(CDS/RBM, 18 March 2002)
REVIEW OF APPLICATION FOR INCLUSION OF A DRUG IN THE WHO ESSENTIAL DRUGS LIST
ARTEMOTIL and a/b ARTEETHER
1. Summary statement on application
Applications were received in 2001 from Artecef, B.V. The Netherlands for the inclusion of artemotil (b arteether) and from Themis Medicare, India for the inclusion of a/b arteether in the Model List of Essential Drugs. Themis Medicare had previous made a submission in 1999 but it was rejected because the data provided was insufficiently detailed to allow proper evaluation.
Both formulations have been registered in their countries of origin for the treatment of severe falciparum malaria and in the case of a/b arteether also for the treatment of uncomplicated falciparum malaria. The development of artemotil has been supported by WHO/TDR.
The application from Artecef B.V. was supported by the documents presented to the Drug Regulatory Authorities in the Netherlands and by reviews from independent experts. The resubmission from Themis Medicare was supported by additional information to that submitted in 1999 and was in the form of a Manufacturers Product Brochure, papers published in the scientific literature and reports submitted by clinical investigators to the Company. The quality and quantity of the data on artemotil was greater than that a/b arteether.
Artemotil and a/b arteether are both formulations of the ethyl ether derivative of artemisinin, the active principal isolated from the Chinese medicinal plant, Artemisia annua L. The two formulations differ only in the chirality of the active compound and in the oil in which the active compound is dissolved. It is not surprising, therefore, that the studies carried out showed that both drugs had similar efficacy in laboratory malaria models, being active against P. falciparum strains that were resistant to chloroquine, mefloquine, halofantrine, quinine, pyrimethamine, cycloquanil and amodiaquine. They also appear to have similar safety profiles in preclinical toxicity studies. Both products were also safe and extremely well tolerated in clinical studies. Although they are no comparative clinical studies between the two products, their profiles of clinical safety and efficacy in patients with both uncomplicated and severe falciparum malaria also appear to be similar from the data available. Thus, for all intent and purposes, the two products appear as intramuscular formulations of the same drug.
As intramuscular injectable formulations, these drugs would only have a major role to play in the management of severe malaria in adults and children. WHO does not recommend the unconditional use of injectable formulations for the management of uncomplicated malaria since effective oral formulations exist to treat this condition. The only situation where the use of injectable formulations might be considered for this
indication would be in the rare cases of when patients are unable to swallow oral medication.
The current registration of artemotil restricts its use to children under the age of 16 years because: (i) slight prolongations of QTc intervals were observed in dogs receiving artemotil; (ii) an inventory of ECG changes in the clinical trials also showed rare and slight QTc-interval prolongation although they were not large enough to give cause for concern; (iii) one patient who received artemether in a comparative trial with artemotil did show QTc prolongation that could have been a cause for concern. The Company recommend therefore that, until this issue is clarified, artemotil should not be used in adults. This decision was made in spite of the fact that (a) there was no correlation between prolongation of QTc levels and artemotil plasma levels and (b) an independent analysis of the ECG data concluded that artemotil did not have the potential for QTc interval prolongation. QTc interval prolongation has not been reported previously as an relevant adverse reaction following the use of artemisinin and its derivatives.
The current available “market competitors” for artemotil and a/b arteether are intramuscular injectable formulations of artemether** and intravenous quinine. Both are currently included in the Model List of Essential Drugs as formulations that are effective, safe and affordable for the treatment of severe falciparum malaria. The addition of other antimalarial drugs for this indication can only be justified if the formulations are more effective, safer, easier to use and more affordable than artemether or quinine for the populations in need.
In conclusion, Artemotil has been shown to:
· be effective against falciparum parasite strains resistant to quinine as well as to chloroquine, mefloquine, halofantrine, pyrimethamine, cycloquanil and amodiaquine in preclinical studies;
· be as effective as artemether against laboratory malaria models and P. falciparum in vitro.
