# Presentation: 138317

## NDA 21-242Rectal Artesunate

- Integrated Safety
- Rosemary Johann-Liang, M.D.
- Division of Special Pathogen and Immunological Drug Products

- FDA AIDAC 7/10/02

**Notes:**
Good Morning:

My task is  to present the FDA’s integrated Safety assessment of NDA 21-242 Rectal Artesunate.

## Proposed Indication

**   “****Single 10 mg/kg dose of artesunate rectal capsules in the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available”**

- FDA AIDAC 7/10/02

**Notes:**
Once again. The proposed indication is ....

## Implications of the Indication

**In the “field”**
**Empiric Therapy (other severe febrile illnesses included)**
**Severe disease (unable to take PO)**
**Mainly very young children**

- FDA AIDAC 7/10/02

**Notes:**
As we go through this talk, please keep in mind the implications of the indication that is being proposed.

These are

Use in the field
Use as empiric therapy (patients with other severe febrile illnesses, such as meningitis,  pneumonia, bacteremia)  will be exposed:

Use in patients with severe disease (at least unable to take PO)
Use mainly in very young children.

## SAFETY SUBMISSIONS

**WHO-Sponsored Studies **
**Safety Review of published and unpublished     safety information on studies of Artemisinin Derivatives**** **
**Summary of the data presented to the Chinese Authorities in 1989**
**Neurotoxicity ****(WHO-sponsored consultation)**

- FDA AIDAC 7/10/02

**Notes:**
Three sets of information relevant to the safety evaluation of rectal artesunate was submitted to this NDA by the applicant.
They are
1) WHO-sponsored Studies consistimg of 13 study data and reports 
2) A  Review of all available safety information on published and unpublished studies of Artemisinin Derivatives
3) Summary of the data on artesunate injection presented to the Chinese regulatory authorities in 1989.  This summary submission was reviewed for sake of completeness but will not be included in this talk.
I will be presenting the overview of these two submissions at this time,  highlighting  points that relate to the implications of the proposed indication.
I would also like to spend several minutes on the important safety issue of neurotoxicity .  The NDA included a WHO-sponsored expert consultation report on the pre-clinical experience of neurotoxicity.

## WHO-sponsored Studies

- FDA AIDAC 7/10/02

**Notes:**
Let’s start  with the overview of the WHO-sponsored studies

## WHO-sponsored Studies

- FDA AIDAC 7/10/02

**Notes:**
The WHO-sponsored studies consist of a total of 501 patients receiving rectal artesunate across 13 studies, 435 of them with malaria disease and  319 of the 435 in clinical studies.  These patients were all hospitalized patients from medical units in Malaysia, Thailand, Ghana, Malawi, South Africa, Kenya, and a few  from Brazil.
I have broken out for you here the types of studies and the #s of patients according to disease state populating these studies.
Included in this NDA were data and reports from 2 Bioavailability studies, 2 bioequivalency studies, 6 clinical studies (3 pediatric and 3 adult) of which studies 5, 6, and 7 were the 3 “pivotal” studies that have been discussed in the efficacy presentations, and 3 already  published studies which were re-analyzed by the WHO from the raw data.  There were 66  healthy volunteers, 344  patients with moderately severe malaria, and 91 patients with severe malaria.  
There were 166 children included in this safety database.  Note that all had moderately severe disease and only 8 of these children were less than 2 years of age.  For the adult patients with severe disease, only 5 were from clinical studies, the rest coming from re-analyzed already published studies.

## WHO-sponsored Studies: Clinical

- FDA AIDAC 7/10/02

**Notes:**
This Table accounts for all the patients enrolled into the SIX WHO-sponsored clinical studies separated out by  numbers in the adult and pediatric population.  

All six clinical studies were open-labeled.  This table illustrates the lack of comparative controlled data in this application

For adults, there were 153 patients who received rectal artesunate, 148 with moderately severe disease and only 5 with severe disease. Comparative statements are not possible because there were only 14 patients in the comparator group, all categorized as severe disease and all received IV quinine.

A comparative look at the pediatric data may be possible with 166 patients all categorized as moderately severe disease in the rectal artesunate group versus 39 patients all with  moderately severe disease in the comparator group where 17 children received PO artesunate and 22 children received IV quinine.

## WHO-sponsored Studies: AE

- FDA AIDAC 7/10/02

**Notes:**
So looking at the comparative adverse event counts in the pediatric population, 
the overall AE  was 20%  for the children receiving rectal artesunate versus 26% for the comparator group.
Looking at the most common AE  by  systems,

Gastrointestinal complaints of nausea, vomiting, and absominal pain were the most frequent reports for both groups.

CNS adverse events were the next most common with reports of headaches, impaired consciousness, and convulsions in 6% of rectal artesunate patients and 5% of the comparators.  Nnone of the impaired consciousness or convulsion events were attributed as treatment-related.
Due to the non-comparative nature of this application plus the fact that patients received subsequent other antimalarials shortly after the rectal artesunate, and the difficulty in sorting out what adverse experience is drug-effect versus disease effect, definitive conclusions are very hard to make about adverse events in this safety dataset.

## WHO-sponsored studies: Deaths

- FDA AIDAC 7/10/02

**Notes:**
Moving onto deaths on study, in total, there were 7 deaths across the 13 studies.

There was the 1 pediatric death from study 5 that the applicant discussed and Dr. Sacks pointed out.  This was a 3 yearold boy who received a rectal artesunate dose of 11.5 mg/kg whose probable cause of death was concluded by the site investigators and the WHO as “iatrogenic water intoxication”.  While in agreement with this conclusion as a plausible etiology,  I want to point out that this little boy’s DHA serum levels at 2 hrsand 4 hrs post dose (noting that the 4 hrs time point is just beofre death) were quite high.  The numbers here in parenthesis are reference mean with SD values from similar age children from Ghana.  What contibution, if any, did the high DHA levels make in the demnise of this child?  I don’t think we have that answer.  The 3 adult deaths in clinical studies all were in patients with severe malaria.  One death was in the AS arm and 2 in IV quinine arm.  We would agree with the WHO assessment that these deaths were due to the underlying malarial disease.

The 3 remaining deaths from the re-analysis study 10 had cleared their parasitemia at the time of death.  The etiology of these deaths are unclear. 

## WHO-sponsored Studies: Labs

- Laboratory monitoring was limited.  Only one clinical study had comprehensive labs recorded (CBC, Chem, LFTs)
- _HCT_ ( n= 250)  Overall, transient decrease at 12-24 hours with rise to baseline by day 7, to normal by day 28
- _SGOT / SGPT_ (n= 48) Only monitored in 1 study.  3 patients with rise over 3X UL after normal baseline, peaking day 7-14, falling by day 21
- _ECG_ (n=48)  Only monitored in 1 study.  No significant abnormalities noted

- FDA AIDAC 7/10/02

**Notes:**
Laboratory monitoring was very limited in the WHO-sponsored studies.  Only one clinical study (study number 3) had comprehensive labs recoreded including CBC, Chemistry and Liver function tests.  

In the 250 patients with malaria who had hematocrit moniotred, there was an overall transient decrease at 12-24 hours post dose with rise to baseline by day 7 and normalization by day 28. Again, it is  not possible to distinguish drug side effect from drug efficacy effect

Of the 48 patients monitored for LFT changes in study 3, there were 3 patients whose transaminase levels rose to 3 times upper limit of normal after starting with normal baselines levels, peaking at day 7-14.  It is possible that this lab abnormality  may be drug effect.

Again only 1 study, study #3, had ECG monitoring.  No significant abnormalities were noted.

