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Medical Review(S) Review of Request for Priority Review CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-268 MEDICAL REVIEW(S) REVIEW OF REQUEST FOR PRIORITY REVIEW To: Edward Cox, MD, MPH Director, Office of Antimicrobial Products Through: Renata Albrecht, M.D Director, DSPTP, OAP From: Joette M. Meyer, Pharm.D. Acting Medical Team Leader, DSPTP, OAP NDA: 22-268 Submission Date: 6/27/08 Date Review Completed 7/25/08 Product: Coartem (artemether/lumefantrine) Sponsor: Novartis Pharmaceuticals Corporation East Hanover, NJ Proposed Indication: Treatment of malaria in patients of 5kg body weight and above with acute, uncomplicated infections due to Plasmodium falciparum or mixed infections including P. falciparum Proposed Dosing Regimen: A standard 3-day treatment schedule with a total of 6 doses is recommended and dosed based on bodyweight: 5 kg to < 15 kg: One tablet as an initial dose, 1 tablet again after 8 hours and then 1 tablet twice daily (morning and evening) for the following two days 15 kg to < 25 kg bodyweight: Two tablets as an initial dose, 2 tablets again after 8 hours and then 2 tablets twice daily (morning and evening) for the following two days 25 kg to < 35 kg bodyweight: Three tablets as an initial dose, 3 tablets again after 8 hours and then 3 tablets twice daily (morning and evening) for the following two days 35 kg bodyweight and above: Four tablets as a single initial dose, 4 tablets again after 8 hours and then 4 tablets twice daily (morning and evening) for the following two days Abbreviations A artemether ACT artemisinin-based combination therapy AL artemether-lumefantrine combination AQ amodiaquine AS artesunate AS+AQ artesunate + amodiaquine combination AS+MQ artesunate + mefloquine combination AS+SP artesunate + sulfadoxine-pyrimethamine combination L lumefantrine MAS mefloquine artesunate combination MQ mefloquine SP sulfadoxine-pyrimethamine RCT randomized controlled trial WHO World Health Organization WHO Levels of Evidence for Treatment Guidelines S formal systematic reviews, such as a Cochrane Review, including more than one randomized controlled trial; T comparative trials without formal systematic review; O observational studies (e.g. surveillance or pharmacological data); E expert opinion/consensus. Coartem® (co-artemether; artemether-lumefantrine; also marketed as Riamet® mainly in countries where malaria is not endemic), is a combination of 20 mg artemether (an artemisinin derivative) and 120 mg lumefantrine (a racemic mixture of a synthetic racemic fluorine derivative formerly known as benflumetol). Co-artemether acts as a blood schizonticide and its components show complementary pharmacokinetics and have dissimilar modes of action providing synergistic activity against Plasmodium falciparum. Coartem is registered and available in over 80 countries world wide to treat malaria. The NDA is for registration of the 6-dose regimen of co-artemether in the treatment of acute uncomplicated infections due to Plasmodium falciparum or mixed infections including P. falciparum. The sponsor was granted Fast Track status on January 14, 2008 and began submission of their rolling review in November 2007. On June 19, 2008 the applicant submitted a request for a Priority Review. This stated, in part: For a number of reasons, Coartem will be an important addition to the few medications available in the US to treat malaria. No new treatment for malaria has been approved in the US since 2000. Coartem provides a significant improvement in terms of lack of resistance and patient compliance, has an acceptable safety profile and is a highly effective treatment for a life-threatening parasitological disease. Novartis concurs with your statements cited above [FDA letter granting Fast Track designation] that Coartem will fill an unmet medical need for patients who do not respond to or who may not tolerate other available antimalarials, or who have an infection with P. falciparum that is resistant to other treatments. For these reasons, Novartis requests that the Agency assign Priority Review to the Coartem NDA 22-268.” On July 2, 2008 the division requested further clarification from the applicant: We note in your request for NDA Priority review that you state "Coartem provides a significant improvement in the treatment of life-threatening malaria in terms of lack of resistance and patient compliance, is highly effective, and has an acceptable safety profile. "Coartem meets an unmet medical need for patients unresponsive to or intolerant of other antimalarials." According to the CDER Manual of Policies and Procedures (MaPP) Review Classification Policy: Priority (P) and Standard (S) [6020.3], a determination for Priority review should be based on whether the drug product