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(CDS/RBM, 18 March 2002)
REVIEW OF APPLICATION FOR INCLUSION OF A DRUG IN THE WHO
ESSENTIAL DRUGS LIST
ARTEMOTIL and / ARTEETHER
1. Summary statement on application
Applications were received in 2001 from Artecef, B.V. The Netherlands for the inclusion
of artemotil ( arteether) and from Themis Medicare, India for the inclusion of /
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 / 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 / arteether.
Artemotil and / 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
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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 / 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:


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
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
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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 / arteether for inclusion the Model List for the
following reasons:
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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 / 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 / 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 / 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
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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 ( arteether) ; and
(ii)
Themis Medicare Ltd., Mumbai, India for E- MAL®, containing /  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  arteether is ARTEMOTIL.
There is no International Non proprietory Name for /  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).
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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)
(ii)
(iii)
(iv)
(v)
there were no differences between the drugs in coma recovery or fever clearance
times, or in the development of neurological sequelae;
the combined adverse outcome of death or neurological sequelae was less
common with artemether treatment;
treatment with artemether was also associated with faster parasite clearance times;
and,
in patients with multi-sytem failure, atemether administration was associated with
significantly lower death rates; and
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, / 
arteether and artemether are probably similar in efficacy, safety and tolerability.
The choice between the use of either artemotil, / arteether or artemether may therefore
eventually be determined by price and availability.
6. Drug substance and formulation
6.1. Synthesis
The original synthesis of / 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 ( 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  and  forms. Artemotil formulations
contain the only the  form whereas / Arteether contains both chiral forms, in the ratio
of 30 parts -arteether: 70 parts -arteether.
6.3. Formulations
6.3.1 Artemotil
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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. / Arteether
/ 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. / Arteether
/ 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  and  arteether.
6.6 Comments
Artemotil was chosen for development by the Company and WHO for the following
reasons:
(i)
(ii)
(iii)
it was considered at that time that the biochemical breakdown of arteether would
give would give ethanol and not the potentially more toxic methanol as would be
the case with artemether (experience so far indicates that this was a theoretical
concern and does not appear to have any practical application);
it could easily be formulated in oil for parenteral use; and
a formulation containing only - form would be more easily standardised.
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The clinical significance of the differences in the two formulations can not be assessed
since they are no comparative studies of artemotil and / arteether. / Arteether is
probably cheaper to produce as it does not require the chemical step to produce the pure
 form from the chiral mixture.
N.B. all current formulations of artemether contain both  and  forms dissolved in 2 ml
arachis oil.
8. Capability of Production
8.1. Artemotil
Production of artemotil is according to GMP and Artecef B.V. has the capability to
produce the formulation in sufficient amounts for international needs.
8.2. / Arteether
Production of / Arteether is by a plant which is WHO approved for GMP and
conforms to international standards. Themis reports that it has a 100,000 ampoule/month
capacity for production and, since registration in 1997, 1, 752, 233 adult treatment doses
have been sold in India (129 891 in 1997, 262 117 in 1998, 356 160 in 1999 and 1,
004,065 in 2000 and 2001).
9. Registration Status and Indications for use
9.1. Artemotil
The two formulations of artemotil, Artecef 150® and Artecef 50®, were registered in the
Netherlands in 2000 for the restricted indication of the treatment of severe falciparum
malaria in children and adolescents of less than 16 years (see also Section 13). An
application for registration was also considered by the South African authorities in
December 2000. The decision on this application was not available to the reviewer.
Artecef 50® is recommended by the manufacturers for the use in infants and children up
to 16 kg body weight and Artecef 150® for children and adolescents weighing above 16
kg.
The indication has been restricted to children and adolescents up to the age of 16 years
for the reasons given in Section 13.3.2 below.
9.2. / Arteether
/ Arteether was registered as E-MAL® in India for the treatment of acute
uncomplicated multi-drug resistant falciparum malaria and for severe malaria in January
1997. The drug released for marketing in April 1997. The external packaging and the
package insert clearly indicate that the drug is for hospital use only.
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9.3 Comments
(i)
There are differences in registered indications of the artemotil and / arteether.
Artemotil has only been registered for the treatment of severe falciparum malaria
in children and adolescents below 16 years ./ arteether was registered for the
treatment of both children and adults suffering from uncomplicated multi-drug
resistant falciparum malaria or severe falciparum malaria. WHO does not
unconditionally recommend the use of injectable formulations for the
management of drug-sensitive or multi-resistant uncomplicated malaria.
(ii)
An injectable artemether formulation, produced according GMP, is available but
is not registered yet in Europe or in the USA (a special licence for restricted use in
hospitals in France does exist). Registration of injectable formulations of
artemether has been obtained in many countries of the African, South East Asian
and the Western Pacific Region’s of WHO.
(iii)
The Companies do not recommend the use of artemotil or / arteether for the
treatment of vivax malaria or their use as a first line antimalarial drugs for the
treatment of falciparum malaria at the periphery of the health services. This is in
line with WHO recommendations
10. WHO Treatment Guidelines
At present, there are no WHO agreed upon treatment guidelines for the use of artemotil
or / arteether. Treatment guidelines do exist for the use of artemisinin, artesunate and
artemether for the treatment of uncomplicated and severe malaria. (WHO, 1997a, 1998,
2001a and b).
It is however important to note that 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. Thus 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 (WHO, 1997a, 1998,
2001a and b).
Arrangements are being made by Roll Back Malaria (RBM) for an Informal Consultation
to review the data that at has been now made available through these two applications to
the WHO Expert Committee on Essential Drugs and to develop guidelines for the use of
artemotil and / arteether.
11. Manufacturer’s Treatment regimens
The regimens recommended by each manufacturer are given below. These have been
strongly influenced by the apparent qualitative and quantitative similarity of both
artemotil and / arteether to artemether
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11.1. Artemotil (children and adolescents up to the age of 16 years only)
Intramuscular injection of: 4.8mg/kg body weight as a loading dose followed by
1.6mg/kg body weight administered 6, 24, 48 and 72 hours after the loading dose.
The Company also recommends that the loading dose must be equally divided and
injected in both anterior thighs, with each subsequent dose injected into alternating
thighs.
Following resolution of the critical phase of the falciparum infection the Company
advises that microscopic examination of the blood of the patient should be carried out
once a week for 4 weeks. In the case of re-infection or recrudescence, the patient should
be treated with a different antimalarial drug.
The use of tuberculin syringes is recommended in the treatment of children.
11.2. / Arteether
11.2.1. Adults
Intramuscular injection of one ampoule, containing 150mg / arteether, daily for 3
consecutive days (i.e. total dose 480 mg irrespectively of body weight or 3mg/kg/day for
a 50kg adult).
11.2.2. Children
Intramuscular injection of 3mg / arteether/kg body weight daily for 3 consecutive
days.
11.3. Comments
(i)
The final dosage regimen of artemotil is based on the experience with 62 children.
All were cured and none suffered any ill effects. This number is not large but was
accepted by the Dutch authorities.
(ii)
The higher loading dose of artemotil seems justified based on pharmocokinetic
and pharmocodynamic data that show that, when artemotil and artemether are
administered at equal mg/kg doses, artemotil is absorbed from the injection
somewhat slower than artemether with resultant longer parasite clearance times.
(iii)
No dose finding studies were carried out with / arteether, the regimen being
based on experiences by other groups with artemether. The currently WHO
recommended for intramuscular injectable artemether is 3.2 mg/kg as a loading
dose given on the first day followed by 1.6 mg/kg daily for a minimum of 3 days
until the patient can be given oral therapy with an effective antimalarial.
(iv)
The continuation of therapy by oral therapy immediately after the completion of
intramuscular therapy with any of the artemisinin derivatives is important as it
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ensures the elimination of parasites and reduces the chances of the development
of drug resistant parasites. This issue has not been properly addressed by either
manufacturer although both recognise that recudescences may occur after
treatment with both formulations (see WHO recommendations Section 10 above).
12. Efficacy including comparisons with other relevant drugs
12.1. Preclinical Efficacy
(i).
Artemotil and / arteether are both blood schizontocides active against
Plasmodium falciparum, from the very early asexual to the mature schizont
stages as well as against early gametocytes.
(ii).
In vitro studies have shown artemotil to be effective against falciparum parasite
strains resistant to chloroquine, mefloquine, halofantrine, quinine, pyrimethamine,
cycloquanil and amodiaquine (Milhous et al., 1986).
(iii)
In vitro studies show that artemotil, / arteether, and artemether have similar
activities against P. falciparum but are slightly less potent than
dihydroartemisinin (Shmuklarsky et al., 1993).
(iv)
Studies in rodent malaria models in vivo show that artemotil is cross-resistant to
artemisinin, but not to chloroquine, mefloquine, halofantrine, quinine and
pyronaridine. When combined with quinine, the antimalarial effect was
potentiated but only additive with mefloquine (Brossi et al., 1988);
(v).
In vitro studies, using a multi-resistant strain of P. falciparum, artemotil was
shown to be synergistic with mefloquine and quinine (Ekong and Warhurst,
1990).
(vi).
A strain of P.yoelli nigeriensis resistant to chloroquine, mefloquine and quinine
was found to be fully susceptible to / arteether (Dutta et al., 1989).
(viii). The blood schizontocidal activites of artemotil and  arteether were shown to be
equal against P.cynomolgi infections in rhesus monkeys (Tripathi et al., 1991).
(ix).
/ arteether was shown to have gametocytocidal activity following a single
intramuscular injection of 2-5 mg/kg in rhesus monkys infected with P.cynomolgi
but sporontocidal activity could not be demonstrated even after doses up to
50mg/kg (Tripathi, et al., 1990).
(x)
Artemotil was marginally less effective than artemether in curing Aotus monkeys
infected with P. falciparum (Shmuklarsky et al., 1993).
12.1. Clinical Efficacy
Details of the clinical studies are given in Annex 2. Clinical efficacy was assessed by
evaluations of cure rates (as defined by parasite at 7,14 or 28 days), fever and parasite
clearance times in patients with uncomplicated malaria and by survival or death,
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resolution of symptoms, and coma, fever and parasite clearance times in patients with
severe malaria (including cerebral malaria). The trials of artemotil were randomised, and
double-blinded wherever possible, and conducted, except for two Phase I trials according
to Good Clinical Practise (GCP).
All efficacy trials with / Arteether were open. It is not possible from the data provided
to determine if these trials were conducted according to GCP.
In summary, these trials indicate that:
12.1.1. Artemotil