· have a similar preclinical toxicity profile to artemether; and
· be at least as safe and effective as both artemether and quinine for the treatment of severe malaria including cerebral malaria in children and adults in randomised comparative trials
BUT it can not be considered at present for inclusion in Model List until the following issues have been addressed:
· determination of the cost of artemotil in the private sector in accordance with the terms of the Agreement between WHO and the Company;
· clarification of the issue of QTc-interval prolongation that is restricting the use of the formulation to children only; and
· rewording of the Company's treatment guidelines so that they are in line with WHO recommendations. The Company's recommendation is a 3-day regimen but WHO recommends that monotherapy with regimens of artemisinin or its derivatives of less than 7 days should not be used because of the unacceptable high levels of
recrudescences. For example, WHO recommends that intramuscular artemether is given for a minimum of 3 days until the patient can take oral therapy of an effective antimalarial to complete 7 days of therapy. A similar wording should appaly to artemotil.
It is also not possible to consider a/b arteether for inclusion the Model List for the following reasons:
· the information provided by the Company for this second submission remained superficial, of poor quality and was difficult to analyse meaningfully;
· data on preclinical toxicity was not presented;
· data on the pharmacokinetics or pharmacodynamics of a/b arteether in patients with uncomplicated or severe malaria was lacking;
· dose finding studies in humans do not appear to have been carried out, the choice of the dose regimen used in the clinical trials appearing to have extrapolated from other group’s experience with artemether and from studies carried out in India on the efficacy of a/b arteether in simian malaria models;
· although the Company recommends the use of the drug in children, the information provided to support this was virtually non-existent and could not be evaluated. In fact, it appears that the drug may have been registered without any experience in children since children under 14 years were excluded from the clinical trials that according to the Company's reports were the basis of its registration;
· one comparative efficacy trial with quinine was reported but could not be analysed due to the lack of details;
· although WHO guidelines on the specific use of a/b arteether do not exist, the Company's recommended 3-day dosage regimen does not conform with WHO recommendations that state that monotherapy with regimens of artemisinin or its derivatives of less than 7 days should not be used because of the unacceptable high levels of recrudescences (see also artemotil above); and
· The use of injectable formulations in the treatment of uncomplicated malaria is not unconditionally recommended by WHO. .
** N.B. In view of recent evidence that shows that intramuscular injectable artemether is (i) at least as effective as quinine in reducing general mortality from malaria,(ii) is associated with lower mortality in malaria patients with multi-systems failure, (iii) is associated with faster parasite clearance times, (iv) is not associated with hypoglycaemia and (v) is easier to use (this is not only a practical advantage but may also be life saving in rural settings where intravenous injections are not possible), it is recommended that the restriction of it’s use to quinine-resistant falciparum cases as indicated in the Report of the Seventh Expert Committee on Essential Drugs should be removed.
2. Focal Point in WHO for application
Dr Andrea Bosman
Roll Back Malaria
3. Companies submitting application
Two applications were received for intramuscular injectable formulations of the ethyl ether derivative of artemisinin. The applications were for the single drug. They were submitted to WHO by:
(i) Artecef B.V., Maarsen, The Netherlands* for the formulations, Artecef 150® and Artecef 50®, containing artemotil (b arteether) ; and
(ii) Themis Medicare Ltd., Mumbai, India for E- MAL®, containing a/ b arteether.
* N.B. Artecef B.V was previously known as ACF Beheer B.V., Maarsen, The Netherlands under whose auspices the formulations were firstly developed and with which WHO concluded an Agreement for the development of the formulation (For details of the history of this collaboration see Annex 1).
4. International Nonproprietary Name
The International Nonproprietary Name for b arteether is ARTEMOTIL.
There is no International Non proprietory Name for a/ b arteether.
5. Public Health Relevance
Malaria continues to be a major health problem in the world today. Between 300-500 people become ill from the disease and approximately 1 million, mainly children die from it each year. The prevalence of drug resistant falciparum malaria has increased so that, in some countries, resistance to all of the available antimalarial drugs, except artemisinin and its derivatives, exists. For patients with falciparum malaria resistant to chloroquine, sulfadoxine/pyrimethamine, mefloquine and quinine, the use of artemisinin and its derivatives is essential (WHO 1994, 1997a,1998, 2001a).