provides safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement compared to marketed products in treating, preventing, or diagnosing disease. In order to aid in our determination of the designation of Coartem, please provide additional information to address your assertion that Coartem provides a significant improvement compared to marketed products. Significant improvement can be interpreted to mean: 1. Evidence of increased effectiveness in treatment, prevention, or diagnosis of disease 2. Elimination or substantial reduction of a treatment-limiting drug reaction 3. Documented enhancement of patient compliance 4. Evidence of safety and effectiveness in a new subpopulation. Evidence to support your justification can come from clinical trials comparing a marketed product(s) with Coartem or from other scientifically valid information. On July 17, 2008 the applicant submitted additional information, as requested. The updated request focuses on three points: 1. Evidence of increased effectiveness in treatment, prevention, or diagnosis of disease The applicant states: Coartem provides significant improvement over marketed products for malaria in that the product is an artemisin-based combination therapy (ACT), the first to be available in the US, and it shows no resistance to date (Guidelines for the treatment of malaria, WHO, 2006 - Annex 6, Resistance to Antimalarials). This significant improvement is underscored by the World Health Organization’s (WHO) prequalification of Coartem in 2004. To date, one ACT – (Coartem®) – has been pre-qualified. (http://www.rbm.who.int/cmc_upload/0/000/015/364/RBMInfosheet_9.htm#n) The applicant cites the following supporting data: • Guidelines for the Treatment of Malaria, WHO, 2006 • World Health Organization’s (WHO) prequalification of Coartem in 2004. (http://www.rbm.who.int/cmc_upload/0/000/015/364/RBMInfosheet_9.htm#n3) The WHO Guidelines recommend ACTs as the “best current treatment for uncomplicated falciparum malaria.” In addition: Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10 000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented. Reviewer’s Comment: WHO Guidelines cite the superiority of combining oral AS with oral AQ, MQ, or SP vs. oral AS alone based on a meta-analysis. No trial included for A vs. AL is discussed (Annex 7.1). However, in the NDA, Study ABMO2 compares A (46%) vs. 4-dose regimen of AL (94%); p < 0.001 WHO document goes on to state: Reviewer’s Comment: The trial discussed in the table above of AL 6-dose vs. 4-dose regimen in which 6-doses resulted in higher cure rate in one trial in Thailand is Study A025 in the NDA submission. AS+ MQ compared to AL in Thailand submitted as Studies A026 and A028 in the NDA. Study 026: 97% for AL vs. 100% for AS + MQ at 28 days Study 028: 95.5% for AL vs. 100% for AS + MQ at 28 days There are insufficient data on the efficacy of AS + MQ to support a non-inferiority margin. WHO bases support of AS + MQ as first line therapy on these two trials. No other data available. AS+AQ vs. AL in Tanzania – RCT with a 14-day follow-up period; 295 children < 5 years of age Burundi 2001-2002. Clinical and parasitological response at Day 14: 99% [95% CI 98%, 100%] for AL vs. 95% [95% CI 92%, 99%] for AS + AQ; p value not reported. Reference: Ndayiragije A et al. Efficacité de combinaisons thérapeutiques avec les dérivés de l’artémisinine dans le traitement de l’accès palustre non-compliqué au Burundi. [Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi.] Tropical Medicine and International Health, 2004, 9:673–679. Summary of WHO recommendations on treatment of uncomplicated falciparum malaria: ACTS are also recommended as first-line treatment for infants and young children [Level of Evidence T, O, and E] and AL is specifically recommended for use in travelers returning to non-endemic countries (along with Malarone and quinine + doxycycline or clindamycin) [Level of Evidence O and E]. (b) (4) WHO document discusses practical aspects with artemether-lumefantrine treatment: An advantage of this combination is that lumefantrine is not available as a monotherapy and has never been used by itself for the treatment of malaria. Recent evidence indicates that the therapeutic response and safety profile in young children of less than 10 kg is similar to that in older children, and artemether-lumefantrine is now recommended for patients ≥ 5 kg. Lumefantrine absorption is enhanced by co-administration with fat. Low blood levels, with resultant treatment failure, could potentially result from inadequate fat intake, and so it is essential that patients or carers are informed of the need to take this ACT with milk or fat-containing food – particularly on the second and third days of treatment.
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