* Brain injury, convulsion and deafness were observed, but were more frequent in the placebo group
**See below
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.
Necrotising enterocolitis
Necrotising enterocolitis is a common cause of morbidity and mortality in premature neonates.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 trial 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 trial 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).
4.9 Overdose
Following overdose, published plasma caffeine levels have ranged from approximately 50 mg/l to 350 mg/l.
Signs and symptoms reported in the literature after caffeine overdose in preterm infants include hyperglycaemia, hypokalaemia, fine tremor of the extremities, restlessness, hypertonia, opisthotonus, tonic clonic movements, seizures, tachypnoea, tachycardia, vomiting, gastric irritation, gastro-intestinal haemorrhage, pyrexia, jitteriness, increased blood urea and 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. No deaths associated with caffeine overdose have been reported in preterm infants.
Treatment of caffeine overdose is primarily symptomatic and supportive. Plasma potassium and glucose concentrations should be monitored and hypokalaemia and hyperglycaemia corrected. Plasma caffeine concentrations have been shown to decrease after exchange transfusion. Convulsions may be treated with intravenous administration of anticonvulsants (diazepam or a barbiturate such as pentobarbital sodium or phenobarbital).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacother