Download Fixed combination of arthemether and lumefantrine

(CDS/RBM, 18 March 2002)
REVIEW OF APPLICATION FOR INCLUSION OF A DRUG IN THE WHO
ESSENTIAL DRUGS LIST
Fixed combination of artemether and lumefantrine (COARTEM)
Background to current application
The first application for the inclusion of artemether/lumefantrine in the WHO Model List
of Essential Drugs was reviewed by the Expert Committee on Essential Drugs in 1999
(WHO, 2000a). The Committee considered that the combination had the potential to play
an important role in the management of uncomplicated falciparum malaria but that it was
not appropriate at that time to include it in the WHO Model List of Essential Drugs since
(i) there was no data operational use of the combination; (ii) the Company proposed two
dosage regimens to be used in non-immune and semi-immune patients which was might
lead to confusion; (iii) there were concerns regarding the degree of compliance that may
be obtained in rural health settings with a drug combination that required a relatively
long and complex treatment regimen (i.e. 6 doses over 60 hrs); and (v) the affordability
of the combination for populations in greatest need.
Following discussions between the Company and WHO/ RBM, a Memorandum of
Understanding was signed by the two parties to address these issues. The terms of this
Memorandum include the following:

The Company will work together to carry out additional clinical studies needed to
support the registration of the combination as a 6-dose regimen for adults and
children in malaria endemic countries where this has not been done. This will include
evaluation of new packaging that will be appropriate for use and assist compliance in
rural populations with limited literary development;

The Company will make the combination available to WHO and the public sector at a
price no greater than cost. This will be supported by the a statement to WHO by
independent auditors that the price does not exceed the costs;

Each party shall notify the other of any serious or other unexpected side effects
associated with the use of the combination;

WHO shall objectively reconsider the inclusion of the combination in any appropriate
malaria treatment guidelines and in WHO Model List of Essential Drugs; and

WHO will establish an Advisory Group of independent experts responsible for
advising WHO on the supply and distribution of the combination to be purchased by
WHO.
1
1. Summary statement on application
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 recommends that artemisinin and its derivatives should be administered in
combination with another effective blood schizontocide in the treatment of acute
uncomplicated multi-drug resistant falciparum malaria to reduce recrudescences and to
slow the development of resistance.
Artemisinin-based combinations have several distinct advantages in that (i). they produce
rapid clinical and parasitological cure; (ii). there is as yet no documented parasite
resistance to them; (iii). they reduce gametocyte carrier rates; and (iv). they are generally
well tolerated
At present, only the ad hoc combination of artesunate with mefloquine is used
operationally for the treatment of acute falciparum malaria in areas of multidrug
resistance. However, fixed combinations of artemisinin derivatives should have
operational advantages since they should be easier to use and provide greater compliance
in the target populations than ad hoc combinations.
Artemether/lumefantrine is the only fixed combination of an artemisinin derivative
which has been both widely studied and registered for the treatment of acute multi-drug
resistant falciparum malaria.
Artemether/lumefantrine has been shown to an efficacious and safe formulation when
used for the treatment of acute uncomplicated falciparum malaria in China, Africa and
Thailand.
Although lumefantrine is similar to halofantrine an antimalarial drug that has been shown
to produce QTc-interval prolongation that may be fatal, extensive studies have failed to
demonstrate QTc-prolongation or any other cardiotoxicity following the administration of
artemether/lumefantrine.
Studies in Thailand indicate that artemether/lumefantrine provides similar cure rates to
artesunate plus mefloquine in areas of multidrug resistant falciparum malaria. Available
results show that it has the potential as an alternative to artesunate plus mefloquine for
use in these areas.
The concerns that were raised when artemether/lumefantrine was considered by the
Expert Committee on Essential Drugs in 1999. These have now been addressed as
follows:
2

Operational experience with artemether/lumefantrine has now been obtained. As a
result of unacceptable levels of resistance to sulfadoxine/pyrimethamine, KwaZulu
Natal was the first Department of Health in Africa to agree upon a malaria treatment
policy with artemether/lumefantrine as the first-level drug. This policy was
implemented in February 2001 in conjunction with improved vector control
measures. The result was a dramatic 78% reduction in the total malaria cases by the
end of 2001 (41 786 cases in 2000 and 9443 cases in 2001). During this period the
number of malaria deaths decreased by 87%. This impressive improvement in the
malaria situation has been attributed to the combined use of residual household
spraying and the replacement of an ineffective treatment by artemether/lumefantrine.

Household surveys showed that, in KwaZulu Natal and Mpumalanga, 95.4% and
86.6% respectively of patients responded that they had completed the treatment
course of artemether/lumefantrine (only 0.5% and 1.3% respectively admitted that
they had treatment remaining at home). New packaging designed to improve patient
compliance in patients of low literary status have been developed and are being
assessed.

WHO treatment guidelines on the use of artemether-lumefantrine were published in
2001. These state that the 6-dose regimen should be adopted as standard treatment for
all age groups and in all situations to avoid confusion and ensure the highest efficacy
and reliability with this combination. The Company agreed to these
recommendations. As only the 4-dose regimen has been registered in certain malaria
endemic developing countries (mainly African), further studies with the 6-dose
regimen are required to support its wider registration in such countries. These studies
are being carried out under the Terms of the Memorandum of Understanding between
the Company and WHO.

The Company has agreed to provide artemether-lumefantrine as Coartem to WHO
at a no-profit price. At present , the cost of a treatment dose based on the 6-dose
regimen is as follows: Children 10-14 kg =US$ 0.90; Children 15-24 kg =US$ 1.40;
Children 25-34 kg =US$ 1.90; Adult > 35 kg = US$ 2.40. This price is
approximately half of the current price of the drug currently being used in KwaZulu
Natal and equivalent to the cheapest price currently available for the ad hoc
combination of artesunate/mefloquine used in Cambodia. The normal price for an
adult of artesunate/mefloquine is US$ 4.06-7.04).

WHO/RBM understands that further reductions in the cost of artemether-lumefantrine
may be possible in the future for the most vulnerable population groups.
In view of the above:
it is recommended that the combination of artemether/lumefantrine is added to the
WHO Model List of Essential Drugs.
3
2. Focal Point in WHO for application
Dr Andrea Bosman
Roll Back Malaria
3. Company submitting application
Novartis Pharma A.G.
Basle
Switzerland
4. International Nonproprietary Name
International Nonproprietary Names are not given to drug combinations. Coartem  is a
fixed combination of two antimalarial drugs with the INN names, artemether and
lumefantrine (previously known as benflumetol).
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 dies
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, 1998, 2000b, 2001a,b).
The importance of artemisinin and its derivatives was also recognised by the WHO
Expert Committee on Essential Drugs (WHO, 1995. 1996, 1997b, 2000a). 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 urgent need and with the full knowledge that
some of the available formulations had not been produced according to GMP.
An informal consultation on "The use of artemisinin and its derivatives as antimalarial
drugs" recommended in June 1998 that artemisinin and its derivatives should be
administered in combination with another effective blood schizontocide in the treatment
of acute uncomplicated multi-drug resistant falciparum malaria to reduce recrudescences
and to slow the development of resistance (WHO 1998). This recommendation was
confirmed by the 20th Expert Committee on Malaria in October 1998. (WHO, 2000b).
Subsequently, an oral formulation of artesunate (the hemisuccinate derivative of
artemisinin), to be used in combination for the treatment of uncomplicated multi-drug
4
resistant falciparum malaria, was added to the Model List of Essential Drugs in 1999
(WHO, 2000a).
Artemisinin-based combinations have several distinct advantages in that (i). they produce
rapid clinical and parasitological cure; (ii). there is as yet no documented parasite
resistance to them; (iii). they reduce gametocyte carrier rates; and (iv). are generally well
tolerated (1998, 2001a).
There is however limited clinical experience for many of the combinations being
considered. It is recognised that full safety and efficacy needs to demonstrated on a case
by case basis involving appropriate prospective studies including where necessary
regulatory and Phase IV studies and appropriate surveillance particularly of adverse
reactions. It is acknowledged that the artemisinin-based combinations will increase
significantly the cost of treatment (WHO, 2001a).
At present, only the ad hoc combination of artesunate with mefloquine is widely used
operationally in areas of multidrug resistant falciparum malaria. Research on the clinical
evaluation of ad hoc combinations of artesunate with other antimalarial drugs such as
amodiaquine, chloroquine, sulfadoxine/pyrimethamine is ongoing. Research is also being
carried out to develop fixed combinations of artesunate with pyronaridine and
chlorproguanil/dapsone but this is only in the initial stages. These studies are all being
carried out under the auspices of WHO/TDR but these combinations will not be available
for operational use for in the immediate future (WHO, 2001a and b).
Fixed combinations of artemisinin derivatives should have operational advantages since
they should be easier to use and provide greater compliance in the target populations than
ad hoc combinations.
The importance of the combination of artemether/lumefantrine was recently emphasised
by the informal consultation on Antimalarial Drug Combination Therapy. This meeting
concluded that, based on available safety and efficacy data, the combination of
artemether/lumefantrine had the greatest priority and potential for deployment for the
treatment acute multi-drug resistant falciparum malaria than other combinations (WHO,
2001a). WHO has recommended guidelines for its use (WHO, 2001b).
Artemether/lumefantrine is a only fixed combination of an artemisinin derivative which
has been both widely studied and registered for the treatment of acute multi-drug
resistant falciparum malaria. Another fixed combination has been registered and is
marketed, i.e. dihydroartemisinin/piperaquine/trimethoprim (Articom). However, it has
only been registered in Viet Nam, and China and preclinical and clinical experience with
is limited. A fixed combination of dihydroartemisinin/piperaquine (Artekin) is also
under development in China but this has not yet been registered or produced
commercially.
6. Drug formulation and characteristics
6.1. Chemical characteristics
5
Artemether is the methyl ether derivative of artemisinin, the antimalarial principal
extracted from Artemisia annua, L.
Lumefantrine is an aryl amino alcohol similar to quinine, mefloquine and halofantrine.
6.2. The formulation
Coartem is available as a GMP product as tablets containing 20mg artemether and 150mg
lumefrantrine.
6.3. Stability studies.
Stability tests show that the formulation is stable for 2 years at room temperatures of 25o
C and below. The manufacturer recommends that it should not be stored above 30o C.
6.4. Pharmacopeal standards
Pharmacopeal standards for artemether have been established by WHO (International
Pharmacopea, Volume 5, 3rd Edition, 2002) but not for lumefantrine or the fixed
combination.
7. Capability of Production
Novartis have the capacity to produce the formulation according to Good Manufacturing
Practice (GMP) and in sufficient quantities to meet the global needs of malaria control.
The formulation is produced under licence by Beijing Novartis Pharma Ltd, Changping
County, Peoples Republic of China and distributed by Novartis Pharma Switzerland.
During the period 1 November 2000 and 31 October 2001, over 7 750 000 treatment
doses of the combination were sold worldwide. The current production capacity in China
is 30 million tablets per year.
8. Registration Status and Indications for use
8.1. Registration status and marketing
The combination of artemether and lumefantrine was first registered in 1998 in
Switzerland and in the UK as reference member state within the Mutual recognition
Procedure for the European Union. It is currently registered in 74 countries* worldwide
including those in Africa, Asia and South America.
It is dual branded by the Company as Riamet (registered in 27 countries) for marketing
in non-malaria endemic countries and developed malaria endemic countries, and as
Coartem (registered in 47 countries) for malaria disease endemic developing countries.
The two brands are packaged differently.
* as of 15 February 2002)
6
8.2. Indications for use.
Registration has been obtained for the use of the combination for the treatment of adults
and children with acute, uncomplicated infections due to Plasmodium falciparum or
mixed infections including P. falciparum.
Registration has also been obtained in some of these countries for the use of the
combination for emergency standby treatment in tourists and business travellers.
The combination is not recommended for prophylactic use or for the treatment of vivax
malaria.
Artemether/lumefantrine has not been evaluated for use in pregnancy or in severe and
complicated malaria. The manufacturer has not registered the product for this purpose
and clearly states in the documentation that it should not be used for such an indication.
9. Manufacturer’s Treatment regimens
The manufacturer currently recommends the 4-dose regimen for use in partially immune
patients with falciparum malaria and a 6-dose regimen for use in patients with multi-drug
resistant falciparum malaria and non-immune patients. Only the 4-dose regimen has been
registered in malaria endemic countries of Africa. (N.B.: the lower body weight limit for
the use of the drug in children differs in the two regimens).
Patients with acute malaria are frequently averse to food. The Company recommends that
the dose should be taken with fluids and patients should be encouraged to resume normal
eating as soon as food, preferably fatty, can be tolerated since this improves the
absorption of artemether and lumefantrine. In the event of vomiting within 1 hour a
repeat dose should be taken.
The manufacturer's treatment dosage regimens are as follows:
9.1. Acute uncomplicated falciparum malaria in partially immune patients:
0 hrs
8 hrs
24 hrs
48 hrs
Total
Children
<5 kg**
NR
NR
NR
NR
NR
Children
5-14 kg
1
1
1
1
4
Number of tablets
Children
Children
15-24 kg
25-34 kg
2
3
2
3
2
3
2
3
8
12
Adults
>35 kg
4
4
4
4
16
** = Not currently recommended due to limited experience in this group. Clinical trials
are ongoing to support the extension of the use in this high risk group.
7
9.2. Multi-drug resistant falciparum malaria and non-immune patients
0 hrs
8 hrs
24 hrs
36 hrs
48 hrs
60hrs
Total
Children
<10 kg**
NR
NR
NR
NR
NR
NR
NR
Children
10-14 kg
1
1
1
1
1
1
6
Number of tablets
Children
Children
15-24 kg
25-34 kg
2
3
2
3
2
3
2
3
2
3
2
3
12
18
Adults
>35 kg
4
4
4
4
4
4
24
** = Not currently recommended due to limited experience in this group. Clinical trials
are ongoing to support the extension of the use in this high risk group.
9.3.
Emergency Treatment.
The recommended regimen for emergency standby treatment in adults and children is the
6-dose regimen i.e. identical to that given above for the treatment of patients with multidrug resistant falciparum and of non-immune patients.
10.
WHO Treatment Guidelines
WHO treatment guidelines on the use of artemether-lumefantrine were published in 2001
(WHO, 2001b). These WHO recommendations state that:


Although, the 4-dose regimen appears safe and effective in adult patients in Africa
children should receive the 6-day regimen because of their lower immunity; and
The 6-dose regimen should be adopted as standard treatment for all age groups and in
all situations to avoid confusion and ensure the highest efficacy and reliability with
this combination.
The WHO recommended regimen for all patients and in all situations is therefore as
follows:
0 hrs
8 hrs
24 hrs
36 hrs
48 hrs
Children
<10 kg**
NR
NR
NR
NR
NR
Children
10-14 kg
1
1
1
1
1
Number of tablets
Children
Children
15-24 kg
25-34 kg
2
3
2
3
2
3
2
3
2
3
Adults
>35 kg
4
4
4
4
4
8
60hrs
Total
NR
NR
1
6
2
12
3
18
4
24
** = Not currently recommended due to limited experience in this group. Clinical trials
are ongoing to support the extension of the use in this high risk group..
Following discussions with RBM in 2001 and the signature of the Memordandum of
Understanding, the Company agreed in principle to these recommendations. As only the
4-dose regimen has been registered in certain malaria endemic developing countries
(mainly African), further studies with the 6-dose regimen are required to support its wider
registration in such countries. These studies are being carried out under the Terms of the
Memorandum of Understanding between the Company and WHO. The Company is,
therefore, working towards the recommendation of 6-dose regimen for all patients.
11.
Efficacy including comparisons with other relevant drugs
11.1. Preclinical Efficacy
(i). The blood schizontocidal and anti-gametocytogenetic activity of artemether are well
documented (WHO (1998). Artemether is active against P. falciparum strains resistant to
all currently used antimalarials. Resistance to artemisinin and its derivatives has not yet
been reported operationally.
(ii). Lumefantrine is also a blood schizontocide active against chloroquine-, quininesulfadoxine/pyrimethamine-, and mefloquine-resistant P. falciparum parasites although
in vitro data suggest some of cross resistance of lumefantrine with mefloquine,
halofantrine and quinine.
(iii). Studies in P. berghei rodent models and with P. falciparum in vitro show (+)
lumefantrine, (-) lumefantrine and the racemate of the two enantiomers to have nearly
identical antimalarial activity.
(iv). Preclinical efficacy studies in rodent models and with P. falciparum in vitro show
the combination of artemether and lumefantrine to be synergistic.
(v). Artemether and lumefantrine do not show anti-relapse activity.
11.2. Clinical Efficacy
(i). A total of 15 clinical efficacy trials were completed prior to registration. The total
number of patients was 3,265 (1 869 with either the 4- or 6-dose regimen and 173 with
lower doses of the combination in dose finding studies – the balance were patients treated
with antimalarial drugs used for comparison).
(ii). Of the 1869 patients receiving either the 4-or 6-dose regimens, 1258 were adults >12
years, 243 children were children between 5-12 years and 368 were children <5 years.
9
(iii). Nine of these trials were randomised and double blinded comparing
artemether/lumefantrine with other antimalarial drugs i.e. chloroquine, halofantrine,
sulfadoxine/pyrimethamine, quinine, quinine/sulfadoxine/pyrimethamine, mefloquine
and artesunate/mefloquine. The primary standard variables for evaluating efficacy were
7, 14, 28 day cure rate (defined as the proportion of patients cleared of asexual
parasitaemia within 7 days of initiation of treatment, without subsequent recrudescence
within 7, 14 or 28 days after initiation of treatment), and parasite clearance time.
Secondary efficacy variables were parasite reduction during the first 72 hrs, fever
clearance time, gametocyte clearance time, and P.vivax clearance time,
(iv). Trials in China comparing the combination with its two components confirmed that
both components contributed to the efficacy of the combination without any additional
toxicity and that the 4-dose regimen given over 48 hours was effective and well tolerated
in China.
(v). The 4-dose regimen of Coartem produced 28-day cure rates in excess of 95%
(n=268) in areas of known chloroquine-resistance with both adults and children. Patients
included those as young as <1 year. (body weight <5 kg). This regimen also produced
cure rates similar to those with sulfadoxine/pyrimethamine in areas where P. falciparum
was sensitive to this latter combination. (von Seidlein et al., 1998; Hatz et al., 1998; van
Vugt et al., 1998; Kshirsagar et al., 2000).
(vi). In one of the trials in Africa, the 28-day cure rate complemented by PCR
(Polymerase Chain Reaction) studies showed a corrected cure rate of 92.7% (von
Seidlein et al., 1998).
(vii). In areas of multi-drug resistance in Thailand, the 4-dose treatment only produced
28-day cure rates of 76.5% (n=646). Both mefloquine and artesunate/mefloquine had
significantly greater 28-day cure rates than the 4 dose regimen of
artemether/lumefantrine. However, the 6-dose regimen of artemether lumefantrine gave
28-day cure rates of over 97% (n=336) in these multidrug resistant areas. These were
significantly higher than those with mefloquine (25mg/kg) and equivalent those of
artesunate/mefloquine (Looareesuwan et al., 1999; van Vugt et al., 1999, 2000).
(viii). During these trials, there was little experience of the 6-dose regimen in children
<10 kg body weight. Consequently at present, WHO does not recommend the use of the
combination in this high risk group (WHO, 2001b). However, following discussions with
WHO, the Company initiated studies in early 2002 in Nigeria, Kenya and Tanzania to
determine the safety and efficacy of the 6-dose regimen in children <10kg body weight
with acute uncomplicated malaria. Between 400-600 children will be included in this
multi-centre study to be conducted according to a protocol agreed upon between the
Company and WHO. The studies should be completed in 2003.
12.
Safety and Tolerability
12.1. Adverse reactions
10
(i). A comprehensive evaluation of the safety and tolerance of artemether/lumefantrine
was carried out in the 1869 patients receiving the combination in the pre-registration
clinical trials described above. These studies were detailed and carried out with particular
attention given to potential cardiotoxicity and neurotoxicity. Since registration, it has
been estimated that over 1.2 million people have been treated with the drug including
over 2000 more patients in clinical trials.
(ii). The most commonly reported and possibly drug-related adverse effects to the
combination therapy were effects on the gastrointestinal (abdominal pain, anorexia,
nausea, vomiting and diarrhoea) and central nervous (headache, dizziness) systems.
Pruritus and rash were reported by less than 2% of patients. More than 90% of these
reported adverse events, many of which overlapped with the clinical symptomology of
acute malaria, were rated mild to moderate in severity ( Bakshi et al., 2000; Ezzet, et al.,
2000).
(iii). The combination was better tolerated than the comparator drugs used in the trials.
Higher incidences of vomiting and pruritis were observed with chloroquine, dizziness,
nausea and vomiting were more common with mefloquine and dizziness, abdominal pain,
nausea and vomiting more frequent with quinine (van Vugt et al., 1998).
(iv). Adminstration of artemether/lumefantrine to both healthy male Caucasian male
volunteers and African and Thai adult and child patients with falciparum malaria did not
lead to significant alterations in clinical laboratory parameters
12.2. Potential Neurotoxicity
(i). Animal studies have demonstrated limited symptomatic and pathological evidence of
neurotoxicity following the intramuscular administration of artemether and arteether
(Brewer et al., 1994; Petras et al., 1995, Genovese et al., 1995). However, the relevance
of these studies to humans is unclear. To date, no significant neurotoxicity has been
reported from the use of artemisinin derivatives in more than 2 million people using these
drugs (WHO, 1998, 1999, 2001b, The Artemether – Quinine Meta analysis Study Group,
2001). These effects were not observed in animal models following oral administration of
artemisinin derivatives.
(ii). There were no serious or persistent neurological adverse reactions to oral
administration of artemether/lumefantrine either in the clinical studies or in preclinical
studies in rats or dogs.
12.3. Potential cardiotoxicity
(i) Lumefantrine belongs to a chemical class of compounds that includes quinine,
mefloquine and halofantrine. Halofantrine has been shown to prolong QTc intervals at
standard recommended doses and there have been rare reports of serious ventricular
dysrhythmias, sometimes fatal.
11
(ii). Serial electrocardiograms were available for over 700 patients given
aeremether/lumefantrine (>100 children and 190 patients who had received the 6 dose
regimen), the frequency of QTc interval prolongation was similar to or lower than that
observed with chloroquine, mefloquine or artesunate plus mefloquine and significantly
lower than with halofantrine. These changes were considerably less than asymptomatic
and no adverse clinical cardiac events were reported (Bakshi et al., 2000, Kshirsagar et
al., 2000; Lefèvre et al., 2001; Price, 200); van Vugt et al., 1999).
(iii). Studies have been carried out in 42 healthy male volunteers to determine whether
prior treatment with mefloquine would affect lumefantrine cardiotoxity. They showed
that there were no clinically significant differences in the QTc-interval after sequential
treatment of mefloquine and artemether/lumefantrine relative to either treatment given
alone (Bindschedler et al, 2000).
(iv). Effects of artemether/lumefantrine and halofantrine on the QTc-interval have been
compared in a randomised double-blind cross-over study in 13 healthy male adults.
Electrocardiograms were recorded from 48hrs before drug administration and 48 hrs
thereafter. The maximum QTc-interval (QTc = QT/RR) was compared before and after
treatments and within treatments, fitting a general linear model. Drug plasma
concentrations were determined concomitantly. All subjects showed an increase in QTcinterval after halofantrine treatment, the mean maximum increase being 28msec. The
QTc-interval remained unchanged after administration of artemether/lumefantrine. The
difference between treatments was statistically significant (Bindschedler et al, 2002).
Conclusion: halofantrine caused significant, exposure dependent increases in the QTcinterval. No such effect was seen with artemether/lumefantrine.
(v). The effect of lumefantrine, desbutyl-lumefantrine, halofantrine, chloroquine and
mefloquine on HERG currents recorded from stably transfected HEK293 cells has also
been studied. Compounds which inhibit HERG current have been shown to prolong the
cardiac potential and therefore QTc-interval in man. All of the compounds examined in
this study inhibited HERG currents stably expressed in HEK293 cells. From the
estimated IC50 values the order of potency of HERG current block was
halofantrine>chloroquinemefloquine>desbutyl-lumefantrine>lumefantrine.
Conclusion: based on this test, lumefantrine and its debutyl metabolite have less potential
for QTc-interval prolongation than mefloquine, chloroquine or halofantrine.
(vi). A drug interaction study with quinine was carried out to determine whether the
concomitant administration of quinine and artemether/lumefantrine exacerbated the
potential cardiotoxicity of either drug (Lefèvre et al., 2002a). The infusion of quinine
alone caused transient prolongation of the QTc-interval with this effect being slightly but
significantly greater than when quinine was infused after artemether/lumefantrine.
However, these prolongations were small and were not followed by abnormal clinical
signs or symptoms. The changes were not considered to be clinically important. The
pharmacokinetics of lumefantrine and quinine were not influenced by the presence of
12
other drugs while exposure to artemether and dihydroartemisninin appeared to be lower
under the combined treatment of artemether/lumefantrine and quinine. The latter was
considered to be clinically irrelevant.
(vii) Ketoconazole is amongst the potent inhibitors of the cytochrome enzyme, CYP3A4.
As artemether and lumefantrine are metabolised by the same enzyme, a study was carried
out to determine whether the metabolism of artemether/lumefantrine was inhibited by
ketaconazole. The results showed that the study medications were all safe and well
tolerated after both treatments. No changes in ECG and no effects on QTc interval were
observed with any of the treatments, given alone or in combination. The
pharmacokinetics of artemether, its metabolite dihydroartemisinin and lumefantrine were
influenced by ketaconazole (exposure increased by a factor 1.3-2.5). This effect was not
considered to be clinically relevant (Lefèvre et al., 2002b).
(viii). There have been no reports to the Company of QTc-prolongation since the
marketing of the combination and its use in over 1.2 million patients.
12.4. Other Reports
One fatal case of Lyell’s syndrome was reported during post marketing surveillance. This
patients was also treated with allopurinol, captopril, hydrochorothiazide, methyldopa and
furosemide. All of these drugs have been associated with severe skin reactions including
Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome. No other case of
Lyell’s syndrome, TEN, and Stevens-Johnson Syndrome, erythema multiforme or
Staphylococcal scaled skin syndrome have been recorded following administration of
artemether/lumefantrine.
13.
Post marketing Surveillance
Post marketing surveillance (PMS) has been in operation since the marketing of the drug
in 1998. Periodic safety up date reports in a format proposed by CIOMS are issued by the
Company and are made available to WHO/RBM. To date no major problems have been
reported.
However, most of these reports come from developed countries as post marketing
surveillance is generally absent or poorly developed in malarious areas. WHO/TDR
initiated in 2002 PMS studies as part of the operational use of the combination in
Kwazulu Natal, South Africa. These studies will address issues particularly related to
safety and the compliance that may be obtained in rural health settings with a drug
combination that requires a relatively long and complex treatment regimen (i.e. 6 doses
over 60 hrs). The newly developed packaging designed to improve compliance in rural
populations with limited literary status will also be assessed in 2002.
As a result of unacceptable levels of resistance to sulfadoxine/pyrimethamine, KwaZulu
Natal was the first Department of Health in Africa to agree upon a malaria treatment
policy with artemether/lumefantrine as the first-level drug. This policy was implemented
13
in February 2001 in conjunction with improved vector control measures. The result was
a dramatic 78% reduction in the total malaria cases by the end of 2001 (41 786 cases in
2000 and 9443 cases in 2001). During this period the number of malaria deaths decreased
by 87%. The South East African Combination Antimalarial Therapy (SEACAT)
Evaluation Project attributes this impressive improvement in the malaria situation to the
combined use of residual household spraying and the replacement of an ineffective
treatment by artemether/lumefantrine.
The impact of artemether/lumefantrine therapy on clinical cure rates, malaria
transmission and the emergence of drug resistance is expected to depend on high
coverage and high patient compliance. SEACAT is monitoring both coverage and
compliance and studying ways to improve them. Household surveys showed that, in
KwaZulu Natal and Mpumalanga, 95.4% and 86.6% respectively of patients responded
that they had completed the treatment course of artemether/lumefantrine (only 0.5% and
1.3% respectively admitted that they had treatment remaining at home). As these methods
are prone to bias, lumefantrine blood levels at 7 days and spot household visits will be
carried out in the future (SEACAT Evaluation Annual Report 2001 and SEACAT
Progress Report to WHO/TDR February 2002). Focus group discussions have shown that
adherence to treatment depends greatly upon the information provided by health care
workers and that within, the SEACAT project malaria control staff and health workers,
are being successful in educating communities to seek effective treatment and to optimise
patient compliance levels.
Progress in the implementation of this antimalarial drug policy on the use of
artemether/lumefantrine as a first line drug also shows that (i). there is a need to extend
and increase educational programmes for patients and health care staff; (ii). it is essential
that patients take each dose of artemether/lumefantrine, particularly the last few with a
fatty meal (this requires educational programmes especially in impoverished
communities) and (iii). Patients > 65kg may be underdosing with adult dose of 24 tablets.
The use of the combination in Indonesia started in March 2001 with the purchase of 0.5
million tablets but no systematic PMS has been put in place together with its deployment.
14.
Pharmacokinetics and Metabolism
Four Phase I human pharmacology trials in healthy volunteers were carried out plus a
bioequivalence trial comparing a Chinese formulation (used in trials conducted in China)
with the one produced outside China which was used in all subsequent clinical trials. One
a food interaction study was also carried out. The results are summarised below.