## WHO-sponsored studies : Dose

- PK and clinical studies: one rectal dose majority receiving 10 mg/kg  (6.8 to 22.2 mg/kg)
- Re-analysis studies: repeated rectal dosing over 3-4 days with mean doses between 25-32 mg/kg total dose (11.3 to 45.7 mg/kg)
- Maximum dose exposure for Adults
- 45.7 mg/kg total dose given over 4 days in 8 divided doses
- Maximum dose exposure for Children
- 21.4 mg/kg with the longest duration of exposure of 7 days (rectal dose x 1 followed by oral dosing: study 5)

- FDA AIDAC 7/10/02

**Notes:**
The majority of patients in PK and clinical studies received one rectal artesunate dose of 10 mg/kg with a range of 6.8 to 22.2 mg/kg.

In the 3 re-analysis studies, repeated  rectal dosing over 3-4 days were given with highest dose up to 45.7 mg/kg

For adults, the maximum dose exposure then was 45.7 mg/kg total dose given over 4 days in 8 divided doses

For children, the maximum dose exposure was 21.4 mg/kg total over 7 days (This was in study 5 where 1 rectal dose was followed by oral artesunate)

## WHO-sponsored Studies: Special Populations

- < 2 years:  only 8 of 166 children
- > 50 years: only 6 of 153 adults with malaria
- Renal  & Hepatic impairment: not specifically studied
- Pregnant: not included in studies
- _preclinical_: consistent findings of impaired fetal survival; no evidence of teratogenicity
- _clinical from literature_: no evidence of fetal injury or impairment of maternal health

- FDA AIDAC 7/10/02

**Notes:**
Some specifics to point out about special populations in this set of safety data.

Only 8 of 166 children were < 2 years of age

Only 6 of the 269 adults with malaria were older than 50 years of age.

Neither renal nor hepatic insufficient patients were specifically studied.

Pregnant patients were also not included in these studies.  The overall impression from preclinical evidence (although pk data is yet lacking) is consistnet findings of impaired fetal survival but no evidence of teratogenicity following first semester exposure to artemisinins in animal studies.  From clinical studies in the literature, there is no evidence of fetal injury or impairment of maternal health over and above the effects on reproductive heatlth or malaria itself.

## WHO-sponsored Studies: Safety Summary

- Very small safety database, all open-labeled
- Studies mainly non-comparative
- Safety assessment not available for special populations, in particular very young children
- Dose exposure: mainly 1 rectal dose at 10 mg/kg
- Overall, no unusual or serious pattern of adverse events; but minimal numbers for comparison
- Overall, no unusual or serious laboratory abnormalities; but monitoring was sparse
- Deaths on study few but not all with clear etiology

- FDA AIDAC 7/10/02

**Notes:**
So then,in summary, 
 this was a Very small safety database 
Studies were all open-labeled with multiple drugs and mainly non-comparative. It is hard to differentiate safety issues between disease and drug effect.  Comparative statements about safety cannot be made.
Furthermore, Safety assessment was not available for special populations, in particular, the  very young children
Dose exposure: mainly 1 rectal dose at 10 mg/kg
Overall, no unusual or serious pattern of adverse events were found; but again  minimal numbers were available, especially for  comparative assessments.
Overall, no unusual or serious laboratory abnormalitieswee noted;  but again monitoring was sparse.
There were few deaths on study but not all had clear etiology.

## Safety Review of Published and Unpublished Clinical Studies on Artemisinin Derivatives

- FDA AIDAC 7/10/02

**Notes:**
Let’s turn our attention now to a different safety submission.

I would like to present an overview of the applicant;s submission:  Safety Review of Published and Unpublished Clinical Studies on Artemisinin Derivatives, once again highlighting as I go along  some issues that particularly relates to the implications of the proposed indication.

Please also note that this safety submission did not contain any raw data for the FDA to review.  This was  really a summary report by the applicant of the clinical experience to date with this class of compounds.

## WHO- Safety Review: Types of Clinical Studies

- FDA AIDAC 7/10/02

**Notes:**
151 published and 18 unpublished studies were reviewed by WHO consultants in order to systematically examine theavailable clinical safety information regarding artemisinin derivatives.  Of these studies, 130 studies resulting in 13, 639 patients had some safety information.  
The applicant broke out  the numbers by the types of trials as shown here at the bottom of the schema.  This results in an impressive numbers of patients collected form comparative randomized trials.

With the implications of the proposed indication in mind however, I want to draw your attention to the fact that when these same patients are re-categorized by the level of disease severity in graphic format, we get the following picture.

## WHO-Safety Review: Disease Population

***        ******Artesunate***_** **_
**           ****N = 6158**

***Artemisinins***
**N = 13,520**

- FDA AIDAC 7/10/02

**Notes:**
On the left side is a pie figure showing artemisinin derivatives taken together (around 13, 000 patients).  The majority of patients included in the safety review were patients with uncomplicated malaria. Only  16% of the whole pie makes up patients with moderate and severe malaria.  

Similar picture applies even when just the patients treated with artesunate around 6000 are pieced out.  

The number of patients with moderate and severe malaria is again much smaller (7%)  than the number of uncomplicated malaria patients.

## WHO-Safety Review:  Adverse Events

- FDA AIDAC 7/10/02

**Notes:**
The applicant makes several conclusions regarding adverse events from their Safety Review.

For comparative studies, the Safety Review states that the most common AE (in the order of <1%) was mild gastrointestinal events consisting of nausea, vomiting, diarrhea, and abdominal pain.

For severe malaria patients,  the Safety Review states that artemisinin derivatives had a better safety profile than quinine.  And for uncomplicated malaria patients, artesunate had a better tolerability profile over chloroquine, quinine, and mefloquine.

Again it’s important to keep in mind that this pooling of adverse events across many studies is quite problematic especially in light of the fact that there were no raw data reviewed either by the applicant or by the FDA.

## WHO-Safety Review: Laboratory and ECG Abnormalities

- _Laboratory abnormalities             _
- _in the order of 1%_
- neutropenia
- reticulocytopenia
- eosinophilia
- anemia
- transaminitis
- culture-negative pyuria
- hemoglobinuria
- Few cases of elevated bilirubin

- _ECG abnormalities  _
- _in the order of 1%_
- bradycardia
- prolongation of QT interval
- Few cases of 1st degree AV block, atrial extra-systoles and T-wave abnormalities

- FDA AIDAC 7/10/02

**Notes:**
Laboratory abnormalities noted by the applicant in the order of 1% included neutropenia, reticulocytopenia, eosinophilia, anemia, transminitis, culture-negative pyuria, hemoglobinuria, and a few cases of elevated bilirubin.

ECG abnormalities in the order of 1% included bradycardia, and prolongation of QT interval.

There were a couple of cases of 1st degree AV block, atrial extra-systoles, and T-wave abnormalities.

## WHO-Safety Review: Neurological Assessments

- Majority: no neurological assessments
- Dizziness most common
- **Price R et al.  Adverse Effects in Patients with acute falciparum malaria treated with artemisinin derivatives.  Am J Trop Hyg. 1999:60; 547-55*
- Patients with uncomplicated malaria
- “ Neurologic examination could be performed reliably only in patients >5 years old”
- Human Histopathology ( *Hien et al* 1999, artemether: n=6)

- FDA AIDAC 7/10/02

**Notes:**
The vast majority of studies included in the safety  review did not have neurologic assessments. Of the available information, dizziness appears to be the most common AE.

