International Approvals

International Approvals: NovoRapid, Fentanyl, Atriance

Yael Waknine

September 24, 2007 — The European Commission (EC) has approved insulin aspart subcutaneous injection for use in the elderly and patients with renal or hepatic impairment; the Japanese Ministry of Health, Labor, and Welfare has approved fentanyl citrate 0.1- and 0.25-mg injections for use in pediatric patients aged 2 years and younger; and the EC has approved nelarabine intravenous infusion for the treatment of refractory and relapsed T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

Insulin Aspart (NovoRapid) for Use in Elderly Patients in EU

On September 20, the European Commission approved an expanded indication for insulin aspart subcutaneous injection (NovoRapid, Novo Nordisk), allowing its use for the treatment of types 1 and 2 diabetes in the elderly and in patients with renal or hepatic impairment.

According to the International Diabetes Federation, approximately 20% of the world's elderly population has diabetes, and that figure is steadily rising, the company said in a news release. Insulin aspart is the only rapid-acting, modern insulin approved for use in this population.

Insulin aspart previously was approved by the EC for use in children aged 2 years and older and pregnant women. Marketed as NovoLog in the United States, it has been approved by the US Food and Drug Administration for the control of hyperglycemia in diabetic patients, with the caveats that its benefits should justify the risk to the fetus during pregnancy and that lower doses may be required in the setting of renal or hepatic impairment.

Fentanyl Injection for Use in Children Aged Less Than 2 Years in Japan

On August 28, the Japanese Ministry of Health, Labor, and Welfare (MHLW) approved an expanded indication for fentanyl citrate 0.1- and 0.25-mg injections (Daiichi Sankyo Company, Ltd), allowing use of the drug in pediatric patients aged 2 years and younger.

According to a company news release, the approval was based on data from a physician-led phase 3 trial that demonstrated the drug's safety in children and infants.

Fentanyl injection is approved by the MHLW and the US Food and Drug Administration (FDA) for use as a short-term analgesic during anesthetic periods, induction/maintenance, and immediate postoperative period; as a narcotic analgesic supplement in general/regional anesthesia; and as an anesthetic agent with oxygen in high-risk patients. It also may be used with a neuroleptic as an anesthetic premedication, for the induction of anesthesia, and as an adjunct in the maintenance of general/regional anesthesia.

Although the FDA does not contraindicate use of fentanyl injection in children aged less than 2 years, the safety labeling states that rare cases of unexplained clinically significant methemoglobinemia have occurred in premature neonates undergoing emergency anesthesia and surgery that included combined use of fentanyl, pancuronium, and atropine. A direct cause between use of these drugs and methemoglobinemia has not been established.

Nelarabine Injection (Atriance) for Refractory T-ALL and T-LBL in EU

On August 28, the European Commission approved nelarabine intravenous injection (Atriance, GlaxoSmithKline) for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in patients who have not responded to or have relapsed after treatment with at least 2 chemotherapy regimens. The approval is valid in all 27 member states of the European Union, with identical national licenses usually issued in Norway, Iceland, and Liechtenstein.

Nelarabine is a prodrug of arabinosylguanine with T-cell selectivity. The nucleoside analog is converted into arabinosylguanine nucleotide triphosphate, which inhibits DNA synthesis and induces apoptosis.

The approval was based on complete response rates induced by nelarabine therapy; randomized trials demonstrating increased survival or other clinical benefits have not been conducted.

Data from 2 multicenter, phase 2 clinical studies of single-agent therapy of nelarabine in relapsed/refractory patients (28 adults, 39 children) showed that 21% of adults and 23% of children achieved a complete response (defined as the disappearance of all detectable signs of disease) both with and without full hematologic recovery. One adult and 4 children went on to receive a stem cell transplant; median overall survival after nelarabine therapy was 21 and 13 weeks in adults and children, respectively.

These findings were supported by those of a German ALL Study Group trial (n = 57), in which 47% of patients treated with nelarabine achieved remission and 74% of those demonstrating complete response were transferred to a stem cell transplant.

Hematologic toxicity was the most common moderate-to-severe (grade 3 – 4) nelarabine-associated adverse event. As with other cytotoxic agents, nelarabine is associated with treatment-limiting neurologic adverse events; close monitoring of patients is recommended, and dosing should be discontinued if neurologic events of grade 2 or greater severity occur.

The recommended regimen for nelarabine in adults is 1500 mg/m², administered intravenously over 2 hours on days 1, 3, and 5 and repeated every 21 days. Pediatric patients should be given 650 mg/m² intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days.

Nelarabine (marketed as Arranon) previously was approved for this indication by the US Food and Drug Administration in October 2005.
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