14.1. Lumefantrine
(i). Pharmacokinetic data on lumefantrine are available from more than 800 patients
treated in the course of clinical trials. There was considerable variation between patients
but not within ethnic groups in all parameters except for the terminal half-life. This is
attributable to the variable absorption of the drug.
14
(ii). The estimated mean absorption half-life of lumefantrine was 3.2 hrs. Cmax was
usually observed between 6 and 12 hrs. following drug administration. The terminal halflife seems to differ between healthy volunteers (2-3days) and malaria patients (3-6 days).
(iii). Food intake affects the drug absorption. For example, the absorbed fractions of dose
3 (at 24 hrs) and dose 4 (at 36 hrs) were about 3 times those of dose 1 (at 0 hrs) and dose
2 (at 8 hrs) in patients receiving the 6-dose regimen in Thailand. A further increase was
observed with dose 5 (at 48 hrs) and dose 6 (at 60 hrs). The first two doses were usually
taken in the fasting state as the patients were anorectric.
(iv). Lumefantrine is eliminated via the liver and faeces. There is some evidence of
enterohepatic circulation.
(v). Lumefantrine is highly protein bound (99.9%), the majority being bound to high
density lipoproteins.
14.2. Artemether
(i).Artemether is both rapidly absorbed and metabolised, the parent drug and the main
metabolite, dihydroartemisinin, being detected in the blood after 30 mins. Peak plasma
concentrations (Cmax) of both compounds are achieved around 2 hours after drug
administration.
(ii). The terminal half life of artemether is about 2 hours, with that of dihyroartemisninin
being slightly longer.
(iii). The pharmacokinetic parameters of artemether shown less variability than those of
lumefantrine.
(iv). Artemether is highly protein bound to plasma proteins (>95%) with a large
proportion (33%) being bound to 1 glycoproteins.
(v). Artemether is almost totally metabolised with practically no parent compound or
dihydroartemisinin being detected in the faeces or urine. A variety of reduced metabolites
are found in the urine.
14.3. General
(i). No specific pharmacokinetic studies have been carried out in patients with hepatic or
renal failure, in children or in elderly patients.
(ii). A food interaction study in healthy volunteers demonstrated the dramatic effect of a
fatty meal in increasing the absorption of lumefantrine (relative bioavailability as
measured by Cmax and AUC increased 16 fold), with a smaller effect on artemether
absorption (Cmax and AUC doubled). This study also showed that the absorption of
lumefantrine under fasting conditions is very poor. As this could have a marked effect on
15
efficacy, patients are strongly advised to take the medication with a normal diet as soon
as food can be tolerated.
(iii). There is no sign of any pharmacokinetic interaction
lumefantrine.
15.
between artemether and
Pharmacodynamics
(i). A significant correlation has been observed between the probability of cure, the
degree of parasitaemia at the start of medication and the lnAUC.
(ii). With the 4-dose regimen given over a 48hr period and a lumefantrine half-life of 3-6
days, it is likely that recrudescences will occur in a significant proportion of non-immune
patients. This will occur especially if patients have a baseline parasitaemia of >50 000/l
and a relatively low Cmax after the last dose so that lumefantrine concentrations drop
below the threshold MIC (EC99) before t min (7 days). This will be particular marked in
areas with of multidrug resistant falciparum malaria.
(iii). A dose finding study in Thailand demonstrated the importance of the number of
doses rather than the dose level on the efficacy of the combination of
artemether/lumefantrine. These studies showed that the cure rate was 97% in patients
receiving a total dose of >50mg/kg lumefantrine regardless of initial parasitaemia but that
cure rates were significantly lower with parasite densities of >20 000//l if the total
lumefantrine dose was <50 mg/kg (van Vugt et al., 1998; Tamariya et al., 2000).
16.
Use in pregnancy and lactation
(i). The safety of artemether/lumefantrine in pregnancy has not been established.
(ii). Reproductive toxicity studies in rats and rabbits did not show any evidence of
teratogenicity after the administration of the combination or its two components singly.
However, artemisinin drugs are known to be embryotoxic in animal models.
(iii) Artemether showed both materno- and embryotoxicity at doses of >60mg/kg in rats.
Materno- and embryotoxicity was also observed in rabbits following administration of
175mg/kg but a dose of 105mg/kg was without treatment-induced effects. Materno-,
embryotoxic, or foetotoxic effects were observed following the administration of doses of
10mg/kg to rats and above 25mg/kg in rabbits.
(iv). Administration to rats and rabbits of doses of lumefrantrine as high as 1000mg/kg
did not induce any materno-, embryotoxic , or foetotoxic effects.
17.
Drug interactions
(i). A drug interaction study with artemether/lumefantrine in human volunteers given the
6-dose regimen 12 hours after receiving a treatment dose of mefloquine showed that,
16
although mefloquine had no effect on the plasma levels of artemether, it did significantly
reduce the plasma levels of lumefantrine, possibly due to a lower absorption secondary to
a mefloquine induced decrease in bile production.
(ii). In vitro studies show that lumefantrine metabolism is affected by halofantrine and
quinine.
(iii). Both artemether and lumefantrine are metabolised by the cytochrome enzyme
CYP3A4 but do not inhibit this enzyme at therapeutic concentrations. Due to the lack of
clinical data and unknown effects on safety, the co-adminstration of drugs that inhibit
CYP3A4 is contraindicated.
(iv). While artemether failed to show interaction with CYP450 enzymes, lumefantrine
was found to inhibit cytochrome P450-IID6. This may be relevant to patients being
treated with substances known to inhibit this enzyme e.g. neuroleptics and tricyclic
antidepressants.
(v). There have been no other specific studies on the interaction of artemether/
lumefantrine with other medicaments. The use of complementary
medication
(antipyretics, fluid and electrolyte replacement etc.) during the clinical trials showed no
evidence of drug interactions.
18. Cost.
Following a meeting between Dr D. Vasella, Chairman and Chief Executive, Novartis
and the Director-General of WHO in November 2000, Novartis Pharma agreed to make
Coartem available to WHO at a no-profit cost price. After a subsequent meeting in
December 2000, Novartis Pharma proposed a triple pricing strategy as follows:



Riamet for sale in the private market in developed counties = US$40 per adult
treatment dose;
Coartem for sale in the private market in developing counties = US$12 per adult
treatment dose;
Coartem for sale to the public sector in developing counties = US$2.35-2.40 per
adult treatment dose (price per tablet US$ 0.098-010).
Novartis calculated the public sector price after negotiations with their Chinese partner. It
is based on a no loss policy and has been calculated on an expected volume of 900 000
treatments per year. Preferential low pricing is conditional on procurement by WHO
possibly in collaboration with other Public Health Agencies such as UNICEF to
undertake transportation and distribution on behalf of WHO. WHO would be responsible
for the "control" of supplies of the low price combination to avoid misuse and the risk of
drug resistance and to ensure that it was only made available for public health use in
countries of need.
17
The updated public sector prices below (quoted on 25 February 2002) are based on the
use of the 6-dose regimen and expressed as cost per unit pack of a treatment dose to be
purchased in multiples of cartons containing 30 packs. They costs are:
Children 10-14 kg
Children 15-24 kg
Children 25-34 kg
Adult
> 35 kg
US$
US$
US$
US$
0.90
1.40
1.90
2.40
This price includes the cost of new packaging with dispensers designed to improve
compliance (US$ 0.40 for each pack irrespective of the number of tablets). The cost per
tablet is US$ 0.083.
WHO/RBM understands that further cost reductions may be possible in the future for the
most vulnerable population groups.
The two "market competitors" to artemether/lumefantrine are artesunate/mefloquine and
the triple combination of dihydroartemisinin/piperaquine/trimethoprim (Artecom)
WHO quotes a price of US$ 5.38 (range US$ 4.06-7.04) for an adult treatment dose of
artesunate/mefloquine (WHO, 2001b) although its current price to the Cambodian
Malaria Control Programme is US$ 2.25.
The cost of an adult treatment dose of Artecom is US$1.30-1.50 but this combination
drug is only registered and available in China and Viet Nam and data on it is limited.
19. Proposed Text for WHO Model Formulatory (if application to Essential Drug List
is accepted)
International Nonproprietary Name
There are no INNs for drug combinations. The INNs for the components are artemether
and lumefantrine
Dosage Form
A fixed combination as tablets containing 20mg artemether and 150mg lumefrantrine.
Uses
Treatment of acute uncomplicated falciparum malaria, including multi-drug resistant
forms.
Contraindications
Patients who are pregnant women or breastfeeding
18
Allergy to either artemether or lumefantrine
Patients with complicated malaria
Prophylactic use.
Special precautions
Artemether/lumefantrine is not indicated for and has not been evaluated in patients with
malaria due to Plasmodium vivax, P.malariae or P. ovale, although some patients in
clinical studies had mixed infections of P. falciparum and P. vivax. The combination is
active against the blood stages of vivax malaria but not the hypnozoites. Therefore in
mixed infections with vivax and falciparum malaria, primaquine should be used to
prevent relapses due to P. vivax.
Several antimalarials are known to cause QTc-prolongation and a slight QTcprolongation has been observed in a few patients treated with artemether/lumefantrine,
mainly in cases where concomitant dehydration or electrolyte imbalance was present. No
correlation was found between QTc-prolongation and peak plasma levels of either
artemether of lumefantrine in individual patients.
Patients who remain adverse to food during treatment should be closely monitored as the
risk of recrudescences may be greater.
Dosage
0 hrs
8 hrs
24 hrs
36 hrs
48 hrs
60hrs
Total
Children
<10 kg**
NR
NR
NR
NR
NR
NR
NR
Children
10-14 kg
1
1
1
1
1
1
6
Number of tablets
Children
Children
15-24 kg
25-34 kg
2
3
2
3
2
3
2
3
2
3
2
3
12
18
Adults
>35 kg
4
4
4
4
4
4
24
** = Not recommended at present due to limited data in this high risk group.
Food enhances the absorption of both drugs. Food interaction studies show that the
absorption of lumefantrine under fasting conditions is poor. As this could have a marked
effect on efficacy, patients are strongly advised to take the medication with a normal diet
as soon as food can be tolerated.
Adverse effects
The most commonly reported adverse effects following the combination therapy were
effects on the gastrointestinal system (abdominal pain, anorexia, nausea, vomiting and
19
diarrhoea), central nervous system (headache, dizziness, sleep disorders), cardiovascular
system (palpitation), musculoskeletal systems (artralgia and myalgia). Asthenia, fatique,
pruritus and rash were reported. More than 90% of these reported adverse events, many
of which overlapped with the clinical symptomology of acute malaria, were rated as mild
to moderate in severity. All resolved spontaneously.
Clinical studies show no evidence of cardiotoxicity
Drug Interactions
No specfic drug interaction studies in humans have been conducted with
artemether/lumefantrine.
Artemether and lumefantrine are synergistic.
Mefloquine significantly reduces the plasma levels of lumefantrine but has no effect on
the plasma levels of artemether.
Lumefantrine metabolism is affected by halofantrine and quinine.
Artemether showed no interactions with cytochrome P450 enzymes but lumefantrine was
found to inhibit cytochrome P450-IID6. This may be relevant to patients being treated
with substances known to inhibit this enzyme e.g. neuroleptics and tricyclic
antidepressants.
Use in pregnancy and lactation
The drug should not be used in pregnancy as the safety of artemether/lumefantrine in
pregnancy has not been established.
Animal data suggest that excretion of the combination into breast milk although no data
are available in humans. The combination should not be taken during breastfeeding. Due
to the long elimination half life of lumefantrine (4-6 days), it is recommended that
breastfeeding should not resume until at least one week after the last dose of the
combination.
REFERENCES
Bakshi, R. et al., (2000). An integrated assessment of the clinical safety of artemetherlumefantrine: a new oral fixed-dose combination antimalaria drug. Transactions of the
Royal Society of Tropical Medicine and Hygiene, 94: 419-424.