The paper by Price et al, is the article that the applicant refers to largely for the clinical neurological safety of artemisin derivatives.
A  total of 1,971 patients had some sort of a neurological assessment out of a total of 3662 patients who received an artemisinin derivative with or without mefloquine.
In keeping with what the implications of the indication that is being sought here, I wanted to point out that in this particular clinical experience, patients with uncomplicated malaria were studied and the authors state in the paper that- “ Neurologic examination could be performed reliably only in patients >5 years old” 

Kissinger et al 1999 Vietnam 242 pts/108 m-controls: only 2 < 5 yrs
Van Vugt et al 2000 Thailand 79 pts/m-con: again only 2 <5 yrs)
Hien et al 1999 Severe malaria Vietnam: AM=6, QN=15, NTx=2 (NCr)

## WHO-Safety Review: reassurance

**comprehensive effort**
**relatively few side effects reported**
**lack of evidence: an association between artemisinin derivatives and increased neurological AE/ sequelae  (in people with malaria)**

- FDA AIDAC 7/10/02

**Notes:**
So in summarizing this second safety submission, 
it can be said that 
-this was a comprehensive effort to examine the available safety information of artemisinin derivates.
-relatively few side effects were noted overall, and mainly mild and transient.  No pattern of adverse events were seen. For comparative studies,  the safety review did not find that patients receiving artemisinin derivatives had an increase in adverse events over comparators.  In fact, the safey review concluded that artemisinin derivatives showed a better tolerability profile over comparators.  

Moreover, there was a lack of clinical evidence to suggest an association between artemisinin derivatives and increased neurotoxic adverse events, neurotoxic sequelae, or death. 

## WHO-Safety Review: problems

- Methodological deficiences
- drug vs. disease effects
- uncertainty of pooling AEs
-  #s for moderate/severe disease
-   # for neurological assessment especially in young children
- No raw data for FDA to review
- Not GMP: sub-potent content of active ingredient                                      *Newton P et al. Fake Artesunate in Southeast Asia. Lancet 2001 Jun 16; 357 (9272):1904*

- FDA AIDAC 7/10/02

**Notes:**
What are some of the problems with the safety review?
There are obvious methodological deficiencies of pooling all different types of studies together, particularly in this case when the safety parameters examined may be a result of either drug or disease effect and the uncertainties of pooling adverse events across studies become magnified.
As I had pointed out, although the number of patients in the collective safety database appears to be large, the relevant assessments in relevant populations are not as large.  
One other issue that is worth mentioning is the issue of the quality of the active ingredient.  The applicant has pointed out that apart from two WHO-sponsored studies, the rest of the safety data derives from studies which used artemisinin active ingredients not produced to GMP and that this supports how remarkable the safety profile of artesunate is.  I would submit that this issue could be looked at in a different light.  It is possible that the many years of actual use safety that we have is based on drugs that contain subpotent content of active ingredient.  Moreover, there is at least one article if not more in the literature that discusses the relative abundant use of counterfeit drugs,  which contains really no active ingredient

## Artemisinin Neurotoxicity

*Class effect*:  	Artemisinin (QHS, qinghaosu),
-    		Artemether (AM),
- 		Arteether (AE) ,
-               	Dihydroartemisinin (DHA)
*Symptomatic*:  apathy, unsteadiness, collapse, coma, death
*Neuropathological*: chromatolysis, unique pattern of neuronal necrosis in brainstem nuclei (vestibular, cochlear, olivary, red and others)

- FDA AIDAC 7/10/02

**Notes:**
Of the various safety issues that the applicant has so aptly discussed, I would like to  focus now on neurotoxicity issues and spend a few minutes discussing what we do know at this point and what we do not know that causes us concern.

 As you have heard,  Neurotoxicity is considered a class effect  of artemisinin derivatives in animals.  Dose-related pattern of fpeuropathology statrting with chromatolysis, then necrosis of specific neurons in the brainstem of rats, monkeys, dogs, and mice followed by gliosis and long tract lesions have been described  with artemisinin, artemether, arteether, and the principal metabolite dihydroartemisinin.

