels. The mean volume of distribution (Vd) of caffeine in infants (0.8-0.9 l/kg) is slightly higher than that in adults (0.6 L/kg). Plasma protein binding data are not available for newborn infants or infants. In adults, the mean plasma protein binding in vitro is reported to be approximately 36%.

    Caffeine readily crosses the placenta into the fetal circulation and is excreted into breast milk.

    Biotransformation

    Caffeine metabolism in preterm newborn infants is very limited due to their immature hepatic enzyme systems and most of the active substance is eliminated in urine. Hepatic cytochrome P450 1A2 (CYP1A2) is involved in caffeine biotransformation in older individuals.

    Inter-conversion between caffeine and theophylline has been reported in preterm newborn infants; caffeine levels are approximately 25% of theophylline levels after theophylline administration and approximately 3-8% of caffeine administered would be expected to convert to theophylline.

    Elimination

    In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. In newborn infants, caffeine clearance is almost entirely by renal excretion. Mean half-life (t1/2) and fraction excreted unchanged in urine (Ae) of caffeine in infants are inversely related to gestational / postmenstrual age. In newborn infants, the t1/2 is approximately 3-4 days and the Ae is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine approximates to that seen in adults (t1/2 = 5 hours and Ae = 1%).

    Studies examining the pharmacokinetics of caffeine in newborn infants with hepatic or renal insufficiency have not been conducted.

    In the presence of significant renal impairment, considering the increased potential for accumulation, a reduced daily maintenance dose of caffeine is required and the doses should be guided by blood caffeine measurements. In premature infants with cholestatic hepatitis a prolonged caffeine elimination half-life with an increase of plasma levels above the normal limit of variation has been found suggesting a particular caution in the dosage of these patients (see sections 4.2 and 4.4).

    5.3 Preclinical safety data

    Non- clinical data revealed no major hazard for humans based on studies of repeated dose toxicity of caffeine. However, at high doses convulsions in rodents were induced. At therapeutic doses some behavioural changes in newborn rats were induced, most likely as a consequence of increased adenosine receptor expression that persisted into adulthood. Caffeine was shown to be devoid of mutagenic and oncogenic risk. Teratogenic potential and effects on reproductive performance observed in animals are not relevant to its indication in the preterm infant population.

    1. PHARMACEUTICAL PARTICULARS

    6.1 List of excipients

    Water for Injections, Sodium Hydroxide, Dilute Hydrochloric Acid, Sodium Chloride, Citric Acid.

    6.2 Incompatibilities

    This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

    6.3 Shelf life

    2 years

    After opening the ampoule, the medicinal product should be used immediately.

    6.4 Special precautions for storage

    No special precautions for storage.

    6.5 Nature and contents of container

    Type I clear glass ampoule containing 1ml or 2ml in packs of 10 ampoules.

    6.6 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.

    1. Manufactured in India by:
      TAJ PHARMACEUTICALS LTD.
      Mumbai, India
      Unit No. 214.Old Bake House,
      Maharashtra chambers of  Commerce Lane,
      Fort, Mumbai – 400001
      at:Gujarat, INDIA.
      Customer Service and Product Inquiries:
      1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
      Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
      E-mail: tajgroup@tajpharma.comCaffeine Citrate Solution for Injection 10mg/ml Taj Pharma(Caffeine Citrate Solution for Injection)Patient leaflet: Information for the userPlease 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.
        If your newborn gets any side effects, talk to your baby’s doctor. This includes any possible side effects not listed in this leaflet. See section 4.

      What is in this leaflet:

      1. What Caffeine Citrate 10mg/ml, 20mg/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, 20mg/ml Solution for Injection is used
        4. Possible side effects
        5. How to store Caffeine Citrate 10mg/ml Solution for Injection
        6. Contents of the pack and other information

       

      1. WHAT CAFFEINE CITRATE 10MG/ML, 20MG/ML SOLUTION FOR INJECTION IS AND WHAT IT IS USED FOR
      • Caffeine belongs to a group of medicines known as methylxanthines
      • It is used in the treatment of interrupted breathing in premature babies (primary apnoea of premature newborns).

      These short periods when premature babies stop breathing are due to the baby’s breathing centres not being fully developed. This medicine has been shown to reduce the number of episodes of interrupted breathing in premature newborns.

      1. 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 allergic to caffeine citrate or to any of the other ingredients of this medicine listed in section 6

      Warnings and precautions

      Talk to your baby’s doctor before your newborn is given Caffeine Citrate 10mg/ml, 20mg/ml Solution for Injection if your baby:

      • has liver or kidney disease
      • has had any unusual heart rhythms detected or heart disease
      • suffers from seizures
      • has frequent regurgitation
      • produces more urine than usual
      • has a reduced weight gain or food intake
      • If you (the mother) consumed caffeine prior to delivery

      Other medicines and Caffeine Citrate 10mg/ml solution for injection

      Tell your baby’s doctor if your newborn is taking, have recently taken or might take any other medicines.

