GENCEBOK Solution for infusion Ref.[49869] Active ingredients: Caffeine

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 (10 mg caffeine citrate are equivalent to 5 mg caffeine base).

^* Beginning 24 hours after the loading dose

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. Higher maintenance doses of 10 mg/kg body weight could be considered in case of insufficient response, taking into account the potential for accumulation of caffeine due to the long half-life in preterm newborn infants and the progressively increasing capacity to metabolise caffeine in relation to post-menstrual age (see section 5.2). Where clinically indicated, caffeine plasma levels should be monitored. The diagnosis of apnoea of prematurity may need to be reconsidered if patients do not respond adequately to a second loading dose or maintenance dose of 10 mg/kg/day (see section 4.4).

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.

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.

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.

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, 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 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 infants, hepatic disease may indicate a need for monitoring caffeine plasma levels and may require dose adjustments (see sections 4.4 and 5.2).

Method of administration

Caffeine citrate can be administered by intravenous infusion and by the oral route. The medicinal product must not be administered by intramuscular, subcutaneous, intrathecal or intraperitoneal injection.

When given intravenously, caffeine citrate should be administered by controlled intravenous infusion, using a syringe infusion pump or other metered infusion device only. Caffeine citrate can be either used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%), or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule (see section 6.6).

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

Symptoms

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, gastrointestinal 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.

Management

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).

3 years.

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

Chemical and physical compatibility of the diluted solution has been demonstrated for 24 hours at 25ºC.

From a microbiological point of view, when administered with solutions for infusion the medicinal product should be used immediately after dilution by aseptic technique.

This medicinal product does not require any special storage condition.

For storage conditions of the diluted medicinal product, see section 6.3.

Type I clear glass 1 ml ampoule coded by 2 blue rings.

Pack size of 50 ampoules.

Aseptic technique must be strictly observed throughout handling of the medicinal product since no preservative is present.

Gencebok should be inspected visually for particulate matter and discoloration prior to administration. Ampoules containing discoloured solution or visible particulate matter should be discarded.

Gencebok can be either used without dilution or diluted in sterile solutions for infusion such as glucose 50 mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) or calcium gluconate 100 mg/ml (10%) immediately after withdrawal from the ampoule.

The diluted solution must be clear and colourless. Undiluted and diluted parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration. The solution must not be used if it is discoloured or foreign particulate matter is present.

For single use only. Any unused portion left in the ampoule should be discarded. Unused portions should not be saved for later administration.

No special requirements for disposal.