## Preclinical evidence: neurotoxicity margin of safety

- WHO-sponsored expert consultation: Conclusions about ***AS***
- Limited Information for AS
- No neuronal necrosis at 420 mg/kg IM x 1 or 200 mg/kg/day PO x 5-7d
- WHO: Briefing Package regarding WHO-sponsored toxicology
- total 210-300 mg/kg via IV / PO
- 21 to 30 fold greater than total proposed human dose
- FDA: BSA conversion to Human Equivalent Dose (HED)
- 35-50 mg/kg (only 3-5 times)

- FDA AIDAC 7/10/02

**Notes:**
The conclusions from the WHO-sponsored expert consultation by Professor Dayan et al stated that only limited information was available for AS but no neuronal necrosis was seen at 420 mg/kg IM x 1 or 200 mg/kg day PO for 5 to 7 days.

And the applicant concluded in their briefing document that for AS, a total of 210 to 300 mg/kg IV or PO doses did not result in neurotoxicity. They further concluded that this is a 21-30 fold greater than the proposed dose indication for humans and thus a wide margin of safety.
If we accept this dose of 210-300 mg/kg as the best available approximation for NOEL for AS, The BSA conversion from the anima l model to Human Equivalent dose would be 35-50 mg/kg giving  us only about 3 to 5  times the safety dose margin.

## Preclinical evidence: margin of safety

- FDA AIDAC 7/10/02

**Notes:**
If we take a more conservative approach to the available evidence, the safety margin gets even more narrow.

For AM and AE, Professor Daya’s expert review of the neuropathology materials concluded that the NOAEL for neurotoxicity in rats was 45-75 mg/kg  
This dose by BSA conversion would translate to a HED of 7.5-12.5 mg/kg for AM or AE.

Looking down through the right side of this schema, unfortunately, the 7-d  rat study in the WHO-commissioned  toxicology program was not specifically targeted enough for determination of neurotoxicity  NOAEL for artesunate. 

Moreover, there were unexplained deaths in 1/16 animals on day 4 of 75 mg/kg dose and 2/16 on day 3 of 150 mg/kg dose.  The HEDs calculated adjusting for BSA from this rat model is 12 to 25 mg/kg if we use the dose at which the unexplained deaths occurred.    This HED is right around the proposed 10 mg/kg rectal dose, not giving us any margin of safety.

## Neurotoxicity: clinical experience

- _WHO-sponsored studies_
- Neurological assessments  performed for studies 5, 6, 7 only  (should give 164 rectal AS recipients tested / 501 total, but missing data common)
- Young patients: assessments not reliable
- No pattern of neurological abnormalities was identified

- _Literature/actual usage_
- Main argument for the safety of artesunate
- Large body of experience
- No evidence of neuro toxicity with AS used in patients with malaria
- Minority were moderate/severe dz
- Main Ref. to *Price et al* study but children <5 did not get neurological assessments
**Adults Highest Dose: 45.7 mg/kg (n<30)**
**Children Highest Dose: 57 mg/kg (n<30)**

- FDA AIDAC 7/10/02

**Notes:**
Having said all that for pre-clinical evidence, what about neurotoxicity and clinical experience in humans?

The WHO sponsored studies contained neurological assessments in the 3 pivotal studies (studies 5,6, and 7) which gives 164 rectal AS recipeitns tested out of the total of 435 patients with malaria.  Healthy volunteer patients were not  specifically tested.  Cranial nerves, nystagmus, hearing, tandem walking, romberg test, line drawing, picking tablets, rapid alternating movements, finger-tapping were some of the assessments.  These data were problematic due to the many mdssing data, especially in young patients who could not be reliably assessed.  Nevertheless, no pattern of neurological abnormalities was reported.

In the literature and the actual  usage experience regarding neurological safety, , the applicant has stated that there is a large body of safety experience with AS.  Again, I point out to you that the actual safety information in patients with severe disease, especially the very young with severe disease and systematic neurological assessments is a very small percentage of that actual usage experience.
What about the  highest dosess used clinically ?
From the literature, in adults it was 45.7 mg/kg total dose given over  4 days in 8 divided doses.  In children, the highest dose found was 57 mg/kg total dose given over 3 days in daily divided doses.  For both studies however, the total experience is less than 30 patients in each group.

## Neurotoxicity: What do we know

- Neurotoxicity: dose-dependent
- Lipid soluble derivatives:  AE, AM
- Water soluble derivatives:  AS, AL
- Most Neurotoxic: DHA > AE, AM >>AS, AL
- Conversion to DHA:  AS > AE, AM >> AL
- Faster Elimination:  AS >> AE, AM
- Lipid soluble agents produce much longer periods of DHA activity.
- Critical factor leading to neurotoxicity: Sustained level rather than peak level

- FDA AIDAC 7/10/02

**Notes:**
So in trying to put together our current collective knowledge,  what do we know about the neurotoxicity of the artemisinin compounds?

We know that the neurotoxic lesions occur in dose-dependent fashion in animal models and that the most neurotoxic substance from this group of compounds appear to be the major metabolite DHA.

So why are neurotoxic lesions seen more with the lipid soluble AM and AE then  the water soluble AS when AS actually is converted the most to DHA?  

This is probably because the lipid solubleagents AM and AE are eliminated more slowly than water soluable compounds likeAS thus producing much longer periods of DHA activity.  Thus, the critical factor leading to neurotosicity appears to be sustained levels of DHA rather than the peak level.

## Neurotoxicity: What we don’t know

- Safety margin from preclinical clinical not determined yet and may not be as “wide”.  HED: one rectal dose OK but unclear with repeated dosing.
- AS elimination faster: IV > PO > Rectal; With repeated dosing, could rectal formulation also act as “depot” , causing sustained levels?
- Brainstem nuclei affected: species specific? Humans?
- DHA Tissue Distribution to parasitized cells, a buffer?
- Empiric Use in febrile children (especially if repeated dosing and no buffer of parasitized cells):  Sustained CNS DHA levels be possible?

- FDA AIDAC 7/10/02

**Notes:**
With that in mind, what about what we do not yet know? And thus causes us concern regarding neurotoxicity?

## Lack of information: populationsCan we make the link?

- FDA AIDAC 7/10/02

**Notes:**
So  finally, in starting to summarize our view of the integrated safety, I want to once again touch upon the GAP in populations.

The NDA application constitutes WHO-sponsored studies done with all hospitalized patients, all with proven malaria, mainly moderate-severe disease and older children and adults.  

The implications for the actual usage in the proposed indication would impact a very different population.  Those in the field with severe disease, unable to take PO and mainly very young children receiving rectal AS as empiric therapy.  This is a population we have very little information on .... Even in the large body of clinical experience to draw upon for safety evaluation.  Could we make this link at this time?

## Safety Summary:  Benefit / Risk

-     _WHO Statements_
- highly favorable safety profile
- number of AE small
- no consistent pattern of toxicity identified

-     _Uncertainties_
- Neurotoxicity, safety margin
- Population for proposed indication

- FDA AIDAC 7/10/02

**Notes:**
In the end, we have to make the Benefit and risk balance assessment.

The applicant has stated that artesunate has a highly favorable safety profile.
The number of AE are small
No consistnet pattern of toxicity identified

I have tried to highlight some of the uncertainties about safety, particularly the as-of-yet unknown  safety margin of neurotoxicity and the as-of-yet  unknown safety parameters for the population implicated in the proposed indication

## Safety Summary: Benefit/Risk

- Impact of the ***disease ***malaria to individual human suffering and global public health
- Proposed rectal dose (10 mg/kg x1) within safety limits of collective current knowledge
- Uncertainties and concerns expand if higher doses or repeated dosing becomes an issue

- FDA AIDAC 7/10/02

**Notes:**
Given all that, we are mindful of the impact of the DISEASE  malaria to individual human suffering and global public health.

Based upon our collective current knowledge, the proposed rectal dose of 10 mg/kg for one dose we feel is within the safety limits.

However, Uncertainties and concerns expand if higher doses or repeated dosing becomes an issue.