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Doses of 3.2 mg/kg artemotil on the first day followed by either 1.6 mg/kg or
0.8mg/kg artemotil on days 2-5 showed cure rates > 80% and similar parasite and
fever clearance times in adult Thai patients with uncomplicated falciparum malaria.
Artemotil and artemether were equally efficacious in dose regimens of 3.2mg/kg
artemotil on the first day followed by 1.6 mg/kg on days 2-5 in adult Thai patients
with uncomplicated malaria. In this study, the regimen of 3.2 mg/kg artemotil on the
first day followed by 0.8mg/kg artemotil on days 2-5 was slightly less effective but
not significantly so. Parasite clearance times were, however, significantly faster with
artemether than artemotil.
Artemotil and artemether were also equally efficacious in curing adult Thai patients
with severe malaria. Adminstration of artemotil or artemether in doses of 3.2mg/kg
on the first day followed by 1.6 mg/kg on days 2-5 resulted in survival rates of 87.0%
and 88.7% respectively. Increasing the loading dose of artemotil on day 1 to
4.8mg/kg followed by 1.6 mg/kg after 6 hours and then consecutively at 24, 48, 72
and 96 hours increased the survival rate to 94.6% but this increase was not
statistically significant. Parasite clearance times were faster with high dose artemotil
probably due to higher observed plasma levels of the drug.
In a 3 centre study in the Cameroon and Zambia, artemotil given at doses of 3.2
mg/kg on the first day followed by 1.6 mg/kg on days 2-5 was at least equally
effective as quinine for the treatment of African children with cerebral malaria.
Artemotil and artemether were equally effective in curing Thai children suffering
from severe falciparum malaria. Artemotil was given in a regimen of 4.8mg/kg on
day 1 followed by 1.6 mg/kg after 6, 24, 48, and 72 hours and artemether in a
regimen of 3.2 mg/kg on the first day followed by 1.6 mg/kg on days 2-5. In this
study, it was decided to omit the dose of artemotil given on the fifth day (96 hours)
for two reasons (i) parasite clearance was achieved within 96 hours in the previous
study with the high loading dose and (ii) the long plasma half life (>20 hours) of
artemotil. The final dosage recommendations made by the Company are based on
this trial.
12.1.2. / Arteether

An open non comparative Phase II trial of / arteether in 51 adult patients with
uncomplicated falciparum malaria showed that after 72 hours parasite and fever
clearance was obtained in 98% and 81% of the patients of the patients respectively
(Mishra et al., 1995, Asthana et al., 1996, Valecha et al., 1997).
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Similar results were also obtained in open Phase II/III trial conducted in 7
geographically distinct sites with 267 adult patients (191 males and 76 females) with
uncomplicated malaria (Asthana et al., 2001a).
/ Arteether administered to 211 adult patients with severe malaria from four sites
gave survival rates of 91.5- 100% with rapid recovery from coma and other
complications (Asthana et al., 2001b).
/ Arteether was reported to have similar efficacy to quinine in the treatment of
severe falciparum malaria (Mishra et al., 1997)
All adult patients received 150mg / arteether on each of 3 consecutive days
irrespective of weight. No dose finding studies were carried out.
It appears that the clinical experience with the drug in children is extremely limited.
Children were excluded from all the trials reported above. However, an unpublished
and undated report to the Company indicates that 21 children aged 3-11 years with
severe falciparum malaria were successfully cured by a dose of 75mg / arteether
given intramuscularly for 3 consecutive days. The same dose seems to have been
given to all children irrespective of weight. No adverse effects were reported. No
other data on children was submitted to WHO.
13. Safety, Tolerability and Adverse Reactions
13.1. Patient exposure
13.1.1. Artemotil
During the Phases I, II and III of clinical development, 264 adults and 162 children
received artemotil. There were 55 adults in Phase I (safety, tolerance and
pharmacokinetic studies), 66 adults in Phase II (safety and efficacy in uncomplicated
falciparum malaria), and 143 adults and 162 children and adolescentsc in Phase III
(severe malaria).
Of the 162 children and adolescents (up to age of 16 years) with severe malaria, 100 were
African and 62 were Thai. The 62 Thai children received the dosage regimen finally
recommended by the Company. Individual data on each of these patients formed part of
the registration submission to the authorities in the Netherlands and were included in this
submission to WHO.
The total number of patients assessed for safety was 431, allowing a comparison with 222
patients with alternative treatments. The age of the patients treated with artemotil and
assessed for safety and tolerance varied from 0.5-60 years, with a male to female ratio of
approximately 3:1 for adults (absolute figures 282:99) and 1.1 for children (absolute
figures 55:45).
Studies were carried out in three different ethnic groups, i.e. Caucasians, African and
Thais
12
13.1.2. / Arteether
The data submitted on / arteether was less detailed and poorly presented but clearly
more patients have been treated with this drug than with artemotil. Nearly 2 million adult
treatment doses have been sold in India since the drug was registered in 1997.
The comments below on safety and tolerance are based mainly on the information
available from 44 healthy adult volunteers treated in Phase I safety and tolerance studies
and the exposure to the drug of 318 adult patients with uncomplicated malaria, and 211
adult patients with severe malaria. The manufacturer also submitted a Post Marketing
Surveillance Report on 300 patients successfully treated up to the end of 1999 but this
report has little scientific value.
The only data submitted on the use of / arteether in children was a limited study of 21
children aged 3-11 years with severe malaria conducted in the tribal belt of Hoshandbad
District. Unfortunately this report was also of little scientific value.
Individual patient data were not available.
13.2 Safety and Tolerance
Both formulations were reported to be very well tolerated. No serious or severe adverse
reactions occurred in any of the clinical trials of either artemotil or / arteether. The
most common adverse reaction with artemotil during Phase I tolerance studies was pain
at the site of injection. This was mild and transitory and was reported less frequently in
malaria patients, As a consequence, the Company recommends that repeated injections
are made in alternate thighs. This was the only adverse reaction that was considered
related to the drug formulation. Such reactions were not reported in any of the clinical
trials with / arteether.
Other reported adverse experiences were intermittent and non-specific central nervous
disorders such as headache, as well as gastrointestinal disorders such as abdominal
discomfort and nausea. The frequency of these events was similar in the treatment and
placebo groups and overlap with the disease symptoms. Slight elevations in reticulocyte
counts in the second half of the Phase I studies were considered as a normal
compensatory reaction to repeated blood sampling.
13.3. Potential serious adverse reactions
13.3.1. Neurotoxicity
Concerns over potential neurotoxicity arose with artemisinin derivatives arose when preclinical toxicity studied were performed with both artemether and artemotil. Degenerative
neurotoxic effects were observed at cumulative doses above 100mg artemotil per kg
bodyweight administered intramuscularly in both rats and dogs. Similar dose-dependent
and potentially fatal events were also described after intramuscular injection of
artemether. These effects were produced by doses around x10 higher than those used for
human treatment (Brewer et al., 1994, WHO, 1997a, 1999). These changes mainly
13
affected the vestibular, motor and auditory functions (Petras et al., Genovese et al.,
1995).
In these circumstances, special attention was given in all the clinical trials of artemotil to
the detection of neurological changes through evaluations of speech, coordination,
muscle tone and strength, reflexes, tremor, eye movements, visual acuity and audiometry
measurements. No drug related changes were observed.
Prospective studies of over 10 000 patients have also shown that there is no clinical
evidence of serious neurotoxicity from the use of any artemisinin drug in man (WHO,
1998). In addition, neurotoxic adverse reactions were not been observed following a
detailed analysis of the clinical studies with artemether involving over 1900 patients
(WHO, 2001a, The Artemether – Quinine Meta analysis Study Group, 2001).
13.3.2. Cardiotoxicity
Slight prolongation of the QTc intervals were observed in dogs receiving artemotil. As a
consequence, an independent detailed analysis was made of the ECG measurements from
four of the clinical trials. These trials were:

Phase I double blind multiple dose safety and tolerance study of artemotil in 27
healthy adult Caucasian males;

Phase II dose finding study of artemotil in 25 Thai adults with uncomplicated
malaria;

Phase II comparative study of artemotil and artemether in 63 Thai adults with
uncomplicated malaria; and