Bindschedler, M. et al., (2000). Cardiac effects of co-artemether (artemetherlumefantrine) and mefloquine given alone or in combination to healthy volunteers.
European Journal of Clinical Pharmacology, 56: 375-381.
Bindschedler, M. et al., (2002). Comparison of the cardiac effects of the antimalarials coartemether and halofantrine. American Journal of Tropical Medicine and Hygiene, (in
press).
20
Brewer, T.G., et al., (1994). Fatal neurotoxicity of arteether and artemether . American
Journal of Tropical Medicine and Hygiene, 51: 251-259.
Ezzet, F. et al., (2000). Pharmacokinetics and pharmacodynamics of lumefantrine
(benflumetol) in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 44:
697-704.
Genovese, R.F. et al., (1995). Arteether neurotoxicity in the absence of deficiency in
behavioral performance in rats. Annals of Tropical Medicine and Parasitology, 89: 447449.
Hatz, C. et al., (1998). Efficacy and safety of CGP 56697(artemether and benflumetol)
compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged
1-5 years. Tropical Medicine and International Health, 3; 498-504.
Kshirsagar, N.A. et al., (2000). A randomized, double-blind, parallel-group, comparative
safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of
acute uncomplicated Plasmodium falciparum malaria. American Journal of Tropical
Medicine and Hygiene, 62: 402-408.
Lefèvre, G. et al., (2001). A clinical and pharmacokinetic trial of six doses of
artemether-lumefantrine for multidrug resistant Plasmodium falciparum malaria in
Thailand. American Journal of Tropical Medicine and Hygiene, 64: 247-256.
Lefèvre, G. et al., (2002). Interaction trial between artemether-lumefantrine (Riamet)
and quinine in healthy subjects. Journal of Clinical Pharmacology. (submitted).
Lefèvre, G. et al., (2002). Pharmcokinetics and electrocardiographic pharmacodynamics
of artemether-lumefantrine (Riamet)with concomitant administration of ketoconazole
on healthy subjects. British Journal of Clinical Pharmacology. (submitted).
Looareesuwan, S. et al., (1999). A randomized, double-blind, comparative trial of a new
oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the
treatment of acute Plasmodium falciparum malaria in Thailand. American Journal of
Tropical Medicine and Hygiene, 60: 238-243.
Petras, J.M., et al., (1993). Brain induced injury in Rattus rattus by the antimalarial drug
arteether (AE): a neuroanatomical and neuropathological analysis. Anatomical Record,
237 (Suppl.1): 95.2
Price, R.N. (2000). Artemisinin drugs: novel antimalarial agents, Expert Opinion on
Investigatory Drugs, 9: 1815-1827.
Tamariya, P. et al., (2000). In vitro sensitivity of Plasmodium falciparum and clinical
response to lumefantrine (benflumetol) and artemether. British Journal of Clinical
Pharmacology, 49: 437-444.
21
The Artemether – Quinine Meta-analysis Study Group (2001). A meta-analysis using
individual patient data of trials comparing artemether with quinine in the treatment of
severe falciparum malaria. Transaction of the Royal Society of Tropical Medicine and
Hygiene, 84: 637-650.
van Vugt, M. et al., (1998). Randomized comparison of artemether-benflumetol and
artesunate-mefloquine in the treatment of multidrug resistant falciparum malaria.
Antimicrobial Agents and Chemotherapy, 42: 135-139.
van Vugt, M. et al., (1999). Efficacy of six doses of artemether-lumefantrine
(benflumetol) in multi-drug resistant falciparum malaria. American Journal of Tropical
Medicine and Hygiene, 60: 936-942.
van Vugt, M. et al., (1999). No evidence of cardiotoxicity during antimalarial treatment
with artemether-lumefantrine, American Journal of Tropical Medicine and Hygiene, 60:
964- 967.
van Vugt, M. et al., (2000). Artemether-lumefantrine for the treatment of multidrug
resistant falciparum malaria. Transactions of the Royal Society of Tropical Medicine and
Hygiene, 94: 545-548.
von Seidlein, L. et al., t al., (1997). Treatment of African children with uncomplicated
falciparum malaria with a new animalarial drug, CGP 56697. Journal of Infectious
Diseases, 176: 1113-1116.
World Health Organization (1994). The role of artemisinin and its derivatives in malaria
treatment (1994-1995). WHO/MAL/94.1067.
World Health Organization (1995). The use of Essential Drugs. Seventh Report of the
WHO Expert Committee (including the revised Model List of Essential Drugs) WHO
Technical Report Series No.867,
World Health Organization (1996). The use of Essential Drugs. Seventh Report of the
WHO Expert Committee (including the revised Model List of Essential Drugs) WHO
Technical Report Series No.867.
World Health Organization (1997a). Management of uncomplicated malaria and the use
of drugs for the protection of Travellers. Report of a WHO Informal Consultation 18-21
September 1995.WHO/MAL/96.1075. Rev.1.
World Health Organization (1997b). The use of Essential Drugs. Eighth Report of the
WHO Expert Committee. WHO Technical Report Series No.882.
World Health Organization (1998). The use of artemisinin and its derivatives as antimalarial drugs. Report of a WHO Informal Consultation 10-12 June1998.
WHO/MAL/98.1086.
22
World Health Organization (1999). WHO Informal Consultation on clinical neurological
investigations required for patients treated with artemisinin compounds and derivatives.
TDR/TDF/99.1.
World Health Organization (2000a). The use of Essential Drugs. Ninth Report of the
WHO Expert Committee (including the revised Model List of Essential Drugs) WHO
Technical Report Series No.895.
World Health Organization (2000b). Report of 20th Expert Committee on Malaria. WHO
Technical Report Series No.892.
World Health Organization (2001a). Antimalarial drug combination therapy. Report of a
WHO Techical Consultation. 4-5 April 2001. WHO/CDS/RBM/2001.35.
World Health Organization (2001b). The use of antimalarial drugs . Report of a WHO
Informal Consultation 13-17 November 2000. WHO/CDS/RBM/2001.33.
23
24