      • As with most medicines, Caffeine Citrate 10mg/ml, 20mg/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.
      • 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.
      • Doxapram (used to treat breathing difficulties)
      • Cimetidine (used to treat gastric disease)
      • Ketoconazole (used to treat fungal infections)
      • This medicine may increase the risk for serious intestinal disease with bloody stools (necrotising enterocolitis) when administered with medicines used to treat gastric disease (such as antihistamine H2 receptor blockers or proton-pump inhibitors that reduces gastric acid secretion).

      Pregnancy and breast-feeding

      If you (the mother) are breast-feeding while your infant is treated with Caffeine Citrate 10mg/ml Solution for Injection, you should not drink coffee or take any other high caffeine product as caffeine passes into breast milk.

      Caffeine Citrate 10mg/ml, 20mg/ml Solution for Injection contains sodium

      • Caffeine Citrate 10mg/ml, 20mg/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, 20mg/ml Solution for Injection be filtered before administration. Filters should notthen be used to administer the dose from the syringe.
      1. HOW CAFFEINE CITRATE 10MG/ML, 20MG/ML SOLUTION FOR INJECTION IS USED

      Caffeine Citrate 10mg/ml, 20mg/ml Solution for Injection should only be used in a neonatal intensive care unit in which adequate facilities are available for patient surveillance and monitoring. Treatment should be initiated under supervision of a physician experienced in neonatal intensive care.

      The doctor or nurse will administer Caffeine Citrate 10mg/ml, 20mg/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.

      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

      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.

      Duration of treatment

      Your baby’s doctor will decide exactly how long your newborn must continue therapy with Caffeine Citrate 10mg/ml Solution for Injection. If your baby has 5 to 7 days without apnoea attacks, the doctor will stop treatment.

      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.

      If your baby is given more Caffeine Citrate 10mg/ml, 20mg/ml Solution for Injection than they should

      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.

      Treatment with Caffeine Citrate 10mg/ml, 20mg/ml Solution for Injection should be stopped immediately and your baby’s doctor should treat the overdose.

      If you have any further questions on the use of this medicinal product, ask your baby’s doctor.

      1. POSSIBLE SIDE EFFECTS

      Like all medicines, this medicine can cause side effects, although not everybody gets them. However, it is difficult to distinguish them from frequent complications occurring in premature babies and complications due to the disease.

      While under treatment with Caffeine Citrate 10 mg/ml Solution for Injection, your newborn may experience some of the following reactions:

      Serious side effects

      • serious intestinal disease with bloody stools (necrotising enterocolitis).
      • serious intestinal disease with bloody stools (necrotising enterocolitis).
      • convulsion
      • allergic reactions
      • bloodstream infection (sepsis)

      Other side effects

      Common (may affect up to 1 in 10 people)

      • cardiac disorders such as fast heart beat (tachycardia)
      • increased sugar in blood or serum (hyperglycaemia)

      Uncommon (may affect up to 1 in 100 people)

      • cardiac disorders such as irregular heart beat (arrhythmia)

      Not known (frequency cannot be estimated from the available data)

      • reduced sugar in blood or serum (hypoglycaemia)
      • failure to grow
      • feeding intolerance
      • stimulation of central nervous system such as irritability
      • nervousness and restlessness
      • brain injury
      • deafness
      • regurgitation
      • increase in stomach aspirate
      • increase of urine flow
      • increase of certain urine components (sodium and calcium)
      • changes in blood tests (reduced levels of haemoglobin after prolonged treatment)
      • reduced thyroid hormone at the start of treatment

      Reporting of side effects

      If your newborn gets any side effects, talk to your baby’s doctor. This includes any possible side effects not listed in this leaflet.

      1. HOW TO STORE CAFFEINE CITRATE 10MG/ML SOLUTION FOR INJECTION

      Keep this medicine out of the sight and reach of children. There are no other special conditions of storage. After opening the ampoule, the medicinal product should be used immediately.

      Do not use this medicine after the expiry date which is stated on the label, or if there are any signs of discolouration or clouding of the solution.

      The expiry date refers to the last day of that month. Ampoules of all parenteral solutions must be inspected visually for particulate matter prior to administration. After opening the ampoules, the medicinal product should be used immediately.

      1. CONTENTS OF THE PACK AND OTHER INFORMATION

      What Caffeine Citrate 10mg/ml Solution for Injection contains

      Caffeine Citrate 10mg/ml Solution for Injection Taj Pharma
      Each 1ml Ampoule Contains:
      Caffeine Citrate                 10mg
      Equivalent to Caffiene       5mg
      Water for Injection             q.s.

      Each 1ml Ampoule Contains:
      Caffeine Citrate                 20mg
      Equivalent to Caffiene       10mg
      Water for Injection             q.s.

      Other ingredients are: Water for Injections, Sodium Hydroxide, Dilute Hydrochloric Acid, Sodium Chloride, Citric Acid.

      What Caffeine Citrate 10mg/ml, 20mg/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, 20mg/ml Solution for Injection is available in ampoules of 1ml or 2ml, in packs of 10 ampoules

      1. Manufactured in India by:
        TAJ PHARMACEUTICALS LTD.
        Mumbai, India
        Unit No. 214.Old Bake House,
        Maharashtra chambers of  Commerce Lane,
        Fort, Mumbai – 400001
        at:Gujarat, INDIA.
        Customer Service and Product Inquiries:
        1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
        Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
        E-mail: tajgroup@tajpharma.com