Phase III comparative study of artemotil and artemether in 126 Thai adults with
severe malaria.
No cardiovascular changes were observed during the Phase I studies of artemotil as
measured by ECG recordings: PR-intervals, QRS-duration and QT-intervals.
An inventory of the ECG data from other trials of artemotil indicated that absolute values
of QTc of >450 msec. (prolonged) were rare (8 out of 710 ECG recordings examined).
There was only one observation of a value of >500msec that gave cause for concern and
this was in a patient that had received artemether. No relation between arteether plasma
levels and QTc-interval duration or prolongation could be detected.
This independent analysis concluded that artemotil did not have a potential for QTcinterval prolongation at the recommended dosage for the treatment of severe falciparum
malaria. However, Company (presumably because of concerns of liability) state in their
Summary of Product Characteristics that:
“In general, artemotil shows no tendancy to QTc-interval prolongation at the
recommended dosage regimens. QTc-interval prolongation may incidently occur in
patients with pre-existing abnormal ECG (high U-waves and old infarctions). Until the
14
clinical consequences of the observed QTc prolongations are clarified, artemotil should
not be used in adults”
The significance of these observed changes in QTc intervals needs to reassessed. The
association of such changes with the administration of artemisinin or its derivatives do
not seem to have been reported previously. Although the changes after artemotil
adminstration were not so great to give concern, one patient receiving artemether in a
comparative trial with artemotil had prolonged QTc intervals that could have been
dangerous.
No cardiovascular changes were reported following adminstration of / arteether in 2
Phase I trials involving 50 health male volunteers. ECG measurements do not appear to
have been carried out during the Phase II/III trials of this drug.
14. Post marketing Surveillance
Post marketing surveillance (PMS) data only exist for / arteether since artemotil has
yet to be marketed.
During 1997, 300 PMS forms were returned to the Company from physicians in 6 States
of India. The details of this study are given in Annex 2 Section 2.4. The report shows that
294 (98%) of the patients were cured and no drug related adverse effects were recorded.
However, the report is of limited scientific value as it does not:





distinguish between the use of the artemotil for severe and for uncomplicated malaria;
provide specific information on children which apparently received the same amount
of drug as the adults (i.e. much higher doses/kg than the adults);
provide information on the reasons why additional antimalarial drugs were given, the
timing of their administration and their contribution to the survival of the patients;
provides only limited information on adverse reactions reported; and
provide estimates of risk and denominators.
15. Pharmacokinetics and Metabolism
Although the data on artemotil is greater, the pharmacokinetics and metabolism of
artemotil and / arteether probably are similar. Studies on the disposition of artemotil
have been carried out in healthy volunteers as well as in adults with uncomplicated and
severe malaria and in children with severe malaria. Studies with / arteether have only
been carried out in healthy male volunteers.
An important feature is the long plasma half-life of the two drugs and their resulting
accumulation during the treatment course. After intramuscular injection, both drugs are
released slowly into the systemic circulation. Peak plasma concentrations are generally
attained between 3-12 hrs. following drug administration. The plasma elimination halflife is determined by the slow release from the injection site and varies dependent on
muscle tone and activity. It is generally around 20-24 hrs. (Artecef B.V. internal reports;
15
Asthana et al., 1997). Elimination of artemether appears shorter with a half life of 4-11
hrs (WHO, 1990).
The steady state area under the curve (AUC) (over 24 hours after the last dose) increases
linearly with dose. No important differences in AUC were observed amongst the different
ethnic populations receiving artemotil although there were variations within these patient
populations. In particular this parameter was similar for both adults and children with
severe malaria, indicating that age was not an important factor for the pharmacokinetics
of that least artemotil.
There are no indications for gender differences in the pharmacokinetics of artemotil.
As the physiochemical properties of the artemotil and / arteether exclude intravenous
administration in humans, it is not possible to determine the bioavailabilty, the clearing or
distribution following drug administration . Plasma protein binding of the drugs is high,
98-99%.
Prior to excretion, the majority of artemotil is metabolized. The most important route is
an oxidative dealkylation by CYP3A4 to dihydroartemisinin and the biliary excretion of
glucronidated dihydroartemisinin with the faeces. A minor part (20-30%) may be
excreted in the urine as dihydroartemisinin glucoronidine. Since dihydroartemisinin has a
short half-life of only a few hours, the temporal pattern of its plasma concentration is
probably determined by its rate of formation from the parent compound.
Dihydroartemisinin is more active as an antimalarial than the parent drug. However,
plasma concentrations of dihydroartemisinin are typically <10% of those of the parent
drug and so the contribution to the therapeutic effect seems to be of less importance.
There are no reported studies of the pharmacokinetics of either artemotil or / arteether
in patients with pre-existing renal or liver failure.
16. Pharmacodynamics
The clinical dose finding study of artemotil indicates that the rate of parasite clearance is
determined by plasma concentrations of the drug during the first two days of treatment. It
appears that a minimum exposure in terms of peak concentration and/or AUC is required
to trigger parasite clearance. When the exposure during the beginning of treatment is too
low, the onset of parasite clearance is delayed. Up to a certain level of exposure the onset
of parasite clearance becomes faster. Thereafter, parasite clearance can not be reduced by
exposure to higher concentrations of the drug. From the studies of artemotil
administration to adults and children with severe malaria, it can be tentatively concluded
that a mean plasma concentration of 100-150 ng/ml during the first day is the optimum
parasite clearance. However, many patients showed rapid clearance of parasites in spite
of lower concentrations.
17. Use in pregnancy and lactation
There is no data available on the use of artemotil or / arteether during pregnancy in
humans.
16
Pre-clinical studies carried out with artemotil revealed embryo toxic effects, including
foetal absorption, but no teratogenic potential. Such results are typical of artemisinin and
its derivatives. Artecef B.V. therefore recommend that artemotil should not be used
during pregnancy until more data becomes available. This is more restrictive than
existing WHO recommendations for the use other artemisinin derivatives for the
treatment of severe malaria during pregnancy (see below).
In contrast, Themis Medicare Ltd. recommend that / arteether should be used with
caution in pregnant women if the benefit justifies the risk to the foetus. However, they do
not distinguish between the use of the drug in pregnant women with uncomplicated or
severe malaria.
WHO recommends that artemisinin derivatives can be used in the second and third
trimesters of pregnancy but their use in the first trimester is not recommended. In severe
malaria , artemisinin drugs are the drug of choice in the second and third trimester. For
the treatment of severe malaria in the first trimester, the advantages of artemisinin drugs
over quinine, especially the lower risk of hypoglycaemia, must be weighed against the
fact that there is still limited documentation on pregnancy following their use. (WHO,
1995, 1998, 2001a).
WHO further recommends that care providers should be made aware of the inadequacy
of the current knowledge of these drugs during pregnancy and that all clinical outcomes,
both successful and adverse events should be made to regulatory authorities.
There are also no data on the excretion of artemotil or / arteether in human milk.
Artecef B.V. therefore recommend that female patients should stop breastfeeding for a
period of two weeks starting from the first dose of the treatment regimen. Themis B.V.
recommend caution when / arteether is administered to lactating mothers (but this
advise is of no practical value - what does this mean?).
18. Drug interactions
Preclinical parasitological studies have shown that the antimalarial effects of artemotil
and mefloquine may be additive and those of artemotil and quinine potentiated when
these drugs are used in combination. However, clinical and pharmacokinetics studies in
vivo have not been carried out on these interactions .
In vitro studies suggest that artemotil is metabolised by cytochrome P4503A4 to
dihydroartemisinin. Thus, drugs with a strong inhibitory action on CYP3A4, such as
HIV-protease inhibitors or ketonazole, could influence this metabolism with resulting
higher artemotil plasma concentrations and drugs with a strong induction effect on
CYP3A4 , like carbazepine and phenobarbitol, could result in lower artemotil plasma
concentrations when given concomitantly.
No drug interaction studies have been carried out with / arteether.
17
19. Cost.
The cost of artemotil both in the private and public sector has still to be determined
although it does appear from correspondence between the Company and WHO that prices
are in the process of being agreed upon between the Company and both IDA, The
Netherlands and Pharma AID Germany. Details of these negotiations are not yet
available to WHO.
Under the Terms of the Agreement between Artecef B.V. and WHO (See Annex 1), the
public sector price should be agreed upon in discussions between the two parties. Such a
meeting has not yet taken place although arrangements are being made by WHO TDR
and RBM for such a meeting to be held shortly although it appears unlikely that this will
occur before these applications are considered by the WHO Expert Committee on
Essential Drugs
The cost of an adult treatment dose of / arteether (using the manufacturer’s
recommended regimen) is US$ 6.25. . This is less expensive in India but more expensive
in the international market than its direct market competitor, intramuscular injectable
artemether. Intramuscular artemether costs US$ 8.80 per adult treatment dose in India
(according to Themis Medicare Ltd) and US$ 5.03 per adult treatment dose if purchased
from IDA, The Netherlands.
20. Proposed Text for WHO Model Formulary (if and when application to Essential
Drug List is accepted)
International Nonproprietary Name
Artemotil (previous known as  arteether).
Dosage Form
Available in colour coded ampoules containing either 50mg or 150 mg artemotil
dissolved in 1ml sesame oil.
Uses
Treatment of severe falciparum malaria in children and adolescents aged less than 16
years.
Contraindications
Adults
Pregnant females below 16 years (Company's recommendation).
Known hypersensitivity to artemotil and/or sesame oil.
Treatment of uncomplicated falciparum malaria.
Treatment of vivax malaria.
18
Special precautions
The product must be used only via the intramuscular route. The use of tuberculin syringes
is recommended for administration, particularly in young children.
The loading dose should be equally divided and injected anteriorly into both thighs with
each subsequent dose injected into alternating thighs.
Severe falciparum infections may require supportive treatment such as glucose–salt
infusion and the use of antipyretics.
The use of artemotil for the treatment of severe malaria in patients with pre-existing renal
or liver failure has not been studied.
The potential of artemisinin derivatives to produce neurotoxity has been observed in
animal studies. Such toxicity has not been observed in prospective studies of the use of
artemisinin and its derivatives in over 10.000 patients. Continued vigilance and postmarketing surveillance is required.
In general artemotil shows no tendency to cause QTc prolongation at the recommended
dose regimens. QTc prolongation may incidentally occur in patients with pre-existing
abnormal ECG (high U-waves and old infartions). Until the clinical consequences of
these observations have been clarified, the use of artemotil in adults is not recommended
by the Company.
Dosage
Intramuscular injection of: 4.8mg/kg body weight as a loading dose followed by
1.6mg/kg body weight after 6, 24, 48 and 72 hours or on further consecutive days until
the patient can take oral therapy with another effective antimalarial drug.
Adverse effects
Artemotil is very well tolerated. No serious or severe adverse reactions have been
observed in any of the clinical trials. Pain at the site of injection may occur but this is
mild and transitory. Other adverse experiences were intermittent, non-specific central
nervous disorders such as headache, and gastrointestinal disorders such as abdominal
discomfort and nausea. The frequency of these events was similar in the treatment and
placebo groups.
Drug Interactions
There is no clinical data on the interaction of artemotil with other drugs. Pre-clinical
studies indicate that the antimalarial activity of artemotil is additive when used in
combination with mefloquine and potentiated in combination with quinine.
In vitro studies suggest that -artemotil is metabolised by cytochrome P4503A4 to
19
dihydroartemisinin. Thus, drugs with a strong inhibitory action on CYP3A4, such as
HIV-protease inhibitors or ketonazole, could influence this metabolism with resulting
higher artemotil plasma concentrations and drugs with a strong induction effect on
CYP3A4 , like carbazepine and phenobarbitol, could result in lower artemotil plasma
contrations when given concomitantly.
20
ANNEX 1
HISTORICAL BACKGROUND TO DEVELOPMENT OF ARTEMOTIL
1.
WHO Decision to Development of Artemotil
The development of artemotil (-arteether – the ethyl ether derivative of artemisinin)
was stimulated by WHO through initiatives taken by the WHO Special Programme on
Research and Training in Tropical Diseases (TDR).
Artemotil and other ether derivatives were first synthesised in the early 1970’s in the
Republic of China in attempts to increase the efficacy and the solubility in oil of
artemisinin, the antimalarial principle isolated from the wormwood plant (Artemisia
annua L.), a traditional Chinese herb (Li et al, 1979).
Chinese scientists at that time decided to develop artemether (the methyl ether derivative)
as an injectable intramuscular formulation for the treatment of both uncomplicated and
severe falciparum malaria as well as a water soluble derivative, artesunate, for
intravenous treatment of severe malaria. Research on arteether in China was therefore
discontinued.
By the end of the 1970’s, extensive clinical experience in the treatment of falciparum
malaria with both artemether and artesunate, had been obtained in China (WHO Special
Programme on Research and Training in Tropical Diseases, 1982).
Following visits by malaria staff from WHO Headquarters to China in 1979 and 1980, a
meeting of the Scientific Working Group on the Chemotherapy of Malaria (CHEMAL)
was held in Beijing in 1982. This meeting gave priority to the development of injectable
formulations of the artemisinin derivatives, artemether or artesunate, for the treatment of
severe malaria. However, it was noted that their development for clinical use in China
had not followed normal standards of GMP, GLP or GCP and much of preclinical data
required for clinical use outside China was not available. The Chinese Authorities in
Beijing requested WHO assistance in the further development of these compounds and a
plan of action involving Chinese Institutions, CHEMAL and the Walter Reed Army
Institute of Research (WRAIR) was drawn up (the Chinese authorities requested WHO
not to approach a commercial company to assist in this development).
The plan depended upon, in the first instance, the Chinese authorities providing
CHEMAL with a kilogram of artemisinin to start the agreed upon studies outside China
according normal regulatory standards (at that time China was the sole source of
artemisinin). Unfortunately difficulties arose when the plan was discussed at the political
rather than technical/medical levels and, in spite of vigorous efforts by WHO, the cooperative plan continued to be blocked and the Chinese authorities were unable to
provide the artemisinin. In these circumstances, the CHEMAL Steering Committee
decided to produce artemisinin outside China according to GMP and, if need be, to
develop an injectable formulation of an artemisinin derivative for the treatment of severe
malaria independently from the Chinese.
This action was taken in view the urgent need to develop artemisinin formulations that
21
would meet the standards required for registration and use outside China and also with
the hope that it would stimulate the Chinese authorities to continue discussions and cooperation with CHEMAL. This action did result later in CHEMAL receiving a kilogram
of artemisinin unofficially from China, the source of which was not disclosed but an
agreement with the Chinese authorities to develop a specific formulation of an
artemisinin derivative was never concluded.
As a consequence CHEMAL chose in 1985 to develop -arteether for the treatment of
severe falciparum malaria. The reasons for this choice were the following:





2.
arteether would not have stability problems experienced with artesunate, the water
soluble derivative of artemisinin;
it was the assumed that arteether would be more lipophylic than artemether, a
possible advantage for its accumulation in brain tissue that might lead to a greater
efficacy in cerebral malaria;
the biochemical breakdown of arteether would give ethanol and not the potentially
more toxic methanol as would be the case with artemether (experience so far
indicated that this is a theoretical concern and does not appear to have any practical
application);
it could more easily be formulated in oil for parenteral use due to its highly crystalline
nature ( both isomers of artemether are low-melting solids); and
a formulation containing only the more active -chiral form would be more easily
standardised.
WHO Initiatives in the Development of Artemotil.
CHEMAL subsequently funded the following studies:



Growth of Artemesia annua and the extraction of artemisinin in kilogram amounts;
Chemical studies on the conversion of artemisinin to -arteether; and
Preclinical studies on -arteether.
These studies resulted in the following WHO patents applications and resultant patents on
the synthesis of - arteether: European Patent Application No. 89301914.1 (subsequently
withdrawn for reasons unknown to this reviewer)and Patent Application No. 07/316282
in the USA.
CHEMAL also actively searched for a commercial partner capable of according to GMP
an injectable formulation of -arteether in suitable amounts for clinical studies. This
culminated in the signature of an Agreement between WHO and ACF Beheer B.V.,
Maarssen, the Netherlands in March 1991. This agreement was subsequently amended in
December 1994.
At the same time, on the initiative of Dr Nitya Anand the Chairman of CHEMAL,
Central Drug Research Institute, Lucknow, India also started independently from
CHEMAL to develop an injectable formulation of / - arteether. CHEMAL did not fund
22
any of these studies although they were informed of the work during the tenure of Dr
Anand on the Steering Committee. These studies culminated in the registration and
marketing in 1997 of /-arteether as E-MAL by Themis Medicare Ltd., Mumbai,
India.
WHO’s Agreement with ACF Beheer B.V.
3.
It is assumed that this Agreement is still effect in spite of the fact that the development ,
registration, production and marketing is carried out under the auspices of Artecef B.V. a
Company created by ACF Beheer S.A. for this purpose.
3.1. Terms of the Agreement
Under the terms of the Agreement signed in 1991, ACF agreed to:







produce 15 kilograms of pure artemisinin derivativised as arteether or another agreed
upon derivative;
carry out non-clinical safety studies on candidate formulations;
carry out Phase I clinical pharmacology and other clinical investigations in normal
healthy volunteers as required by WHO;
provide WHO with all the data related to these studies;
assemble all data and results for registration in the Netherlands and provide WHO
with the data;
file the registration if so requested by WHO, and
provide WHO with 6- monthly reports on activities.
Under the terms of the Agreement, WHO paid ACF 2.4 million guilders to carry out
these studies. These funds were a contribution to TDR from the Netherlands Government.
The Agreement also contained a provision for the long term production and pricing of
the formulation as indicated below.
3.2.
Public Sector Pricing
Article 11 point1 of the Agreement signed in 1991 states:
“if and when both parties agree that one or more candidate drug substances in a specific
formulation and dosage form are safe and effective for use as an antimalarial drug in
humans and can be produced in commercially viable quantities, ACF shall ensure that the
product shall be made available to the Public Sector Agencies in sufficient quantities to
meet the needs of such agencies for the distribution of the such product through the
Public Sector of Developing countries at a price reflecting no more than the actual
fully absorbed costs of manufacture, excluding research and development, plus a
mark-up of 15%.”
In this context and under the terms of this Agreement, ACF has to provide WHO with a
written justification and the calculation used to determine the price in the public sector.
23
To date no such discussions have taken place between WHO and Artecef B.V. although
steps are being taken by Roll Back Malaria and TDR to arrange such meetings.
3.3
Private Sector Pricing
Article 11 point 2 of the Agreement signed in 1991 states that:
“ACF has right to fix the price for the private sector without the agreement of WHO.
However, it has agreed to provide WHO with a royalty of 4% of the net sales revenue of
all products sold for distribution through the private sector”.
3.4.
Addendum to the Agreement.
The Addendum to the Agreement signed in 1994 does not appear to this reviewer to
change the issues on pricing discussed above except that it clarifies that the royalty
payment to WHO on private sales would not include the sales of products between ACF
on one side and its licensees and designees on the other.
The Addendum contained the following amendments:












4.
stated that the original Agreement remains in effect, unless explicitly amended by the
Addendum
redefined the definition of developing countries;
redefined the “net sales revenue” to include the amounts received by ACF licensees
and designees in addition to the company itself;
covered the provision by ACF of formulations and dosage forms that may be required
by WHO to carry out Phase II and III trials;
ACF agreed to full fill all requirements necessary for registration of candidate drug
formulations;
modified the article on the quality of the products to cover those produced by ACF,
its licensees and designees;
increased the amount of funds to be made available for the development up to a
maximum of 6,400,000 Dutch Guilders;
increased the amount of the advance payable by WHO to ACF to 400, 000 Dutch
Guilders (the conditions of payments remained the same);
defined actions to be taken in the event of the Dutch Government withdrawing
support to the project;
provided the conditions for licensing for a period of 6 years after the registration of
the formulation of -arteether (now artemotil);
deleted reference to European Patent Application No 89301914.1 that was
withdrawn;
empowered ACF to ensure that its licensees and designees meet their obligations to
WHO.
Recent Correspondence from Artecef B.V. to WHO
Dr Charles Lugt’s letter of 6 December 2001 to Dr Andrea Bosman, RBM stated that:
24







South African authorities will register artemotil and give market authorisation in
December 2001;
Artecef B.V. will manufacture 164 400 ampoules of Artecef 50 and 338 000
ampoules of Artecef 150, sufficient for the needs of 80 000 patients. The date of
production was not given;
registration of artemotil will also be sought in selected malaria endemic countries in
Africa. (specific countries were not named and no mention was made of countries
outside Africa);
a marketing campaign has been launched in order to make the products widely
available to the non-profit sector and aid agencies;
a Memorandum of Understanding has been signed with IDA;
3200 ampoules of Artecef 50 and 3500 ampoules of Artecef 150 have been sold, the
majority to IDA with the balance to Dutch hospitals;
negotiations are underway with PHARMA AID, Germany for Artecef B.V. to supply
substantial quantities of the drug to aid projects in Chad.
The letter also provides arguments for inclusion of the drug in the WHO Model List of
Essential Drugs but surprisingly no reference is made to the Agreement between the
Company and WHO!
5.
Suggested Action by WHO.
This reviewer recommends that:

WHO should, as soon as possible, discuss with Artecef B.V. the price of artemotil
within the Public Sector. This information is essential for consideration of the
inclusion of this product in the Model Essential Drugs List. This action is both
important and urgent in view of the facts that (i) a marketing campaign aimed at the
public sector has been launched by the Company and (ii) a Memorandum of
Understanding has been signed by the Company and IDA, the Netherlands who have
already purchased the majority of the 6700 ampoules sold to date.

