Peyona (Previously Nymusa)

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 dose regimen in previously untreated infants is a loading dose of 20 mg caffeine citrate per kg body weight administered by slow intravenous infusion over 30 minutes, using a syringe infusion pump or other metered infusion device.

After an interval of 24 hours, maintenance doses of 5 mg per kg body weight may be administered by slow intravenous infusion over 10 minutes every 24 hours. Alternatively, maintenance doses of 5 mg per kg body weight may be administered by oral administration, such as through a nasogastric tube every 24 hours.

The recommended loading dose and maintenance doses of caffeine citrate are provided in the following table which clarifies the relationship between injection volumes and administered doses expressed as caffeine citrate. The dose expressed as caffeine base is one-half the dose when expressed as caffeine citrate (20 mg caffeine citrate are equivalent to 10 mg caffeine base).

25 mL/kg body weight 5 mg/kg body weight Intravenous infusion (over 10 minutes) or by oral administration Every 24 hours* * Beginning 24 hours after the loading dose 3 In preterm newborn infants with insufficient clinical response to the recommended loading dose, a second loading dose of 10 -20 mg/kg maximum may be given after 24 hours.

2). Where clinically indicated, caffeine plasma levels should be monitored. 4). 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.

5)  infants whose mothers consume caffeine while providing breast milk for feeding. 4)  infants who have previously been treated with theophylline, which is metabolized to caffeine. 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. In clinical practice, treatment is usually continued until the infant has reached a post-menstrual age of 37 weeks, by which time apnoea of prematurity usually resolves spontaneously.

This limit may however be revised according to clinical judgment in individual cases depending on the response to treatment, the continuing presence of apnoeic episodes despite treatment, or other clinical considerations. 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. 4 Hepatic and renal impairment There is limited experience in patients with renal and hepatic impairment.

8). In the presence of renal impairment, there is increased potential for accumulation. A reduced daily maintenance dose of caffeine citrate is required and the dose should be guided by plasma caffeine measurements. In very […]

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. 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).

7 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 Class Adverse Reaction Frequency Infections and infestations Sepsis Not known Immune system disorders Hypersensitivity reaction Rare Hyperglycaemia CommonMetabolism and nutrition disorders Hypoglycaemia, failure to thrive, feeding intolerance Not known Convulsion UncommonNervous system disorders Irritability, jitteriness, restlessness, brain injury Not known Ear and labyrinth disorders Deafness Not known Tachycardia Common Arrhythmia Uncommon Cardiac disorders Increased left ventricular output and increased stroke volume Not known Gastrointestinal disorders Regurgitation, increased gastric aspirate, necrotising enterocolitis Not known General disorders and administration site conditions Infusion site phlebitis, infusion site inflammation Common Investigations Urine output increased, urine sodium and calcium increased, haemoglobin decreased, thyroxine decreased Not 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.

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.

1) did not show an increased frequency of necrotising enterocolitis in the caffeine group when compared to placebo. 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 8 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Apnoea Apnoea of prematurity is a diagnosis of exclusion. , 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.

Failure to respond to caffeine treatment (confirmed if necessary by measurement of plasma levels) could be an indication of another cause of apnoea. 2). 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.

5 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.

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.

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. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

1.