International Approvals: Byetta and Noxafil

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International Approvals: Byetta and Noxafil

Medscape

Yael Waknine

http://www.medscape.com/viewarticle/548360

November 28, 2006 — The European Commission has approved exenatide

injection as adjunctive therapy to improve glycemic control in

diabetic patients who are inadequately controlled with metformin

and/or a sulfonylurea; and a new indication for posaconazole oral

suspension, allowing its use in the treatment of oropharyngeal

candidiasis.

Exenatide (Byetta) as Adjunctive Diabetic Therapy in the EU

On November 21, the European Commission (EC) approved exenatide

injection (Byetta, made by Amylin Pharmaceuticals, Inc, and Eli

Lilly and Co) for use as adjunctive therapy to improve glycemic

control in patients with type 2 diabetes mellitus who have not

achieved adequate control with maximally tolerated doses of

metformin and/or a sulfonylurea. According to a news release, the

companies anticipate launching the product in the European market

during 2007.

Exenatide is the first in a new class of drugs known as incretin

mimetics. A functional analog of glucagon-like peptide-1 (GLP-1),

exenatide enhances glucose-dependent insulin secretion and exhibits

other antihyperglycemic actions after its release into the

circulation from the gut.

The GLP-1 system is self-regulated, stimulating insulin release only

in the presence of elevated plasma glucose levels, which reduces the

risk for hypoglycemia. Also, peak serum glucagon levels are

moderated during postprandial hyperglycemic periods without

affecting hormonal response to hypoglycemia. Secondary effects

include decreased gastric emptying rate and food intake. In contrast

with most other therapeutic options for patients with diabetes, use

of exenatide is linked to weight loss.

The EC approval followed a positive opinion adopted on September 21,

2006, by the European Medicines Evaluation Agency and was based on

data collected from 35 studies of nearly 4000 patients in more than

20 countries. In these trials, the addition of 5 or 10 µg of

exenatide per day to existing regimens significantly improved long-

term glycemic control (as evaluated by decreases from baseline in

glycated hemoglobin levels) by lowering both fasting and

postprandial plasma glucose concentrations. Most patients also

experienced progressive reductions in weight, a secondary study end

point.

In 3 comparative studies, exenatide was found to control blood sugar

as effectively as several types of insulin often used in patients

who fail to respond to oral agents. Moreover, exenatide therapy was

associated with mean weight loss rather than the gain observed in

insulin-treated patients.

Adverse events related to exenatide therapy were generally mild to

moderate in intensity, with dose-dependent nausea most commonly

reported. Most patients experienced a decrease in the frequency and

severity of nausea with continued therapy.

Exenatide is self-administered as a fixed-dose 5- or 10-µg

subcutaneous injection via prefilled pen device prior to morning and

evening meals; treatment should be initiated at the 5-µg twice-daily

dose and then increased after 1 month to 10 µg twice daily to

further improve glycemic control. No dose adjustments are required

based on the effects of exercise, food intake, or blood glucose

monitoring results.

Exenatide was previously approved by the US Food and Drug

Administration on April 28, 2005.

Posaconazole Oral Suspension (Noxafil) for the Treatment of

Oropharyngeal Candidiasis

On November 9, the European Commission approved a new indication for

posaconazole 40-mg/mL oral suspension (Noxafil, made by Schering-

Plough Corp), allowing its use for the treatment of oropharyngeal

candidiasis (including cases that are refractory to itraconazole

and/or fluconazole therapy) in the European Union's 25 member

states, as well as Iceland and Norway.

The approval was based primarily on a study of HIV-infected patients

with oropharyngeal candidiasis, which showed that posaconazole

therapy achieved similar rates of clinical success (complete or

partial resolution of all ulcers and/or plaques and symptoms) and

mycologic eradication (absence of colony-forming units) at 14 days

compared with fluconazole (91.7% vs 92.5% and 52.1% vs 50.0%,

respectively). Clinical and mycologic relapse rates at 4 weeks

posttherapy were also comparable between groups (29.0% vs 35.1% and

55.6% vs 63.7%, respectively).

The recommended dosing regimen for patients with oropharyngeal

candidiasis consists of a 100-mg (2.5-mL) twice-daily loading dose

on the first day, followed by a 100-mg once-daily dose for 13 days.

Those with refractory oropharyngeal candidiasis do not require a

loading dose and should receive 400 mg of posaconazole (10 mL) twice

daily for a period deemed consistent with the severity of underlying

disease and clinical response.

To optimize posaconazole absorption and plasma concentrations, each

dose should be taken with a full meal or nutritional supplement.

Patients who are unable to eat a full meal or tolerate

supplementation should receive alternative antifungal therapy or be

closely monitored for breakthrough fungal infections.

Because cimetidine, rifabutin, and phenytoin can decrease

posaconazole plasma concentrations, their coadministration should

generally be avoided unless the benefit outweighs the potential risk

for breakthrough infection.

Concomitant use of posaconazole with the cytochrome-P450 3A4

(CYP3A4) substrates terfenadine, astemizole, cisapride, pimozide,

halofantrine, or quinidine is contraindicated because of the risk

for increased plasma concentrations that can lead to QTc

prolongation and rare occurrences of torsades de pointes.

Coadministration with ergot alkaloids is also contraindicated.

Dose reductions and more frequent clinical monitoring of

cyclosporine, tacrolimus, and sirolimus are recommended on

initiation of posaconazole therapy because of the risk for rare

serious adverse events associated with their increased concentration

in the blood.

Posaconazole was previously approved for this indication by the US

Food and Drug Administration on October 20, 2006. The antifungal

drug is also approved by the EC and FDA for the prophylaxis of

invasive fungal infections in high-risk, severely immunocompromised

adults aged 18 years and older and 13 years and older, respectively,

and by the EC and Australia's Therapeutic Goods Administration for

the treatment of invasive aspergillosis, fusariosis,

chromoblastomycosis, mycetoma, and coccidioidomycosis infections in

adult patients with refractory disease or who are intolerant of

certain commonly used antifungal agents.