RBM/TDR should take advise from WHO’s Legal Counsel to determine whether the
following contravene the Agreement signed between ACF and WHO: (i) the signing
of this Memorandum of Understanding with IDA,(ii) the selling of the drug to IDA at
a price not agreed upon with WHO and (iii) the negotiations with Pharma AID,.
Drugs purchased by IDA are mostly resold to developing countries.

RBM/TDR should clarify the reasons for the withdrawal of the European patent to
which reference is made above. This is not possible from the documents currently
available to this reviewer.

RBM should determine the status of the application by Artecef B.V. for the
registration of artemotil in South Africa and to obtain more details on the proposal of
the Company to seek wider registration of the drug, particularly in Africa.

RBM should consider organising a technical group to review the clinical data on
artemotil and / arteether with particular reference to the restricted labelling due to
QTc prolongations observed in adults.
25
ANNEX 2 CLINICAL STUDIES
1.
Artemotil
The registration and the Company's recommended dosage regimens were based on the
results of the following clinical trials. The design of the these trials was strongly
influenced by the assumptions that injectable artemotil would be used solely for the
treatment of severe malaria and that it would probably be administered in regimens
similar to those currently recommended for artemether.










Phase I Single dose safety and tolerance study, in healthy male subjects, including
pharmacokinetic study (23 subjects);
Phase I Double-blind, controlled, randomised multiple-dose safety and tolerance
study in healthy adult male volunteers, including a pharmacokinetic study (27
subjects);
Phase I Double-blind, controlled, randomised multiple-dose safety and tolerance
study in healthy adult male volunteers, including a pharmacokinetic study (27
subjects);
Phase II Open, randomised dose–finding, efficacy and tolerability study in adult
Thai patients with uncomplicated falciparum malaria (25 patients);
Phase II Open, randomised comparative study of the efficacy and tolerability of
artemotil and and artemether in adult Thai patients with uncomplicated falciparum
malaria (63 patients);
Phase III Open, randomised comparative study of the efficacy and tolerability of
artemotil and artemether in adult Thai patients with severe falciparum malaria (200
patients);
Phase III open, randomised comparative study of the efficacy and tolerability of
artemotil versus quinine treatment in adults with cerebral malaria in Zambia (12
patients);
Phase III open, randomised comparative study of the efficacy and tolerability of
artemotil versus quinine treatment in adults with cerebral malaria in Cameroon (10
patients);
Phase III Multi-centre, open, randomised comparative study of the efficacy and
tolerability of artemotil versus quinine treatment in children with cerebral malaria in
Africa (Cameroon and Zambia - 200 patients);
Phase III Double-blind controlled, randomised comparative efficacy study of
artemotil and artemether in the treatment of Thai children with severe falciparum
malaria (127 patients).
1. 1.
Phase I Single Dose Study
The Phase I single dose study was a rising dose, double blind, placebo controlled
randomised study (the lower two doses and the pharmacokinetic study did not have
placebo groups).
Twenty-three healthy Caucasian males were included in the study. They were aged
between 19-39 years. All completed the study.
26
Single doses of 0.3mg/kg, 0.6mg/kg, 0.9mg/kg, 1.8mg/kg, 2.7mg/kg and 3.6mg/kg
artemotil were injected intramuscularly.
Eight out of the 23 subjects reported a total of 11 adverse events such as pain at the
injection site and headache. All these events were mild and resolved spontaneously. Vital
signs, ECG recordings, physical examinations, inspections of the injection site and
clinical laboratory tests showed no clinically relevant abnormalities and no differences
between artemotil administration and placebo. Pain at the injection site was considered to
be related to use of the sesame oil.
Only preliminary plasma concentration data of 3 subjects who received a dose 3.6mg/kg
were obtained from this non GLP study and no evaluation of the pharmacokinetics was
reported.
1.2.
Phase 1 Multiple Dose Studies
Two Phase I multiple dose studies were conducted.
In the first, 27 healthy Caucasian males were included of which 26 completed the study.
They were aged between 18-38 years.
The dosage regimens were:



3.2mg/kg on day1 followed by 0.8mg/ kg daily on days 2-5;
3.2mg/kg on day1 followed by 1.6mg/ kg daily on days 2-5; and
a placebo of sesame oil.
The same safety parameters as in the single dose study were monitored with special
attention given to audiometric tests and neurological examinations.
Thirty-three adverse reactions were reported by 15 of the 27 subjects. All were mild and
resolved spontaneously. Six subjects had flu’ like symptoms (5 receiving artemotil and 1
in the placebo group). One subject withdrew from the trial as a result of these symptoms.
Rechallenge with the sesame oil alone caused a similar intolerance. The investigators
concluded that this reaction was due to oil used in the batch of medication.
Vital signs, ECG recordings, physical examinations, inspections of the injection site and
clinical laboratory tests showed no clinically relevant abnormalities and no differences
between artemotil administration and the placebo.
An increase in eosinophils was observed both in those receiving artemotil and the
placebo. This was associated with the flu’ like symptoms described above. Audiometry
tests showed no baseline changes except for one subject who received the highest dose of
artemotil. This person showed a slight hearing loss.
Only preliminary plasma concentrations (non GLP) were obtained and so no formal
evaluation of the pharmacokinetics was made.
27
Before initiating clinical trials in patients with falciparum malaria, it was decided that
more information was required on safety and pharmocokinetics parameters. The more so
since the first 2 Phase I trials were not conducted according to GCP. Therefore a second
multi-dose study was conducted. This was also in 27 healthy Caucasian males. They were
aged between 19-31 years. All completed the study.
In this second multi-dose study, artemotil drug was administered intramuscularly as:




2.7mg/kg on day 1 followed by 1.35 mg/ kg daily on days 2-5;
3.6mg/kg on day 1 followed by 1.8mg/ kg daily on days 2-5;
4.5mg/kg on day 1 followed by 2.25mg/ kg daily on days 2-5; and
a placebo of sesame oil.
Twenty adverse events with possible or probable relationship to artemotil were reported
by 13 of the 27 subjects. The nature and incidence were similar in the artemotil and
placebo groups. Pain at the injection site was the only adverse reaction related to
treatment. In all cases, it was of mild intensity and relatively of short duration. It was
concluded that this adverse event was related to the intramuscular injection of the sesame
oil rather than to artemotil since the occurrence was evenly distributed in all groups
including the placebo. (N.B. This appears to contrast with the Phase I single dose study
but the numbers in the groups are relatively small).
The results of vital signs, ECG parameters, neurological examinations (including
audiometry), inspection of injection site and clinical biochemical tests did not show any
abnormalities.
The pharmacokinetic study showed that artemotil peak concentrations occurred typically
between 8-12 hrs after drug administration. Steady state was generally attained from the
4th injection onwards but the highest steady state (about 100ng/ml.) was achieved already
with the highest loading dose of 4.5mg/kg. Concentrations of dihydroartemisinin were
very low as compared with the parent compound and were below the limit of detection in
many samples.
1.3.
Phase II Studies in Uncomplicated malaria
1.3.1 Dose finding study in uncomplicated malaria
The objective of this study was to determine the optimum 5-day regimen of intramuscular
artemotil that would provide a curative effect of >80% in patients with uncomplicated
falciparum malaria. In addition, safety, tolerance and pharmacokinetics parameters were
assessed.
The study was carried out in 25 adult Thai patients, aged between 16-40 years. 17 were
males and 8 were females. 19 patients completed the 28-day follow-up period.
The dosage regimens were:
28



3.2mg/kg on day 1 followed by 1.6mg/ kg daily on days 2-5 (6 patients completed 28
day follow-up)
3.2mg/kg on day1 followed by 0.8mg/ kg daily on days 2-5 (8 patients completed 28
day follow-up); and
1.6.mg/kg on day1 followed by 0.8mg/ kg daily on days 2-5 (5 patients completed 28
day follow-up).
Dose regimens of 3.2 mg/kg on the first day followed by either 1.6 mg/kg or 0.8 mg/kg
showed cure rates greater than 80% and similar efficacy in adult patients with
uncomplicated falciparum malaria (with fever clearance times of 42.5  28.6 hours and
22.4  11.2 hrs respectively and parasite clearance times of 36.5  11.0 and 35.1  9.8 hrs
respectively).
A dose regimen with a loading dose of 1.6mg/kg followed by 0.8 mg/kg produced only a
40% cure rate.
All treatments were well tolerated, both locally and systemically, based on evaluations of
adverse reactions, neurological examinations including audiometry, local tolerabilty at
the injection site, vital signs, ECG parameters and clinical biochemical tests.
A pharmacokinetic–pharmacodynamic evaluation of the patients showed that plasma
concentrations of artemotil during the first two treatment days were an important
determinant of parasite clearance times in uncomplicated falciparum malaria. Absorption
of the drug from the injection site was highly variable.
1.3.2. Comparison of artemotil and artemether for treatment of uncomplicated
falciparum malaria in Thai adults.
This comparative efficacy and tolerance study of artemotil and artemether was carried out
to confirm the results of the previous study in Thailand with artemotil and to compare it’s
efficacy with the standard regimen of artemether used in the country. It was in an open
randomised study in patients with uncomplicated falciparum malaria. 63 patients (37
males and 26 females) aged between 15-50 years entered the trial. Sixty patients
completed the 28-day follow-up. The 3 "drop-outs" were females.
The dosage regimens were as follows:



3.2mg/kg artemotil on day 1 followed by 1.6mg/ kg artemotil daily on days 2-5 (21
patients, 15 males and 6 females) completed 28-day follow-up)
3.2mg/kg artemotil on day1 followed by 0.8mg/ kg artemotil daily on days 2-5 (19
patients, 11 males and 8 females) completed 28-day follow-up); and
3.2mg/kg artemether on day 1 followed by 1.6mg/ kg artemether daily on days 2-5
(20 patients, 11 males and 9 females) completed 28-day follow-up).
Evaluation of 28-day cure rates, fever clearance times and parasite clearance times
indicated that dosage regimens of 3.2mg/kg on day 1 followed by 1.6mg/ kg daily on
days 2-5 of artemotil or artemether show similar cure rates (both greater than 80%) and
efficacy in patients with uncomplicated falciparum malaria as measured by fever
29
clearance time. Parasite clearance times were significantly faster in the artemether group
(43.113.1hrs ) than in the 2 groups receiving artemotil (51.7  11.7 hrs and 54.9  17.1
hrs).
The regimen of 3.2mg/kg artemotil on day 1 followed by 0.8mg/kg artemotil daily on
days 2-5 was slightly less effect although the differences were not statistically significant.
A fever clearance time of around 50 hrs was observed in all 3 groups.
All treatments were well tolerated, both locally and systemically based on evaluations of
adverse reactions, neurological examinations including audiometry, local tolerability at
the injection site, vital signs, ECG parameters and clinical biochemical tests. One patient
receiving artemotil experienced mild pain at the site of the second injection. Adverse
events for which a relationship with artemotil was not entirely excluded were headache
and myalgia.
1.4.
Phase III studies of efficacy in severe falciparum malaria
1.4.1 Comparison of artemotil and artemether in the treatment of severe falciparum
malaria in Thailand.
The primary objective of this study was to compare the survival rates of patients with
severe malaria that had received either intramuscular artemotil or intramuscular
artemether.
Secondary objectives were to (i) compare the efficacy of artemotil and artemether with
respect to parasite clearance times, fever clearance times, coma resolution times and 28day cure rates; (ii) study the pharmacokinetics of artemotil after administration of two
dose levels and after administration in the gluteal region and the thigh; (iii) study the
effect of disease parameters and demographics on the pharmacokinetics of artemotil, and
(iv) evaluate safety and tolerability.
The study was originally intended to be only a comparative efficacy study. However
there was no prospectively defined sample size. Instead, the study design was determined
by an ongoing evaluation of efficacy, tolerability and pharmacokinetic data. Blinding of
the study would have required adding extra placebo injections in the drug regimens and
extra blood sampling in the first 50 patients that were treated with artemether. It was
thought prudent therefore to minimise the burden on the patients and perform an openlabel study.
To avoid bias in baseline parameters, patients were randomly assigned to one of three
treatments based on the allocation of sequential treatment numbers in order of admission.
To avoid bias in the outcome of parasite counts and parasite clearance times, the
technicians reading the slides were blinded with respect to treatment and time of
sampling. However, it should be noted that the primary end point, survival rate, was also
dependent on the clinical judgement of the principal investigator concerning the need for
intervention with the rescue treatment (artesunate). Thus, a bias in the outcome of
survival can not be excluded.
30
Two hundred patients, aged 15-60 years, entered the trial. 196 patients were evaluated of
which 136 were males and 60 females.
The dose regimens were:



3.2mg/kg of artemotil given intramuscularly on day 1 followed by 1.6mg/ kg daily
on days 2-5
4.8mg/kg of artemotil given intramuscularly on day 1 followed by 1.6mg/ kg daily
on days 2-5
3.2mg/kg of artemether given intramuscularly on day 1 followed by 1.6mg/ kg daily
on days 2-5
During the study 3 deaths and 16 cases of RIII (defined as patients with increasing or
persistently high parasitaemias until 48 hours) were reported. (Note that this definition is
different from the normal WHO definition of RIII). These patients with RIII received
the rescue treatment much earlier than 48 hours (often within 12-18 hours) which was too
early to know the effect of artemotil or artemether in the long term..
Comparisons of survival rates showed a higher survival rate with the artemotil high
loading dose regimen (94.6%) compared to the artemotil low loading dose regimen
(87.0%) and to artemether (88.7%). Statistical analysis showed no difference in the
survival rates between the 3 drug regimens, indicating that high dose artemotil was not
inferior to the standard artemether regimen used in Thailand.
Higher loading dose artemotil produced, however, significantly faster parasite clearance
times than either artemether (PCT high artemotil = 59.4 hrs; PCT artemether = 72.2 hrs;
p< 0.001). Fever clearance (around 76 hrs) and coma resolution times (around 30 hrs)
were similar in all treatment groups.
In the patient population with 28 day follow-up or follow-up until recrudescence, the cure
rates were higher in the high loading dose artemotil group (55.9%) than in those patients
receiving either artemether (40.0%) or low loading dose artemotil (41.5%).
The total number of adverse events and percentage subjects with adverse events were 47
(32%), 17 (21%) and 84(62%) for low dose artemotil, artemether and high dose artemotil
respectively. None of the adverse events was considered related to drug administration.
There were also no clinically relevant differences in vital signs, ECG parameters,
neurological examinations, inspection of injection site or clinical biochemical tests.
High dose artemotil administration (loading dose of 4.8 mg/kg) resulted in approximately
1.7 times higher Cmax values and 1.5 higher AUC values on day 0 compared to normal
dose artemotil regimens (loading dose of 3.2 mg/kg). These higher concentrations could
explain the reason for the lower parasite clearance times in the artemotil group receiving
the higher loading dose.
1.4.2. Comparision of artemotil and quinine in adult Zambian patients with cerebral
malaria.
31
It was originally planned that this open, randomised, single centre trial in Zambia would
include 120 patients but only 12 (9 males and 3 females, aged between 17 and 56 years)
could be enrolled from February 1996-January 1998 in spite of a relaxation in the criteria
for inclusion. The trial was, therefore, terminated prematurely and the patients only
evaluated for tolerance and safety.
The dosage regimens were:


3.2mg/kg artemotil on day 1 followed by 1.6mg/ kg artemotil daily on days 2-5, and
20mg/kg quinine dihydrochloride intravenously over 4 hours as a loading dose,
followed by 10mg/kg quinine dihydrochloride given (intravenously and then orally)
eight hourly up to 6 days. Oral treatment with quinine commenced when the patient
was able to take the medicine by mouth and after at least 3 intravenous doses.
Two patients died during the artemotil treatment and 3 patients died after quinine
administration. The patients that survived all left the study in good health. Patients treated
with quinine experienced the normal and expected adverse reactions. The results of
physical examinations, vital signs, clinical biochemical tests and ECG recordings
provided no indications of untoward effects of either treatment.
1.4.3. Comparision of artemotil and quinine in adult Cameroonian patients with
cerebral malaria.
It was originally planned that this open, randomised, single centre trial in Cameroon
would include 60 patients but only 10 (4 males and 6 females, aged between 17 and 56
years) could be enrolled from October 1997- February 1998 in spite of a relaxation in the
criteria for inclusion. The trial was, therefore, terminated prematurely and the patients
only evaluated for tolerance and safety.
The dosage regimens were:


3.2mg/kg artemotil on day 1 followed by 1.6mg/ kg artemotil daily on days 2-5, and
20mg/kg quinine dihydrochloride intravenously over 4 hours as a loading dose,
followed by 10mg/kg quinine dihydrochloride given (intravenously and then orally)
eight hourly up to 6 days. Oral treatment with quinine commenced when the patient
was able to take the medicine by mouth and after at least 3 intravenous doses.
Two patients died after artemotil admintration and two after treatment with quinine.
The results of safety assessments i.e. physical examinations, vital signs ECG recordings
and clinical laboratory tests showed no untowards effects of either artemotil or quinine
administration.
The patients who survived the study left in a good state of health.
1.4.4 Comparison of artemotil and quinine African children with cerebral malaria.
32
This multicentre open, randomised parallel group comparative study was orginally
planned to include 480 patients from 5 Centres in Africa. A double blind study design
was considered ethically unacceptable since this would require unnecessary
administration of either placebo infusions or placebo intramuscular injections which
would be an unacceptable burden on very sick children. Two centres were unable to start
the study and patient recrutement in the others was slow. The trial was therefore modified
as a three Centre study with a total of 200 patients.
The trial was carried out in Yaounde, Cameroon (103 patients evaluated - 52 treated with
artemotil and 51 given quinine), Macha, Zambia (45 patients evaluated - 23 artemotil
and 22 quinine) and Lusaka, Zambia (45 patients evaluated - 23 artemotil and 22
quinine).
The dosage regimens were:


3.2mg/kg artemotil (Artecef 50 formulation) on day 1 followed by 1.6mg/ kg
artemotil daily on days 2-5, and
20mg/kg quinine dihydrochloride intravenously over 4 hours as a loading dose,
followed by 10mg/kg quinine dihydrochloride given (intravenously and then orally)
eight hourly up to 6 days. Oral treatment with quinine commenced when the patient
was able to take the medicine by mouth and after at least 3 intravenous doses.
Children, aged up to 10 years old showing signs of cerebral malaria with a Blantyre coma
score of <2, asexual falciparum parasites in the peripheral circulation and no other
obvious causes of coma were included in the study. The follow-up period was 28 days.
200 patients were included of which 193 were evaluated for safety, tolerability and
efficacy and 197 for safety and tolerability.
The mean age of the patients from all centres was 3.42 (range 0.5-9.9) years, with a mean
body weight of 13.17 (range 4.9 – 36.0) kg. 117 of the patients evaluated were males and
80 females. The distribution of patients into age terciles was defined as low (66 patients),
medium (71) and high (60). The corresponding distribution according to body weight
terciles was defined as low <5kg (66), medium 5-10 kg (66) and high 11-15 kg (65).
To avoid bias due to the open design, treatment allocation occurred after the decision that
a patient was eligible for the study and assignment of the patient number by opening a
sealed envelope with the treatment allocation for the corresponding patient number. In
contrast to the Thai studies no alternative rescue treatment was available. Non survivors
mainly consisted of deaths. Deaths were however not differentiated with respect to time,
i.e. as either early or late deaths.
Forty-four deaths were reported from the three centres of which 3 occurred before
treatment was started. Eighty-two (82%) patients given artemotil and 67 (72%) given
quinine survived in the three Centres. The 90% confidence interval for the difference
(artemotil- quinine) was –0.0%- 19.9%, indicating that artemotil was at least equivalent
in efficacy to quinine (lower limit of 90% confidence interval above  of –5%). Initial
parasite counts, initial Blantyre coma score and history of illness were significant
baseline characteristics, but they did not confound the comparison of treatments.
33
Coma resolution times (42.1  35.9 hrs artemotil and 40.8  61.06 hrs quinine) and
parasite clearance times (48.3  25.3 hrs artemotil and 46.9  21.0 hrs quinine) did not
significantly differ between the two treatments. Fever clearance times, however, were
significantly shorter (p = < 0.05) after quinine treatment (39.5  26.0hrs) than after
artemotil treatment (56.5  60.5 hrs). Parasites persisted until 7 days in 3 patients, all
receiving quinine but the number of patients in which recrudescences occurred during
28 days follow-up was similar in both treatment groups.
Both treatments were well tolerated, both locally and systemically, although the number
of possibly drug related adverse events was higher in the quinine group than in the
artemotil treatment group. Artemotil was easier to administer.
1.4.5 Comparison of artemotil and quinine in Thai children with severe malaria
This was designed as the final pivital study to support the registration of artemotil.
The primary objective of this study was to compare the efficacy of the artemotil regimen
with the high loading dose with the standard regimen of artemether used in Thailand.
Secondary objectives were to assess the pharmacokinetics/pharmacodynamics of
artemotil and its metabolite, dihydroartemisinin, in this age group and to assess the
tolerability of the artemotil regimen in children.
This double-blind, controlled, randomised-comparative study was carried out in Bangkok
and Mae Sod, Thailand in children aged between 1-16 years, with one or more
symptoms of severe or complicated malaria as defined by WHO (WHO, 1990) and/or
inability to swallow or retain oral medication and at least 1000 P. falciparum per l
blood. It was originally planned to include 100 patients (50 in each treatment group) but
in total 127 patients were included of which 125 were evaluated for survival as the
primary end-point of efficacy.
The artemotil formulations used were Artecef 50 and Artecef 150. The dosage regimens
were:


intramuscular administration of 4.8g/kg artemotil at t=0hrs (equally divided over both
thighs), followed by 1.6mg/ kg artemotil intramuscularly at t=6hrs, 24, 48 and 72 hrs,
followed by placebo at t=96 hours); and
intramuscular administration of 3.2 mg/kg of artemether t = 0hrs (equally divided
over both thighs), and placebo at t=6hrs, followed by 1.6mg/ kg artemether
intramuscularly at 24, 48, 72 and 96 hrs.
The dose of artemotil was chosen since a loading dose of 4.8 mg/kg was shown in Thai
adults to produce higher initial blood levels (as measured by Cmax and AUC) and faster
parasite clearance times than a loading dose of 3.2 mg/kg.
The mean age of the patients was 8.7 years in the artemotil group and 9.0 years in the
artemether group. There were twice as many male children than females in each group
34
(total 83 males and 42 females).The individual demographic details of the patients was
not included in the file so that it is not possible to determine the number of experiences in
each age/weight group.
Surprisingly no deaths were recorded in the study and all 125 evaluated patients (62
given artemotil and 63 artemether) recovered. Four of these patients (1 receiving
artemotil and 3 artemether) should have received rescue treatment according to the
protocol. If survival rate is adjusted to take account of these cases, survival rates of
98.4% for artemotil and 95.2% for artemether are obtained. It was concluded that the
intramuscular administration of artemotil and artemether resulted in similar high survival
rates with full clearance of parasites within 96 hrs. The confidence limits for survival rate
with artemotil were within the equivalence margin of 5%. In spite of the unexpected high
survival rate, post hoc power evaluation indicates that the study had sufficient power to
support the conclusions of the study.
The principal investigator attributed the higher survival rates in this study to the
following factors: (i) a tendency in the Mae Sod and Bangkok area to refer malaria
patients earlier to the study centres for specialised treatment at the first signs of
progression from acute to severe malaria; (ii) improvement in the supportive treatment of
severe malaria in the centres; and (iii) more experience among the staff with
intramuscular artemether and more confidence in the therapeutic result even if there is no
immediate improvement of the patient
No clinically relevant differences were observed in parasite and fever clearance times and
coma resolution times between the two treatments.
Although there were wide variations in the pharmocokinetics of the drugs, there were no
indications that this affected efficacy and pharmacodynamics. Absorption of artemotil
from the injection site was immediate with measurable concentrations for all patients in
the blood sample taken 1 hour after the first dose. Concentrations of dihydroartemisinin
were typically less than 10% of those of artemotil.
Both treatments were well tolerated, both locally and systemically and the safety data
indicate that artemotil can be given to children with severe or complicated malaria
malaria.
Both formulations of artemotil (Artecef 50 and Artecef 150) were used in this trial. They
were equally efficacious and safe in the 2 study sites and against infections in either
males or females.
This trial of the adminstration of artemotil to 62 Thai children with severe malaria is the
sole experience with the final dosage regimen recommended by the manufacturer and
accepted by registration in the Netherlands.
1.5. Evaluation of QTc interval changes in clinical trials with artemotil.
Slight prolongations of the QTc intervals were observed in dogs receiving artemotil. As a
consequence, an independent detailed analysis was made of the ECG measurements from
35
four of the clinical trials. These trials were:




Phase I double blind multiple dose safety and tolerance study in 27 healthy adult
Caucasian males;
Phase II dose finding study of artemotil in 25 Thai adults with uncomplicated
malaria;
Phase II comparative study of artemotil and artemether in 63 Thai adults with
uncomplicated malaria; and
Phase III comparative study of artemotil and artemether in 126 Thai adults with
severe malaria.
Data from all ECG recordings in these trials were analysed. For this analysis, four
categories of QTc intervals were used:




Normal - a QTc interval of less than or equal to 430 msec. for males and less than 450
msec. for females;
Borderline - a QTc interval between 431- 450 msec. for males and between 451- 470
msec. for females;
Prolonged – a QTc interval between 451 – 500 msec for males and between 471 –
500 msec. for females; and
Cause for concern – all QTc values above 500 msec. in males and females.
For QTc interval changes versus baseline the following categories were used without
differentiation between males and females:



No concern - >30 msec.;
Some concern – 30-60 msec.; and
Clear concern - > 60 msec.
In the multiple dose Phase I study in healthy male volunteers, all absolute values after
artemotil administration (n=243) were normal (below 430 msec.) with one exception in
the category borderline which was in the placebo group. There were no values in the
ranges prolonged or cause for concern. In fact, QTc tended to decrease rather than
increase. These values were similar in the group receiving active treatment and in the
placebo group. Four decreases of>60 msec. occurred in the placebo group and one of >60
msec. in the intermediate dose group.
In the dose finding study of patients with uncomplicated falciparum malaria, 7 out of 188
observations (3.7%) were in the borderline range. There were no values in the ranges
prolonged or cause for concern or any changes >60 msec. during the entire study..
In the comparative efficacy study of artemotil and artemether in uncomplicated malaria,
12 out of 117 observations (10.3%) after artemotil administration were in the borderline
category. All observations after artemether administration were normal.
In the study of adult patients with severe malaria in Thailand, there was one value of
clear concern (525 msec.) in the artemether group. Eight out of 162 observations (4.9%)
36
were prolonged, of which 6 were in the low dose artemotil group and 2 in the artemether
group. Eighteen observations (11.1%) were borderline values. In this study, 12 patients
had already borderline (n=2) and prolonged (n=10) QTc values before drug
administration. This was probably related to their clinical condition or previous drug
administration. In this study there was also a tendency for more decreases than increases
in the QTc interval which was similar in all dose regimens. Prolongation of < 60 msec.
was observed in two ECGs (1.2%) in the low dose artemotil group These changes were in
two different patients with baseline values below 400msec.
Analysis of 6 subjects that developed marked prolonged QTc intervals following drug
treatment although not to level of cause for concern showed that two had abnormal
patterns before treatment with high U waves and predisposing for increased susceptibility
to QT prolongation and another had evidence of a previous myocardial infarction..
The independent evaluator concluded that overall these results do not show significant
effects of artemotil on QTc intervals. In addition, there were no dose related effects.
However, the manufacturers of artemotil state in their Summary of Product
Characteristics that “In general, artemotil shows no tendancy to QTc-interval
prolongation at the recommended dosage regimens. QTc-interval prolongation may
incidently occur in patients with pre-existing abnormal ECG (high U-waves and old
infarctions). Until the clinical consequences of the observed QTc prolongations are
clarified, artemotil should not be used in adults”
The significance of the observed changes in QTc intervals needs to assessed. The
association of such changes with the administration of artemisinin or its derivatives does
not appear to have been reported previously. Although the changes after artemotil
administration were not so great to give concern, one patient receiving artemether in a
comparative trial with artemotil had prolonged QTc intervals that could have been
dangerous.
2.
/ Arteether
Only limited clinical studies of / Arteether were carried out prior to registration which
according to the Company was based on the following trials:




Phase I single-dose safety and tolerance study in healthy adult male volunteers (30
subjects);
Phase I multiple-dose safety and tolerance study in healthy adult male volunteers (20
subjects);
Phase II open non-comparative efficacy study in adults with uncomplicated
falciparum malaria (51 subjects); and
Phase III open non-comparative multicentre study efficacy study in patients with
uncomplicated falciparum malaria (267 adult patients) and severe falciparum malaria
(211 patients) – documents available make it impossible to determine the number of
children in this study but from the material and methods sections of published
documents children under 14 years of age were excluded).
37
All the above studies were carried out in India, details of which have been published in
the international or Indian scientific press. The following evaluation has been based on
these published documents, abstracts of papers presented to scientific meetings, the
Company’s Product brochure, and internal Company reports from investigators.
Individual patient data and detailed protocols were not provided.
From the data provided by the Company, it appears that;





there is no data on the pharmacokinetics or pharmacodynamics of / arteether in
patients with uncomplicated or severe malaria;
clinical dose finding studies do not appear to have been carried out;
the choice of the dose regimen used in the clinical trials appears to have extrapolated
from other group’s experience with artemether and studies carried out in India on the
efficacy of / arteether in simian malaria models (Asthana et al., 1994); and
although the Company recommends the use of the drug in children, the information
provided to support this was minimal and can not be evaluated (only a summary
report of the use in 21 children was provided); and
the drug may have been registered without any experience in children since children
under 14 years were excluded from the clinical trials used for registration (listed
above) ;
2.1 Phase 1 Single and Multi-dose study in adult male volunteers
The Phase I single dose study was a double blind, placebo controlled and non-crossover.
There were 6 adult male volunteers in the placebo group and 4 in each of the treatment
groups, receiving 20, 50, 100, 150, 200 and 300 mg / arteether respectively.
In the Phase I multi-dose study 10 adult male subjects received 100 mg / arteether and
10 subjects received 150 mg / arteether once a day as a intramuscular injection for 3
consecutive days.
Detailed pre- and post- drug administration monitoring of clinical, haematological and
biochemical parameters did not suggest any drug related abnormalities. Single as well as
repeated injections were well tolerated. No tenderness, swelling or discomfort at the site
of the injections was experienced by any subject. The subjects were monitored for 4
weeks after drug administration (Asthana et al., 1994).
There were no pharmacokinetic data provided from these trials and it not clear even
whether they were carried s incorporated into these studies.
2.2 Phase II efficacy study in adults with uncomplicated falciparum malaria
Fifty-one (43 male and 8 female) adult patients suffering from uncomplicated falciparum
were included in the open Phase II efficacy study. All received 150 mg / arteether
injected intramuscularly on each of three consecutive days. Two patients were withdrawn
from the trial. One of these was a male patient who failed to respond after 2 days of
treatment with artemotil but did respond to quinine treatment. The other was given
chloroquine inadvertently after parasite clearance.
38
Complete parasite clearance from the peripheral blood was observed in 80% of the
patients at 48 hours and 98% at 72 hours. The median parasite clearance time was 2 days
(range 1- 4 days). Sixty five percent of the patients became afebrile after within 48 hours
and 81% by 72 hours. The mean fever clearance time was 52 hours. No drug related
adverse reactions were observed. Patients were followed up for 28 days after drug
administration during which 7 were admitted to hospital but it could not be ascertained
whether these were re-infections or recrudescences (Mishra et al., 1995, Asthana et al.,
1996, 1997).
2.3. Phase III Studies in patients with uncomplicated and severe falciparum
malaria
A total of 267 patients (191 males and 76 females) with uncomplicated falciparum
malaria were included in an open, non comparative, non-controlled multi-centre Phase
III study carried out in seven geographically distinct sites (Bhilai, Delhi, Dibrugarth,
Guwarhati, Jabalpur, Jamshedpur and Rourkela). The patients were aged between 18-70
(mean 31.06  12.57) years. / arteether was given intramuscularly as a dose of 150 mg
daily for 3 consecutive days. Each patient was hospitalised for 7 days and followed up for
28 days as an out-patient.
The cure rate was 97% with mean fever clearance times of 2.1 days (range 1-7 days) and
mean parasite clearance times of 1.3 days (range 1-3 days). Parasites reappeared in 3% of
the patients and were reported at 3 of the Centres (i.e. Dehli, Dirugarh and Jabalpur). No
drug related changes were observed in the clinical, haematological and biochemical
parameters measured (Asthana et al., 1997, 2001a).
211 patients suffering from complicated falciparum (as defined by WHO criteria, WHO,
1990) also received / arteether intramuscularly as a dose of 150 mg daily for 3
consecutive days.The study was carried out at four sites (Bhilai, Guwahati, Jamsedpur
and Rourkela). It was open and prospective. Patients were aged 18-60 (mean 34.04
14.34) years, of which 141 were male and 70 were female.
Fourteen patients died in this trial, death occurring in 10 of these patients within the first
2 days of treatment. Four died after completing the 3 days treatment but each had cerebral
symptoms and renal complications.
197 patients recovered. The cure rate at the 7 centres ranged from 91.5-100% with rapid
recovery from coma in cerebral malaria patients and of other complications. Fever and
parasite clearance times ranged from 24-168 hours and 24-120 hours respectively
(Asthana et al., 1997. 2001b, Mohanty et al. 1997). Only one patient at Jamshedpur
showed parasite recrudescence after treatment.
2.4.
Studies in children.
There are no data published in the scientific literature on the use of / arteether in
young children. However, reference is made in the E-MAL Product Monograph to a
clinical study of artemotil in the treatment of in a tribal belt of Hoshangabad District in
39
India in which 21 children aged 3-11 years and 11 (8 males and 3 females) adults were all
cured from complicated falciparum malaria. Coma clearance times ranged from 3-5 days,
fever clearance times between 24-48 hours and parasite clearance times between 24-72
hours. The details reported on this study were minimal and separate data were not given
for the group of children treated (U.K. Shukla, undated report to Themis Chemical Ltd.).
2.5.
Comparision of efficacy of / arteether and quinine for treatment of severe
falciparum malaria
The efficacy of / arteether and quinine for treatment of severe falciparum malaria has
been compared in 48 patients (age and sex not indicated) suffering from severe
falciparum malaria. 26 patients received 150mg / arteether for 3 days and 22 received
intravenous quinine (regimen not given). No details were reported on the study design.
Mortality was reported to be less followingh / arteether treatment (3.85%) than with
quinine (27.27%) Recovery from coma was also reported to be more rapid with /
arteether (24.5  14.7 hours) than with quinine (38.1  26.8 hours) but the difference
does not appear to be statistically significant.
There were no differences in fever or parasite clearance times between the two drugs.
The adverse reactions were significant with quinine: two patients had hypoglycaemia and
7 developed cinchonism during therapy (Mishra et al., 1997).
This report was an abstract from a scientific meeting and gave little information. In the
absence of details of study design it is not possible to determine the significance of the
results.
2.5.
Other Studies
A further unpublished report was provided by Themis of a study of the efficacy of /
arteether in 220 patients with uncomplicated malaria (200 cases falciparum malaria and
20 of vivax malaria) as well as 30 patients with severe falciparum malaria. This study
was carried out in Jodhpur, Western Rajasthan in an area of chloroquine resistant
falciparum malaria.
Patients were aged between 15-70 years. Of the 220 patients with uncomplicated malaria.
136 were males and 84 females. No details were given on the study design. All received
150mg / arteether given intramuscularly on three consecutive days. (unpublished and
undated report by A.Jain et al. to Themis Ltd).
All patients with vivax malaria were reported as cured based on fever resolution and
parasite clearance rates but it appears that the patients were not followed up after
apparent cure (note artemisinin and its derivatives do not have anti-relapse activity). It
appears that parasites were cleared in 91.5% of the patients with uncomplicated
falciparum malaria (parasite clearance time of 54 (31-86) hours).
A total of 8 deaths occurred in the 20 patients with severe malaria, 7 of which occurred
within 48 hours after the first treatment, the remaining death occurred after 3 days (a very
high failure rate!).
40
18 pregnant women were reported as having been treated with / arteether, none of
which had an abortion. Nine patients delivered their babies during the study, all of which
were reported as normal. It was not clear if these patients suffered from uncomplicated or
severe malaria.
Asymptomatic sinus bradycardia was observed in 6 patients (2 with severe malaria and 4
with uncomplicated malaria) following treatment. All cases resolved spontaneously
without specific treatment.
It was impossible to analyse the results because of incomplete data, apparent errors in the
reported numbers and the lack of details of the study design and procedures carried out.
2.7.
Phase IV Post Marketing Surveillance
Following permission to market the drug in January 1997, the Drug Controller General,
India recommended that monitoring of adverse reactions to / arteether should take
place as part of post-marketing surveillance according to a protocol agreed upon by his
offices. This protocol was developed with clinicians as part of a series of country-wide
symposia on the use of / arteether.
During the period January- December 1997, 300 signed PMS forms were returned to the
Company. These reports were from 6 States, Gujarat (65% of total reports), Rajasthan
(27%), Madhya Pradesh (3.7%), Bihar (2.7%), Maharashtra (1%) and Uttar Pradesh
(1%).
The reports were of the treatment of patients, aged from 5-75 years, of which 216 were
males and 84 females. The majority of the patients (76%) were aged between 16 and 45
years. Each patient received 150 mg artemotil intramuscularly daily for 3 days. Blood
smear examinations showed that 257 patients had falciparum malaria, 20 vivax malaria
and 17 a mixed infection. Six patients did not have malaria parasites on the peripheral
circulation.
The efficacy and safety was analysed based on the information provided by the treating
physicians. The results show that 294 (98%) were cured, 5 cases improved and one
patient did not show any change in clinical status during the 3 day period (it is not clear
from the summary report whether this patient had parasites in the blood.). 123 patients
were cured on Day 1, another 33 on by Day 2 and a further 138 on the third day. There
were no reported deaths.
Ninety-eight of the patients did not receive concomitant medication. Of the remaining
202, 44 received additional antimalarials (33 received quinine, 8 mefloquine and 3
chloroquine) (if the figures are correct 3 patients must have received 3 antimalarials i.e.
artemotil plus 2 others), 69 antipyretics/analgesics, 89 antibiotics, 3 sedatives, 15
vitamins and 40 i.v. fluids.
Adverse reactions such as headache, vomiting, nausea, giddiness were reported in only
14 cases but the causal relationship with drug administration could not be ascertained
(These symptoms are all indicative of malaria and as i.v. fluids were given to 40 patients
it is suprising that this list of adverse reactions is not greater).
41
This report is of limited value. It does not:





distinquish between the use of the / arteether for severe and for uncomplicated
malaria;
provide specific information on children which apparently received the same amount
of drug as the adults (i.e. much higher doses/kg than the adults);
provide information on the reasons why additional antimalarial drugs were given, the
timing of their administration and their contribution to the survival of the patients;
provides only limited information on adverse reactions reported; and
provide estimates of risk and denominators.
42
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