Caffeine citrate

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Cafnea (Phebra)
2 mL vials containing 40 mg/2 mL for injection and 7 mL vials containing 25 mg/5 mL oral solution
Approved indication: apnoea of pre-maturity
Australian Medicines Handbook section 19

Premature babies are at risk of apnoea. This can occur in the absence of other problems, such as infection. Primary apnoea appears between two and seven days after birth and is most common in premature babies with a low birth weight. If the apnoea of pre-maturity is recurrent and prolonged, ventilation may be needed. Methylxanthines such as theophylline have been used as respiratory stimulants. Caffeine is also a methylxanthine and it has been used overseas to treat the apnoea of pre-maturity.

The mechanism of action is uncertain, but caffeine is thought to increase the response to hypercapnia and increase the respiratory rate. A loading dose is given intravenously over 30 minutes. The subsequent daily maintenance doses can be given intravenously or by mouth. Some of the dose is converted to theophylline, but this occurs slowly in premature babies. The half-life of caffeine in these babies is 80-120 hours. Most of the dose is excreted unchanged in the urine.

A study compared caffeine citrate with placebo in 82 babies, born between 25 and 32 weeks of gestation, who were having at least six episodes of apnoea in 24 hours. Over 7-10 days 69% of the caffeine group, but only 43% of the placebo group, achieved at least a 50% reduction in episodes of apnoea.¹

A larger placebo-controlled study included babies with birth weights of 500-1250 g. The 2006 babies had an average gestational age of 27 weeks. Many were being treated for apnoea, but some babies were given treatment to prevent apnoea or to assist the removal of an endotracheal tube. The first doses were given at a median age of 28 weeks and were stopped before 35 weeks. Supplemental oxygen was needed by 36% of the babies given caffeine citrate and 47% of those given a placebo. Compared to the placebo group, babies given caffeine citrate were significantly less likely to require surgical closure of a patent ductus arteriosus.²

Babies given caffeine may initially gain less weight than other premature babies. Most adverse effects are probably related to the stimulant action of caffeine. They include tachycardia, tachypnoea and jitteriness. Maternal consumption of caffeine should be considered when prescribing caffeine citrate.

Premature babies are very vulnerable patients. In long-term follow-up, 40% of the babies given caffeine died or survived with a neuro developmental disability. This was a statistically better outcome than the 46% rate seen in the placebo group. To prevent one adverse outcome 16 babies need to be treated for 37 days. Much of the benefit of caffeine is from earlier discontinuation of positive airways pressure.³

The results of the larger study are difficult to interpret because of the different indications for giving caffeine. In Australia the use of caffeine citrate will be restricted to the short-term treatment of the apnoea of pre-maturity in babies between 28 and 33 weeks of gestational age.

manufacturer provided the clinical evaluation

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Note on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).