This situation was recognised by the 6th WHO Expert Committee on Essential Drugs (WHO, 1995). As a consequence, artemether (the methyl ether derivative of artemisinin) as an intramuscular injectable formulation was added to the Model list of Essential Drugs for the treatment of severe falciparum malaria resistant or suspected of being resistant to quinine (WHO, 1996). This decision was taken because of an urgent operational need for the drug and with the full knowledge that some of the available formulations had not been produced according to GMP.
Subsequently, an oral formulation of artesunate (the hemisuccinate derivative of artemisinin), to be used in combination for the treatment of uncomplicated multidrug resistant falciparum malaria, was added to the Model List of Essential Drugs in 1999
(WHO, 2000a).
Thus, the Model List already contains two injectable formulations of drugs, i.e. quinine and artemether, that can be used in the management of severe malaria. Is there a need for a third formulation?
Recent comparisons of intravenous quinine and intramuscular injectable artemether for the treatment of severe malaria in 1919 patients (The Artemether-Quinine Meta-analysis Study Group, 2001) indicate that:
(i) there were no differences between the drugs in coma recovery or fever clearance times, or in the development of neurological sequelae;
(ii) the combined adverse outcome of death or neurological sequelae was less common with artemether treatment;
(iii) treatment with artemether was also associated with faster parasite clearance times; and,
(iv) in patients with multi-sytem failure, atemether administration was associated with significantly lower death rates; and
(v) artemether as an intramuscular injectable formulations was easier to administer than quinine. This is not just a simply practical advantage but may also be life saving in rural setting where intravenous administration is not possible.
The preclinical and clinical studies summarised below suggest that artemotil, a/ b arteether and artemether are probably similar in efficacy, safety and tolerability.
The choice between the use of either artemotil, a/b arteether or artemether may therefore eventually be determined by price and availability.
6. Drug substance and formulation
6.1. Synthesis
The original synthesis of a/b arteether was performed by the reduction of artemisinin with sodium borohydride, followed by etherification with ethanol in the presence of boron trifluoride etherate (Li et al., 1981, CCRGQ, 1982). There is no patent covering this process. A detailed description of the synthesis of artemotil (b arteether) was described by Brossi, et al. (1988) and was covered by the following patents taken out by WHO: European Patent Application No. 89301914.1(subsequently withdrawn) and Patent Application No. 07/316282 in the USA.
6.2. Characteristics
Arteether is a chiral substance, existing in the a and b forms. Artemotil formulations contain the only the b form whereas a/b Arteether contains both chiral forms, in the ratio of 30 parts a-arteether: 70 parts b-arteether.
6.3. Formulations
6.3.1 Artemotil
Artemotil is available as an injectable formulation as ampoules containing either 150mg (Artecef® 150) or 50mg artemotil (Artecef® 50) respectively dissolved in 1 ml sesame oil. The ampoules are colour coded to prevent confusion between the two formulations. It is recommended by the manufacturer that the ampoules containing 50mg artemotil are used in children weighing <16 kilogram body weight.
Sesame oil was chosen as a solvent because (i) it is widely used for intramuscular injectable formulations, (ii) it is described in the US National Formulary and (iii) its viscosity was ideal for use in syringes.
6.3.2. a/b Arteether
a/b Arteether is available also as an injectable formulation in ampoules containing either 150 mg dissolved in 2 ml. arachis oil or 80 mg dissolved in 1 ml arachis oil.. There is no specific paediatric formulation.
6.4. Stability studies
6.4.1. Artemotil
Stability studies support the storage life of 3 years for ampoules containing 150 mg artemotil at temperatures up to 31°C and seem reasonable also for the paediatric formulation, although specific data on 36 months storage are lacking for the latter. The Company clearly indicates in the packaging that the drug should not be stored at temperatures above 25°C.
6.4.2. a/b Arteether
a/b Arteether is reported to be stable at room temperatures of 25°C for 27 months and for 6 months at 40°C based on accelerated studies. The Company states that the product is stable for 2 years at room temperatures of 25°C and also recommends storage in a cool place.
6.5. Pharmacopeal standards
Pharmacopeal standards for artemotil have been established by WHO (International Pharmacopea, Volume 5, 3rd Edition, 2002) but not for a and b arteether.
6.6 Comments
Artemotil was chosen for development by the Company and WHO for the following reasons: