Application for Inclusion of Miltefosine on WHO Model List of Essential Medicines November 2010 Submission

Application for Inclusion of

MILTEFOSINE

On WHO Model List of Essential Medicines

Submitted to the EML Secretariat for consideration November, 2010

1. Summary statement of proposal for inclusion, change or deletion

Miltefosine (as tradename Impavido®) is proposed to be included in WHO Model list of Essential Medicines as a single agent for treatment of visceral, cutaneous, and mucosal leishmaniasis.

Summary of comparative efficacy and safety The efficacy of miltefosine for each of visceral, cutaneous, and mucosal disease is reviewed in Sections 8.1 and 8.2, and compared to each present Essential Medicine in Section 8.3.

The safety of miltefosine for each disease is reviewed in Sections 8.1, 8.2, and 9.1-9.3, and compared to each Essential Medicine in Section 9.4.

The summary of comparative therapeutic indices (efficacy, safety, and feasibility) vs . the four agents currently on the List of Essential Medicines for leishmaniasis (pentavalent antimony, amphotericin B deoxycholate, liposomal amphotericin B, paromomycin injectible) is provided in Section 9.5. Of the comparisons provided, miltefosine has been shown to be superior or equivalent to presently approved Essential Medicines for at least one of visceral, cutaneous or mucosal leishmaniasis. More specifically, miltefosine is superior to three of the four present Essential Medicines for VL [ i.e ., all present Essential Medicines other than liposomal amphotericin B] and superior to all present Essential Medicines for CL and ML.

Summary of comparative costs Miltefosine is less expensive than three of the four presently approved Essential Medicines. The comparative costs are provided in Section 10.1.

Overall summary of comparisons Miltefosine is proposed for three different diseases and there are four possible comparators (the present Essential Medicines) for each disease. It is not to be expected that miltefosine or indeed any drug will be superior to every comparator for every disease. The above summaries of therapeutic indices and costs demonstrate that for the majority of comparisons, miltefosine compares favourably to the presently approved Essential Medicines. Paladin therefore considers that miltefosine qualifies to be included on the Essential Medicine List for all forms of leishmaniasis based on overall safety, efficacy, and feasibility of administration.

1.1 Historical note

An Essential Medicine application for miltefosine was previously made by Zentaris GmbH in 2004, and declined by the WHO. At that time, several issues were raised owing primarily to the early stage of commercial and clinical data that was available on the drug. The experience with miltefosine has vastly expanded in the intervening years. As a result, it is possible to provide a summarized response to the issues raised in 2004 below:

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- Lack of extensive regulatory experience: Miltefosine is now registered in 14 countries (see Section 11), variously for children ( i.e ., in India) as well as adults. In 13 countries, regulatory approval is for cutaneous as well as for visceral leishmaniasis.

- Teratogenicity/Adverse Drug Reactions: The EMEA-approved Product Insert deals with preclinical teratogenicity findings by strictly requiring female contraception. At the present time, Paladin’s pharmacovigilence group has received no reports of any birth defects from the first regulatory approval, since which over 60,000 courses of drug have been administered (see Section 9.1).

- Private market risks: Paladin policy as described in Section 10.4 deals effectively with private market risks.

- Pharmacokinetics: Dorlo et al. reported on the PK of miltefosine in 2008.

- Resistance: Resistance for any drug administered singly is a possibility, and the long-half life of miltefosine does theoretically predispose to resistance, but we note that paromomycin was approved as an Essential (single agent) Medicine in 2006 and aminoglycosides are notorious for the generation of resistance, at least by bacteria.

- Lack of superiority to Amphotericin B: Amphotericin B is a very effective agent for the leishmaniases. Its disadvantages are modes of administration (IV), toxicity (for amphotericin B deoxycholate), and price (for liposomal amphotericin B), but not lack of efficacy. Given this, the non-significant difference in efficacy for miltefosine (94%) vs . amphotericin B (97%) for Indian VL is almost identical to the experience for paromomycin (94.6%) vs . amphotericin B (98.8%) which was reviewed in the course of approval of paromomycin as an Essential Medicine.

Finally, we note that letters of support have been submitted for the present Essential Medicine application from several parties responsible for expanding the clinical dataset on miltefosine, as well as by parties who previously had reservations on its inclusion on the Essential Medicines Listing.

In this regard, it is important to note that miltefosine is now the treatment of choice for VL in the Indian public health system [see letter of support from Dr Sundar].

It is also important to note that miltefosine is presently a treatment of choice for PKDL in the Indian subcontinent [see submitted letters of support].

2. Name of the focal point in WHO submitting or supporting the application

Not applicable.

3. Name of the organisations consulted and/or supporting the application

Paladin Labs Barbados Worthing Corporate Center Worthing Main Road Christ Church BB15008, Barbados

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Paladin Labs Barbados is a wholly-owned subsidiary of:

Paladin Labs Inc. 100 Blvd. Alexis Nihon, Suite 600 St-Laurent, Québec H4M 2P2

Point of contact for this application:

Dr. Robert Vinson, Ph.D. Director, Product Development Paladin Labs Inc. 100 Blvd. Alexis Nihon, Suite 600 St-Laurent, Québec, Canada H4M 2P2 Tel: (514) 669-5323 [email protected]

4. International Nonproprietary Name (INN, generic name) of the medicine

Miltefosine.

5. Whether listing is requested as an individual medicine or as an example of a therapeutic group

Listing is requested as individual medicine. Miltefosine is the only phospholipid that has been proven to be safe and effective in leishmaniasis therapy.

6. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

It is estimated that 350 million people are at risk for leishmaniasis. Twelve million people are currently infected, with 1.5-2 million new cases being reported annually, and 70,000 deaths occurring annually [Reithinger 2007].

The disease is transmitted by a species of sandfly ( Phlebotomus sp . and Lutzomyia sp .), and is found in 88 countries in both the Old World (Europe, Africa, Asia) and the New World (Americas). Several different strains of the parasite are responsible for the varying leishmaniasis diseases, showing geographic and disease specificity.

There are two major forms of the disease. Internal or visceral leishmaniasis (VL) is the most dangerous and is fatal within 6-12 months if left untreated. Visceral leishmaniasis is found in the Old World (L. donovani and L. infantum strains) and New World (L. chagasi strain). It particularly affects the Indian subcontinent (India, Bangladesh and Nepal), parts of East Africa (Sudan and Ethiopia) and parts of South America (primarily Brazil). The estimated number of new cases per year is 500,000 with a high rate of mortality.

Cutaneous leishmaniasis (CL), leads to lesions and ulceration of the skin. In cases where no spontaneous healing occurs it leads to disfiguring scars on the body and face. The rate of self-healing varies between 10-50%; however, self-healing cannot be predicted a priori . If left untreated secondary infections of the ulcer occur, and in the New World development of the mucosal form of leishmaniasis is a possible complication, which can lead to the destruction of the cartilaginous structures of the face and mucosa.

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Cutaneous leishmaniasis is widespread in both New World and Old World locations. In the Old World L. major and L. tropica are the main strains of the disease. L. major is found in rural areas whereas L. tropica is found predominantly in urban areas. The main countries affected are Afghanistan, Pakistan and the entire Middle East especially Iran, Iraq, Syria and Saudi Arabia. In the Old World, there is a tendency to leave patients untreated because scars and painful ulcers are considered non life-threatening; the high risk of side effects from the current preferred treatment with antimony may explain this wait-and-see position. The ease of treatment with an oral medication such as miltefosine may change this approach and will give physicians the opportunity to more easily treat patients and prevent them from living a disfigured life. Importantly, untreated patients remain a reservoir for anthroponotic L. tropica infections , keeping the disease within the community and allowing for its spread.

In the New World the situation is more dangerous. Patients suffering from CL may develop the mucosal form which will lead to painful and disfiguring lesions in areas of the face such as the nares and pharynx. Cutaneous leishmaniasis is found all over Central and South America with focal points in Mexico, Guatemala, Colombia, Venezuela, Peru, Bolivia and Brazil. Governments have or are in the process of setting up treatment programs for leishmaniasis, but the application of parenteral drugs in often rural, jungle areas, remains difficult. Mucosal disease is found in all of these regions except for Mexico-Guatemala.

Figure 1 : Global distribution of leishmaniasis.

In summary, leishmaniasis is one of the neglected tropical diseases. Research and medical breakthroughs are rare. For more than 50 years no new drugs specifically for leishmaniasis have been developed. Miltefosine is a novel agent that enables a safe and effective new

Page 4 of 31 Application for Inclusion of Miltefosine on WHO Model List of Essential Medicines November 2010 Submission treatment for all forms of leishmaniasis. The oral route of administration facilitates its use in treatment programmes in rural areas as no hospitalisation, or equipment for parenteral administration of intravenous drugs, is required.

7. Treatment details

The recommended treatment regimen for non-immunocompromised patients is 2.5 mg/kg/day for 28 days.

7.1 Visceral leishmaniasis

To achieve the daily dose of approximately 2.5 mg/kg/day for children aged 3 years and older, the daily dose is as outlined in Table 1 .

Bodyweight Daily Dosage Number of Capsules 9 – 11 kg 20 mg 2 capsules Impavido 10 mg 12 – 16 kg 30 mg 3 capsules Impavido 10 mg 17 – 20 kg 40 mg 4 capsules Impavido 10 mg 21 – 25 kg 50 mg 5 capsules Impavido 10 mg 26 – 31 kg 60 mg 6 capsules Impavido 10 mg 32 – 39 kg 80 mg 8 capsules Impavido 10 mg 40 kg and above 100 mg 2 capsules Impavido 50 mg

Table 1 : Dosing details for miltefosine use in VL.

Note that no data from clinical studies are available for patients with a bodyweight lower than 9 kg and higher than 67 kg. An increase of the daily dosage to 150 mg (3 capsules Impavido® 50 mg) could be considered in patients with a bodyweight above 67 kg under monitoring of the tolerability, as this dose has been used in CL and ML patients (see below).

7.2 Cutaneous and Mucosal leishmaniasis

To achieve the daily dose of approximately 2.5 mg/kg/day:

The daily dosage for children aged 12 years and older and a body weight of at least 30 kg, and adolescents and adults with a body weight of lower than 45 kg, is 100 mg miltefosine (2 capsules Impavido® 50 mg).

Patients with a bodyweight higher than 45 kg receive 150 mg miltefosine daily (3 capsules Impavido® 50 mg).

No data from clinical studies are available for patients with a bodyweight lower than 30 kg. Therapy may be considered using the dosages recommended for visceral leishmaniasis.

Dosages of 2 - 8 capsules per day should be divided into 2 - 3 individual doses to be taken either in the morning and in the evening or in the morning, at noon and in the evening. The capsules should be taken with meals.

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8. Summary of comparative effectiveness in a variety of clinical settings

8.1 Identification of clinical evidence

Nine Industry-sponsored clinical trials have been performed in both VL and CL, as shown in Table 2 . All studies were conducted according to Good Clinical Practice (GCP) principles; the Industry sponsor’s study ID number is indicated. VL studies (except 033 and 3089) were conducted in collaboration with WHO/TDR. All studies used appropriate criteria for evaluating the safety and efficacy of the product, e.g . recording of adverse events and repeated evaluations of laboratory and 6 month post treatment follow-up to verify definite cure, respectively. While dose-finding studies had sequential or parallel dose groups without use of an active comparator drug, the Phase III trial in adult VL patients was active controlled (intravenous amphotericin B), while the confirmatory study in CL patients was placebo- controlled.

Study Principal Investigator(s) Group: Dosages / ranges tested No. of patients Studies in VL patients aged 12 years and older 0033 1 S Sundar 50 mg q2d x 14 days up to 30 250 mg/day x 28 days 3089 2 S Sundar 100 mg/day x 28 days up to 46 200 mg/day x 28 days 3109 3 TK Jha, S Sundar, 50 mg/day x 42 days up to 120 CP Thakur (WHO) 100 mg/day x 7 days + 150 mg/day x 21 days 3127 4 S Sundar 100 mg/day x 14 days up to 54 100 mg/day x 28 days 3154 5 TK Jha, S Sundar, Miltefosine: 100 mg/day x 28 days 400 (300 +100) CP Thakur (WHO) (below 25 kg: 50 mg/day x 28 days) Amphotericin B: 1 mg/kg/day x 30 days Studies in VL patients aged 11 years and younger 3091 6 S Sundar 1: 1.5 mg/kg/day x 28 days 39 2: 2.5 mg/kg/day x 28 days 3206 7 TK Jha, S Sundar, 2.5 mg/kg/day x 28 days 80 CP Thakur, S Bhattacharya (WHO) Studies in CL patients aged 12 years and older 3092 8 J Soto, Bolivia 50 mg/day x 20 days up to 64 150 mg/ day x 28 days 3168 9 J Soto, Bolivia 150 mg/day x 28 days vs. 133 (89 + 44) B Arana / M Gilardi, Placebo Guatemala (1) Sundar S. 1998; (2) Sundar S. 1999; (3) Jha TK. 1999 ; (4) Sundar S. 2000; (5) Sundar S. 2002; (6) Sundar S. 2003, (7) Bhattacharya SK 2004; (8) Soto J. 2001; (9) Soto J. 2004

Table 2: Studies of miltefosine in patients with visceral leishmaniasis (VL) or cutaneous leishmaniasis (CL).

In addition to the above Industry-sponsored data from clinical trials in VL and CL patients, data on HIV co-infected patients are available from an MSF study in Ethiopia, and data on mucosal leishmaniasis is available from an investigator-initiated study in Bolivia.

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8.2 Summary of available data

8.2.1 Industry-sponsored studies in visceral leishmaniasis

8.2.1.1 Global cure rates by study Table 3 shows for the intent-to-treat (ITT) populations of all studies the final cure rates irrespective of dosage used. Except for the dose-finding pilot study (0033), all subsequent studies resulted in high global rates of final cure rates, underlining the therapeutic potential of miltefosine in this indication.

Final parasitological cure, ITT population Missing/ not assessable No Yes All Study n % n % n % n 0033 0 0 8 26.7 22 73.3 30 3089 All patients treated 1 2.2 0 0 44 97.8 45 with miltefosine, 3109 0 0 6 5.0 114 95.0 120 irrespective of 3127 0 0 2 3.7 52 96.3 54 daily dose, 3154 age, 8 3.0 9 3.0 282 96.6 299 3091 and treatment duration 1 2.6 4 10.3 34 87.2 39 3206 2 2.5 3 3.7 75 93.4 80 All patients treated with miltefosine aged > 12 years * ) 9 1.6 25 4.6 514 93.8 548 All patients treated with miltefosine (any age) 12 1.8 32 4.8 623 93.4 667 3154 Patients allocated to treat- ment with amphotericin B 3 3.0 0 0 96 97.0 99 All patients (any treatment) 15 2.0 32 4.2 719 93.9 766 *) i.e. excluding studies 3091 and 3206 Table 3: Cure rates of VL patients after treatment with miltefosine, irrespective of administered dosage (ITT analyses).

8.2.1.2 Cure rates by dosage As the clinical studies included dose groups with higher and lower dose intensities compared with the approved dosage scheme, Table 4 shows the cure rates according to the administered daily dose.

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Final parasitological cure, ITT population*

Missing/not assessable No Yes All Dose group* n % n % n % n ≤ 50 mg 1 0.9 12 11.2 94 87.9 107 100 mg 9 2.2 14 3.4 384 94.3 407 150 mg 0 0 2 3.8 51 96.2 53 200-250 mg 0 0 1 5.0 19 95.0 20 AMP 3 3.0 0 0 96 97.0 99 all* 13 1.9 29 4.2 644 93.9 686 * excluding data from study 3206 in which all patients received the same target dosage of 2.5 mg/kg/day and variability in dosage was caused by rounding to 10 mg increments. AMP= amphotericin B Table 4 : Cure rates of VL patients after treatment with miltefosine, by administered daily dose (ITT analyses).

It is evident that all dose groups with a daily dosage of 100 mg and higher showed final cure rates around 95%, which is not statistically different from the control, Amphotericin B. The cure rate for the dose group ≤ 50 mg/day is lower as it includes data from pediatric patients from Study 3091 as well as patients treated at the first dose levels in the dose finding Studies 0033 and 3109. It should be noted that the dose group of 100 mg/day includes data from those patients of Study 3127 who received the treatment for only 2 and 3 weeks. Failure to achieve cure was noticed for the short treatment duration.

8.2.1.3 Cure rates by patients’ age Table 5 shows the cure rate of VL patients by age group. The lower global response rate in the group of patients aged 15 years and above results from the inclusion of early dose- finding studies. These studies with higher failure rates due to under-dosing, had a lower age limit of 14 years. Thus, the higher cure rate in the age group 12-14 years is due to the fact that this age group comprised patients from studies excluding sub-optimal dosage schemes. Cure rates in the patients aged 2-11 years draw upon data from both the dose-finding study (Study 3091) and the confirmatory study in this age group (Study 3206).

Final parasitological cure, ITT population

Missing/ not assessable No Yes All Age [years] n % n % n % n 2-11 3 2.6 7 10.3 109 91.6 119 12-14 2 1.4 1 0.7 139 97.9 142 >= 15 10 2.0 24 4.8 471 93.3 505 All 15 2.0 32 4.2 719 93.9 766

Table 5 : Cure rates of VL patients treated with miltefosine by patient age (ITT analyses).

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8.2.1.4 Cure rates in relation to pre-treatment In patients of all ages, miltefosine was effective both in pre-treated and treatment-naïve patients. All studies consistently showed similarly high global cure rates for miltefosine in both pre-treated patients and in patients with newly diagnosed VL. Pre-treatment, in most cases with pentavalent antimonial drugs, did not adversely affect the response rate to treatment with miltefosine. Response rates, both in pre-treated and in treatment-naïve patients did not show a significant difference between oral treatment using miltefosine and intravenous treatment using amphotericin B.

Final parasitological cure, ITT population Missing/ not assessable No Yes All Treatment / status of leishmaniasis n % n % n % n Newly diagnosed 9 2.1 24 5.5 407 92.7 439 Previously treated 3 1.3 8 3.5 218 95.6 228 All patients 12 1.8 32 4.8 623 93.4 667

Table 6 : Cure rates of VL patients after treatment with miltefosine by patient age (ITT analyses).

8.2.1.5 Improvement in clinical and laboratory parameters [Sundar et al. NEJM 2002] Treatment with miltefosine was associated with rapid resolution of all signs and symptoms due to leishmaniasis, specifically including disappearance of splenomegaly, recovery from decreased weight, fever, and anemia.

Within less than one week from start of treatment, miltefosine-treated patients were afebrile and remained so until end of treatment, while in amphotericin B-treated patients each drug application was associated with a recurrent fever reaction due to amphotericin B toxicity.

8.2.1.6 Tolerability [Sundar et al. NEJM 2002] In the pivotal Phase 3 study (Study 3154), there were no serious adverse events (SAEs) and no premature discontinuation of therapy.

Subjective adverse events were gastrointestinal in nature. Twenty-six percent and 25% of patients had episodes of vomiting or diarrhea, respectively. The durations of vomiting and diarrhea were short, and the intensity was mild (CTC Grade 1) to moderate (CTC Grade 2) only, except for a single instance of CTC Grade 3 vomiting out of 400 patients. Vomiting and diarrhea were treated with oral rehydration salt solution and did not lead to discontinuation of therapy for any patient.

In terms of laboratory parameters, 55% of patients had a transient increase in ASAT levels, but only one patient had an increase to CTC Grade 3 levels. Changes in kidney function were uncommon and mild.

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8.2.2 Visceral leishmaniasis study performed by Médecins Sans Frontières [Ritmeijer et al. 2006]

An MSF trial in Ethiopia compared miltefosine to standard of care (pentavalent antimony) in patients both non-immunosuppressed and with HIV co-infection. The data is divided into patients known to be HIV co-infected, known not to be co-infected, and those for whom their HIV status was unknown. Table 7 gives the main results (taken from Ritmeijer et al ., 2006). Among patients not infected with HIV, both the initial cure rate (94%) and final cure rate (75%) were similar for miltefosine as compared with antimony (95% and 77%, respectively).

Table 7 : Main results from MSF-sponsored miltefosine study (taken from Ritmeijer et al ., 2006).

For all patients combined, the initial cure was the same (88%) for both treatment groups. The final cure rate was slightly less for miltefosine compared with antimony (60% vs . 65%, respectively; not statistically significant), and the relapse rate was higher for miltefosine (10% vs . 2%). However, the mortality rate was significantly lower for miltefosine (6%) compared to antimony (12%; p= 0.02).

One explanation for the disparate data on relapses and death may be that miltefosine was more effective than antimony and therefore prevented initial deaths, but was not sufficiently effective to prevent later relapses of the saved patients.

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8.2.3 Industry-sponsored studies in cutaneous leishmaniasis

8.2.3.1 Dose finding study (Study 3092) [Soto 2001] Study 3092 was a dose-escalating, open-label Phase I/II CL trial of oral miltefosine in Colombia. The study was conducted in 72 male Colombian soldiers, with a mean weight of 67 kg. The dosage groups are shown in Table 8.

Group Dosage ranges tested No. of patients 1 50 mg qd x 20 16 2 50 mg qd x 7; 100 mg qd x 19 13 3 100 mg qd x 7; 150 mg qd x 17 13 4 150 mg qd x 28 20

Table 8: Dose groups for Study 3092.

The cure rate in the per-protocol Population (PPP) is shown in Table 9.

PP Population Group 1 Group 2 Group 3 Group 4 Rate of definite cure 9/14 12/18 14/14 16/18 (64.3%) (66.7%) (100.0%) (88.9%) 95% (90%) lower 39.0% 44.6% 80.7% 69.0% confidence bound (43.7%) (48.8%) (84.8%) (73.1%)

Table 9: Cure rates in Per-Protocol Population (PPP) for Study 3092.

There was a trend between cure rate and dosage group (p=0.05). In addition, there was a significant difference between the cure rate for the lower dosage groups (groups 1-plus-2 combined: 21 of 32 = 66%) and the cure rate for the groups who essentially received 150 mg/day (groups 3-plus-4 combined: 30 of 32 = 94%) (p=0.01).

The most common side effect was motion sickness, defined as lack of balance plus gastrointestinal unease. Forty percent of patients reported motion sickness at some time during therapy; the incidence increased significantly between Group 1 and Group 4. With the exception of one patient, motion sickness lasted from only 1 to 7 days over the 3-4 weeks of treatment and did not prevent normal duties. Vomiting and diarrhea were infrequent and not dose-related (p=1.0), and was experienced by only 21% of patients for no more than 5 days per patient. During treatment, transient elevation in liver transaminases (CTC Grade 1, i.e . <2.5 times upper limit of normal) was seen in Groups 1, 2, 3 and 4 in 38%, 42%, 35%, and 20% of patients, respectively. Elevations to CTC Grade 2 (2.6-5.0 times upper limit of normal) were seen in a single patient in each of Groups 1, 2, and 4. Again, all elevations were transient.

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8.2.3.2 Pivotal CL study (Study 3168) [Soto/Arana 2004] This was a double blind placebo-controlled study of miltefosine (2.5 mg/kg/day orally for 28 days) in Colombia and Guatemala in 133 patients.

The number of patients in the two treatment groups is shown in Table 10.

Group Dosage ranges tested No. of patients 1 150 mg/day x 28 89 2 Placebo 44

Table 10: Treatment groups in Study 3168.

In Lv. panamensis regions in Colombia, the per-protocol cure rates for miltefosine and placebo were 91% (40/44) and 38% (9/24), respectively ( Table 11). The miltefosine and placebo cure rates in this study are similar to historic values for the standard of care, parenteral meglumine for 20 days, and for placebo, respectively.

Colombian Site Miltefosine Placebo Number of patients 49 24 Number cured 40 9 Number failed 4 15 ITT cure rate 82% 38% PP cure rate 91% 38% Age (years) 24±10 25±13 Weight (kg) 60±13 57±14 No. Of lesions 1(1-8) 1(1-5) Ulcer size (mm 2) 171(72-1775) 238(6-2110) Previous Rx failure (# [%]) 3[6%] 2[8%] Time since first diagnosis 8(5-47) 8(3-39) (days)

Table 11: Study details for Study 3168: Colombian site.

In the combined Lv. braziliensis and Lm. mexicana regions of Guatemala, the per-protocol cure rates were 53% (20/38) for miltefosine and 21% (4/19) for placebo, respectively (Table 12 ). The miltefosine cure rate was lower than historic antimony cure rates of >90% in Guatemala for Lv. braziliensis in this region.

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Guatemalan Site Miltefosine Placebo Number of patients 40 20 Number cured 20 4 Number failed 18 15 ITT cure rate 50% 20% PP cure rate 53% 21% Age (years) 26±10 28±12 Weight (kg) 59±8 60±8 No. Of lesions 1(1-10) 1(1-3) Ulcer size (mm 2) 165(6-1650) 154(6-3300) Previous Rx failure (# [%]) 10[25%] 8[40%] Time since first diagnosis (days) 9(7-21) 9(7-21)

Table 12: Study details for Study 3168: Guatemalan site.

As Study 3168 was placebo-controlled, particular importance is placed on safety data from this study.

While the frequency of nausea and vomiting was significantly higher in miltefosine patients (Table 13), the large majority of affected patients had a small number of episodes (1 or 2 occasions only). Only three patients had a higher number of episodes; however, none more than seven episodes. No patient discontinued therapy prematurely due to nausea or vomiting. One premature discontinuation was due to repeated “motion sickness” and headache.

Increases in creatinine above the normal range was seen in 32% of miltefosine-treated patients compared to 9% in the placebo group. In all cases but one, the increase was only to CTC Grade 1. There was no difference between miltefosine and placebo in the percentage of patients who experienced increases in liver function tests; all increases were CTC Grade 1 (< 2.5 times the upper limit of normal).

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Miltefosine Placebo Number patients 89 44

Treatment Emergent Adverse Events Nausea 32 (36%) 4 (9%)* Motion sickness 26 (29%) 10 (23%) Headache 24 (27%) 9 (21%) Vomiting 1 or more 28 (32%) 2 (5%)** 1-2 22 (25%) 1 (2%) 3-4 3 (3%) 1 (2%) >4 3 (3%) 0 (0%) Diarrhea 1 or more 5 (6%) 1 (2%) 1-2 4 (5%) 1 (2%) >2 1 (1%) 0 (0%)

Laboratory parameters Creatinine increased 29 (33%) 4 (9%)*** CTC Grade 1 28 (31%) 4 (9%) CTC Grade 2 1 (1%) 0 (0%) AST increased 7 (8%) 8 (18%) ALT increased 9 (10%) 5 (11%) *p<0.001 (chi-square test); ** p<0.001 (chi-square test); *** p=0.003 (chi- square test) For creatinine: CTC Grade 1 signifies values less than 1.5 times the upper limit of normal. CTC Grade 2 signifies values between 1.5 and 3.0 times the upper limit of normal.

Table 13: Safety data from Study 3168.

Importantly, both ophthalmological examinations and spermiograms did not reveal adverse changes.

8.2.4 Mucosal leishmaniasis [Soto 2007]

In this investigator-sponsored study, the initial study design was a randomized equivalency study of oral miltefosine (50 patients) versus standard therapy with pentavalent antimony (25 patients). Due to changes in regional standard of care to amphotericin B (45 mg/kg as 1mg/kg doses for 45 consecutive days), and due to initial positive response rates in the miltefosine group, patients refused to be treated with antimony or to be randomized to the amphotericin B arm of the study. Therefore, the final study design became an evaluation of one cohort of 78 patients who received miltefosine (2.5 mg/kg/day for 28 days).

Of the 78 patients who received miltefosine, 72 were evaluable. Fifty-one (71%) of the 72 evaluable miltefosine patients were cured (>90% diminution in the mucosal severity score) at 12 months of follow up. The large majority of these patients (49 [96%]) demonstrated complete resolution of their clinical signs. The cure rate for the 36 patients who had mild disease ( i.e ., affecting only the nasal skin and nasal mucosa) was 83%, while the cure rate for the 36 patients who had more extensive disease (involving the palate, pharynx, and larynx) was 58%. The ITT cure rate for all 78 patients who received drug was 51/78 (65%).

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Miltefosine was well tolerated in this study. Nausea, vomiting, and diarrhea were each reported by 8–17 patients. Most episodes were CTC Grade 1, with the exception of a single Grade 3 episode. Most episodes lasted 1–2 days and few lasted 3–4 days. Mean values of liver function tests and kidney function tests did not change; a few patients had values that were slightly above the upper limit of normal after treatment.

8.3 Summary of available estimates of comparative effectiveness

Four antileishmanial drugs are on the Essential Medicine list: pentavalent antimony, amphotericin B, liposomal amphotericin B (AmBisome), and paromomycin.

8.3.1 Visceral leishmaniasis

In direct comparison to sodium stibogluconate (pentavalent antimony) in Ethiopia, miltefosine showed a non-statistically lower cure rate (60% vs . 65% for antimony) due to a higher relapse rate (10% vs . 2%), but with a statistically significant lower mortality rate (6% vs . 12%). Given the high degree of mortality with VL, the significantly lower death rate outweighs the lower cure rate and higher relapse rate. Note that for regions other than Ethiopia for which antimony resistance is present, miltefosine is superior in efficacy to antimony.

In direct comparison to amphotericin B deoxycholate in the Indian Phase 3 trial, miltefosine had an ITT cure rate of 94% and amphotericin B demonstrated a 97% ITT cure rate. The difference in cure rates between miltefosine and amphotericin B was not statistically significant; therefore, miltefosine is equivalent in efficacy to amphotericin B.

Miltefosine has not been directly compared to liposomal amphotericin B. For Indian VL, literature reports show a 15 mg/kg and 10 mg/kg total dose of amphotericin B in the form of AmBisome has the same efficacy (96-97% ITT cure rate: Sundar AJTMH 2002; Sundar NEJM 2010) as a 15 mg/kg total dose of amphotericin B deoxycholate. Therefore, miltefosine should be comparable to intravenous liposomal amphotericin B in terms of efficacy.

Miltefosine has not been directly compared to paromomycin. In India, paromomycin demonstrated an ITT cure rate of 96% [Sundar et al ., 2007], a value similar to that of miltefosine in the same region.

In summary: for VL in the Indian subcontinent, miltefosine, amphotericin B, AmBisome, and paromomycin have similar efficacies of > 95%.

8.3.1.1 Post-kala-azar dermal leishmaniasis (PKDL) as a sequella to VL

Indian PKDL is an under-investigated disease for which treatment is widely regarded as unsatisfactory. Although PKDL in Sudan and in India are both due to L. donovani , Sudanese PKDL frequently self-heals (84% of patients at one year) whereas Indian PKDL is believed not to self heal within one year. The best studies of the response of Indian PKDL to antimony have been by Thakur et al. The current recommended treatment for PKDL includes either daily injections of pentavalent antimonials for 120-200 days, or 60 infusions of amphotericin B given over 80 days [Thakur 1997].

WHO/TDR has sponsored a trial of miltefosine (12 weeks vs . 8 weeks) for Indian PKDL. Although the results are not yet formally known, miltefosine (12 weeks) is now being routinely used in the Indian subcontinent, as attested by the supporting letters for this application discussing the apparent efficacy of this regimen, which clearly is superior in feasibility to 60- 200 injections of amphotericin B or antimony.

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8.3.2. Cutaneous leishmaniasis

The only Essential Medicine routinely used for CL is antimony. The toxicity of amphotericin B deoxycholate precludes its use in routine CL therapy. Because of the expense and the requirement for intravenous administration, AmBisome has rarely been tried for CL. Paromomycin has been evaluated for CL in Belize and in Colombia and found to be relatively ineffective [Hepburn 1994, Soto 1994].

The historic cure rates for pentavalent antimony in both regions where miltefosine was evaluated in Industry-sponsored studies - Colombia and Guatemala - are between 80% and 90% [Soto 2004]. Thus, in Colombia, but not in Guatemala, the miltefosine cure rate was comparable to historic values for antimony.

As investigator initiated trials from many regions of the world are performed and published, Paladin expects that the results will be consistent with those of the Colombia/Guatemala study: that miltefosine is comparable in efficacy to antimony in some but not all regions in which antimony is highly active. In addition, miltefosine may be superior in regions in which antimony is less active. Thus, miltefosine was comparable to antimony as tested in Bolivia [Soto 2008], inferior as recently tested in Colombia [Velez 2010], and superior as recently tested in Brazil [abstract of one study in L. guyanensis is in Appendix I; abstract of the second study in L. braziliensis to be submitted when available]. Paladin also notes reports of antimony efficacy failures in single-group studies in some regions: L. guyanensis in Brazil [Romero 2001] and early L. braziliensis in Brazil [Arevalo 2007].

In summary, miltefosine has demonstrated statistical superiority over placebo for disease from 2 locales: L. panamensis areas in Colombia and L. braziliensis /L. Mexicana areas in Guatemala. Additional data soon to be published will also expand the list of effective regions to include Brazilian CL due to both L. braziliensis and L. guyanensis .

8.3.3. Mucosal leishmaniasis

No comparative trials of miltefosine vs . antimony, amphotericin B, liposomal amphotericin B, or paromomycin have been performed. The miltefosine data from Bolivia suggests that miltefosine is as effective as historic values for antimony, amphotericin B, and liposomal amphotericin B. Paromomycin was relatively ineffective against Peruvian ML [Llanos- Cuentas 2007].

9.0 Summary of comparative evidence on safety

9.1 Estimate of total patient exposure

From Nov 2004 through Mar 2009, 62,659 treatment courses were supplied either for clinical trials, for public Government treatment programs, or individual treatment use in Europe. These patient courses were contained in the Periodic Safety Update Reporting requirements for regulatory purposes.

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9.2 Description of adverse effects/reactions

9.2.1 Common and Uncommon Adverse Events (AEs) as summarized in package insert

The most commonly reported adverse drug reactions are transient gastrointestinal discomfort, vomiting, diarrhea, elevation of liver enzymes and serum creatinine. These effects are usually mild to moderate and transient or reversible at the end of treatment and therefore do not require discontinuation of treatment or dosage reduction. Table 14 lists AEs observed in 564 patients treated in clinical trials at the recommended treatment dosages.

Organ systems Very common side Common side Uncommon side effects effects effects (10% of patients) (1 – 10% of (0.1 – 1% of patients) patients) Gastrointestinal Vomiting Anorexia Abdominal pain disorders Diarrhea Nausea Hepatobiliary Increase in liver disorders enzymes (SGOT, - - SGPT, AP) Renal and urinary Increase of BUN, - - disorders Creatinine

Table 14: AEs observed during clinical trials.

9.2.2 Fatal SAEs (to Mar 2009) in surveillance reports

There were 13 deaths unlikely attributable to miltefosine. Three occurred in HIV-coinfected patients; four were due to presumed bacterial infection; six were reported with little data. One of these fatalities occurred in the mucosal leishmaniasis study. One patient died of gastrointestinal symptoms plus hypotension, two days post a family dinner after which two other persons were diagnosed as having “Typhoid Fever”.

There were five deaths possibly or probably attributable to miltefosine. Each involved gastrointestinal symptoms accompanied by high values of bilirubin, transaminases, or creatinine. Analyses of these cases have led to the monitoring measures for gastrointestinal symptoms and serum chemistries given in Section 4.4 of the product insert.

These numbers indicate that possibly-attributable fatalities are very rare: approximately 1/10,000 cases of VL.

9.2.3 Male Reproductive studies

Toxicological studies have shown an impairment of reproductive function in male rats. Data on reproductive performance of 267 male patients who were treated with miltefosine in clinical studies did not indicate an effect on fertility [Product brochure—Appendix II].

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9.2.4 Pharmacokinetic considerations

In vitro investigations have shown that interactions are unlikely with medications that are metabolised by cytochrome P450 or glucuronised or conjugated otherwise. However, the possibility of interactions with commonly used medicinal products cannot entirely be excluded.

The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half- life of 30.9 days [Dorlo 2008].

9.2.5 Pregnancy and lactation

Pregnancy There are no adequate data from the use of miltefosine in pregnant women. Studies in animals have shown reproductive toxicity. Miltefosine is contraindicated in pregnancy. Women of childbearing potential have to use effective contraception during and, given the initial elimination half-life, up to 3 months after treatment [Product brochure—Appendix II].

Lactation It is not known whether miltefosine is excreted in the milk. Miltefosine should not be used by breast feeding women [Product brochure—Appendix II].

9.3 Identification of variation in safety due to health systems and patient factors

VL is a systemic infection, whereas patients with CL and ML are systemically normal. Although the qualitative side effect profile of miltefosine in CL/ML is the same as in VL, namely gastrointestinal and renal in nature, the severity of these side effects is less in CL/ML than in VL patients.

9.4 Summary of comparative safety against Essential Medicine comparators

Comparison to Antimony On an absolute basis, the disadvantages of antimony are well-known: its mode of administration is parenteral, and its side effects include arthralgias, liver function abnormalities, a high rate of pancreatic enzyme abnormalities (especially in HIV co-infected individuals), neutropenia and thrombocytopenia, and EKG abnormalities such as t-wave flattening, QTc prolongation, ventricular extrasystoles, and occasionally ventricular tachycardia and death [Herwaldt 1992].

Clinical side effects for miltefosine are, as outlined above in Section 9.2.1, qualitatively different except for liver function abnormalities in VL patients. Overall, miltefosine is better tolerated than antimony.

Comparison to amphotericin B for VL Miltefosine was directly compared to amphotericin B in the Phase 3 VL study in India. For miltefosine, vomiting and diarrhea occurred in 38% and 20% of patients, respectively, was predominately mild in severity, and was of short duration. Grade 3 liver function test abnormalities occurred in 5% of patients. Elevations of renal-function tests occurred in 16% of patients.

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For amphotericin B, fever or chills occurred in 90% of patients. Grade 3 liver function test abnormalities occurred in 3% of patients. The well-known adverse effect of renal function abnormalities occurred in 60% of patients.

Clinical side effects of the two agents are therefore qualitatively different: gastrointestinal for miltefosine vs . fever/chills for amphotericin B. Laboratory adverse effects (liver and kidney dysfunction) are lower for miltefosine than for amphotericin B. Overall, miltefosine is better tolerated than is amphotericin B (deoxycholate).

Comparison to amphotericin B for CL Amphotericin B is rarely used for CL given its toxicity (see above); therefore, miltefosine is considered the primary choice from a safety perspective for this indication.

Comparison to Liposomal amphotericin B (AmBisome) AmBisome was designed to be a better-tolerated amphotericin B formulation and has proven to be an important advance in antileishmanial chemotherapy. Despite significantly fewer infusion-related reactions, chills, rigors, fever, nausea, vomiting, and cardiorespiratory events may still be seen with AmBisome. The latter adverse reaction, as well as reported cases of anaphylaxis with AmBisome, is of significant importance in relation to the use of the drug in less severe forms of leishmaniasis, i.e. for CL/ML.

9.5. Summary of comparative therapeutic indices of miltefosine re other antileishmanial Essential Medicines

Comparison to Antimony For VL, miltefosine is superior to antimony on the basis of efficacy (approximately equal to antimony for antimony-sensitive disease, but superior to antimony for antimony-resistant disease), tolerance, and feasibility of administration (oral miltefosine vs . parenteral antimony).

For CL/ML, miltefosine is equal to antimony for efficacy, superior for tolerance, and superior for feasibility of administration.

Comparison to amphotericin B For VL, miltefosine was statistically equivalent to amphotericin B on the basis of efficacy, superior in tolerance, and superior for feasibility of administration (oral miltefosine vs . IV amphotericin B).

For CL/ML, amphotericin B is rarely used for the milder leishmaniasis syndromes (CL/ML) due to the drug’s toxicity profile.

Comparison to liposomal amphotericin B (AmBisome) For VL, miltefosine may be slightly inferior to AmBisome on the basis of efficacy, tolerance, and feasibility now that very short courses of this IV medicine are being used.

For CL, miltefosine is superior since AmBisome has not been widely used, is superior in tolerance, and superior in feasibility (oral miltefosine vs . multiple administrations of IV liposomal amphotericin B).

Comparison to paromomycin For VL, miltefosine is equal to paromomycin on the basis of efficacy, probably inferior for tolerance, and superior in terms of feasibility of administration (oral miltefosine vs . parenteral paromomycin).

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For CL/ML, paromomycin has not been found effective and therefore has not been used.

Overall comparison to present antileishmanial Essential Medicines

The above comparisons can be qualitatively summarized as per Table 15 below:

Miltefosine Feasibility of compared to: Disease Efficacy Tolerance Administration Antimony VL superior superior superior CL/ML equal superior superior

Amphotericin B VL inferior superior superior CL/ML [not known] superior [superior]

Liposomal VL inferior inferior inferior Amphotericin B CL/ML superior superior superior

Paromomycin VL equal inferior superior CL/ML superior [not known] [superior]

Table 15: Pair wise comparisons of miltefosine to currently listed Essential Medicines for leishmaniasis.

Table 15 shows that for the 24 possible comparisons (4 drugs x 2 diseases x 3 criteria), Paladin considers miltefosine to be superior in 15 instances, miltefosine to be equal or unable to judge in four instances, and miltefosine to be inferior in five instances.

With respect to each disease separately: miltefosine is superior to three of the four present Essential Medicines for VL (i.e ., all present Essential Medicines other than liposomal amphotericin B) and superior to all present Essential Medicines for CL and ML.

Paladin therefore proposes that miltefosine qualifies to be one of the antileishmanial drugs on the Essential Medicine list.

10 Summary of available data on comparative cost and cost effectiveness within the pharmacological class of therapeutic group

Paladin has historically supplied, and commits to continuing to supply, miltefosine at a special low price for public use and control programmes, if patients are treated free of charge in developing countries. This price is heavily discounted from the price for Industrialized nations.

10.1 VL in India treated in the public sector

Current treatment costs for VL have been estimated in a 2010 publication [Meheus et al. , 2010]. This assessment evaluated the costs in three countries where public Government treatment programs are in place, namely India, Nepal and Bangladesh. The regimens considered are listed in Table 16, adapted from that publication.

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Strategy Strategy Drug Length of abbreviation treatment (days) A L-AmB+MF Liposomal Amphotericin B (5mg/kg) + miltefosine 8 (50 or 100mg/day) B L-AmB+PM Liposomal Amphotericin B (5mg/kg) + 11 paromomycin (15mg/kg/day) C MF+PM Miltefosine (50 or 100mg/day*) + paromomycin 10 (15mg/kg/day) D SSG+PM Antimony (SSG; 20mg/kg/day) + paromomycin 17 (15mg/kg/day) E MF Miltefosine (50 or 100mg/day) 28 F PM Paromomycin (15mg/kg/day) 21 G AmB Amphotericin B deoxycholate (1mg/kg/day) 30 H L-AmB10 Liposomal Amphotericin B (10mg/kg) 1 I L-AmB20 Liposomal Amphotericin B (5mk/kg/day) 4 J SSG Antimony (SSG; 20mg/kg/day) 30 *miltefosine is given at 50mg/day if body weight is <25kg

Table 16: Overview of current leishmaniasis treatment strategies (adapted from Meheus et al ., 2010)

The costs for these regimens, inclusive of other direct and indirect costs associated with administering the medication, are shown in Table 17.

Strategy Strategy Drug cost Other direct Non-medical Total cost 2 abbreviation medical 1 and indirect A L-AmB+MF 95.7 14.8 12.8 123.4 B L-AmB+PM 87.1 20.5 25.3 132.9 C MF+PM 29.5 19.5 23.8 72.9 D SSG+PM 45.1 29.9 43.6 118.6 E MF 62.8 22.0 45.4 130.2 F PM 14.9 30.6 51.1 96.6 G AmB 20.9 131.6 45.4 197.9 H L-AmB10 140.0 11.0 2.5 153.4 I L-AmB20 280.0 24.7 6.9 311.6 J SSG 57.8 40.7 73.4 171.8 1Includes costs for contraceptives, administration (intravenous kits, solutions, syringes), laboratory investigations. It also includes the cost per inpatient bed-day and outpatient visit obtained. 2Total costs of strategies with MF in this table do not include cost of AmB given to women of childbearing age that refuse to take contraceptives and are therefore different from total costs mentioned.

Table 17: Cost estimates of each treatment strategy per patient treated (adapted from Meheus et al. , 2010). Costs are in 2008 $USD.

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For the purpose of this Essential Medicine application, the relevant costs are for the stand- alone therapies:

Miltefosine: Total cost = $130.20 SSG: Total cost = $171.80 Amphotericin B: Total cost = $197.90 Liposomal amphotericin B (10-20 mg): Total cost = $153.40-$311.60 Paromomycin: Total cost = $96.60

This data indicates that even where the cost of goods for Liposomal amphotericin B has been reduced 90% via an agreement with the WHO, miltefosine treatment is the least expensive regimen with the exception for paromomycin.

10.2 Public sector CL/ML treatment programs

The dose of drug and duration of treatment does not markedly vary with the indication or region. Other direct and non-medical costs would vary by region, but as a first approximation it is simplest to apply the above costs from the Indian subcontinent to other public sector situations. One exception to this is the cost of AmBisome: in regions for which the 90% reduction in the cost of Liposomal amphotericin B has not been achieved by the WHO , Ambisome-containing regimens will be prohibitively expensive for the public sector.

Importantly, the absence of efficacy with paromomycin in CL and ML means that miltefosine is the least expensive therapy for treating cutaneous and mucosal forms of leishmaniasis, and therefore the least expensive therapy overall when considering all forms of leishmaniasis combined (visceral, cutaneous, and mucosal).

10.3 Other public sector situations

Paladin is working with non-governmental organizations (NGOs) to expand access to miltefosine in areas where either the drug is not yet registered, or the regional or national Government does not have an effective leishmaniasis treatment program in place, such as in East Africa. Paladin plans on working with NGOs to serve as an agent to provide the treatment to patients and to minimize the risk of misuse.

10.4 Private sector situations

In Industrialized nations, miltefosine is available in the private sector as a prescription medication sold on a named-patient basis, and is not openly available on the market. It is sold at a price that is in keeping with the price of other standard therapies.

For developing countries, in particular countries to which Paladin is supplying miltefosine to Government or NGO treatment programs, Paladin is not supplying miltefosine for private sector use.

Paladin supports the idea of implementing measures for the control of patient compliance, and has held discussions with key stakeholders on how to ensure a safe supply chain for miltefosine.

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11. Summary of regulatory status of the medicine

The current status of marketing authorization for miltefosine worldwide is shown in Table 18. In addition, miltefosine was granted Orphan Drug Status by the US FDA in November 2006 and by the European Medicines Agency in June 2002. Paladin is in the process of filing for additional regulatory approvals worldwide to expand the availability of miltefosine.

Country Registration Approved Indication(s) Date Argentina August 2005 Visceral and cutaneous leishmaniasis Bangladesh June 2006 Visceral and cutaneous leishmaniasis Bolivia March 2006 Visceral and cutaneous leishmaniasis Colombia March 2005 Visceral and cutaneous leishmaniasis Ecuador November 2005 Visceral and cutaneous leishmaniasis Germany November 2004 Visceral and cutaneous leishmaniasis Guatemala August 2005 Visceral and cutaneous leishmaniasis Honduras February 2006 Visceral and cutaneous leishmaniasis India March 2002 Visceral and cutaneous leishmaniasis Mexico July 2006 Visceral and cutaneous leishmaniasis Nepal January 2006 Visceral leishmaniasis Pakistan August 2006 Visceral and cutaneous leishmaniasis Paraguay August 2005 Visceral and cutaneous leishmaniasis Peru May 2005 Visceral and cutaneous leishmaniasis

Table 18: Listing of current regulatory approvals for miltefosine.

12. Availability of pharmacopoieal standards

A pharmacopoieal standard is not available for miltefosine.

13. Proposed text for the WHO Model Formulary

FORMS RATIONALE ATC LISTING CODE 10mg and 50mg oral For the treatment of visceral, Main List capsule containing cutaneous, and mucosal miltefosine leishmaniasis. (tradename Dose: 2.5mg/kg/day for 28 days Impavido®)

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References

Arevalo J et al . J Infect Dis 2007;195:1846-51.

Bhattacharya SK et al. Clin Infect Dis. 2004;38:217-21.

Dorlo T et al . Antimicrob Agents Chemother. 2008 ;52:2855-60.

Hepburn N et al. Trans R Soc Trop Med Hyg. 1994;88:700-3.

Herwaldt BL, Berman JD. Am J Trop Med Hyg 1992;46:296-306.

Jha TK et al . N Engl J Med. 1999;341:1795-800.

Llanos-Cuentas et al . Am J Trop Med Hyg 2007;76:1128-31.

Meheus F et al . PLoS NTD 2010; 4: e818.

Reithinger R et al. Lancet Infect Dis 2007; 7:581–96.

Ritmeijer K et al . Clin Infect Dis 2006;43:357-64.

Romero GA et al . Clin Infect Dis 2001;32:1304-12.

Soto J et al . TRSTMH 1994 ; 88, 695-698.

Soto J et al . Clin Infect Dis 2001;33:E57-61.

Soto J, Arana BA et al . Clin Infect Dis 2004;38:1266-72.

Soto J et al . Clinical Infectious Diseases 2007; 44:350–6.

Soto J et al . Am. J. Trop. Med. Hyg. 2008; 78: 210–11.

Sundar S et al . Lancet. 1998;352:1821-3.

Sundar S et al . Ann Trop Med Parasitol. 1999;93:589-97.

Sundar S et al . Clin Infect Dis. 2000;31:1110-3.

Sundar S et al . Am J Trop Med Hyg 2002;66:143-6.

Sundar S et al . N Engl J Med 2002;347:1739-46.

Sundar S et al . Pediatr Infect Dis J. 2003;22:434-8.

Sundar S et al . N Engl J Med 2007;356:2571-81.

Sundar S et al . N Engl J Med 2010;362:504-12.

Thakur CP et al . Ann Trop Med Parasitol . 1997;91:611-6.

Velez I et al . Am. J. Trop. Med. Hyg. 2010; 83: 351-6.

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APPENDIX I: ABSTRACT OF STUDY COMPARING MILTEFOSINE TO ANTIMONY IN BRAZILIAN CL

L guyanensis in Manaus, Brazil. [Machado, Carvalho et al . ASTMH 2009 Abstract]

Miltefosine has been used in the treatment of visceral leishmaniasis in India. Recently, miltefosine has been tested in New World cutaneous leishmaniasis (CL) and Old World CL. The cure rate from the studies in New World CL in Colombia and Guatemala ranged from 91% (Leishmania panamensis) to 33% (L. braziliensis). There are no data regarding miltefosine use in CL caused by L. braziliensis in Brazil.

This is a phase II randomized trial with 90 CL patients from the endemic area of Corte de Pedra in Bahia, Brazil. Patients included presented 1 to 3 months of untreated CL, with 1 to 5 ulcerative lesions. Diagnosis was confirmed by a positive culture or polymerase chain reaction methods and by intradermal leishmania skin test. After randomization 30 participants were treated with parenteral meglumine antimoniate (20mg/kg/day x 20 days) and 60 with miltefosine administered orally (2.5mg/kg/day x 28 days). Outcome measures were cure rate or complete cicatrization of the ulcer 2 and 6 months after the end of the treatment.

Cure rate at 2 months for the antimony group was 65% and for the miltefosine group 75%. The final cure rate at 6 months was 58% in the antimony group and 62% in the miltefosine arm. Intent to treat analysis showed no difference regarding the primary and final cure rate in both groups. Adverse events occurred in 80% of antimony patients compared to 77% in miltefosine patients. In the antimony group the most common side effects were headache (43%), fever (23%), arthralgia (22%) and mialgia (22%). In the miltefosine group, vomiting and nausea (39%), headache (29%) and dizziness (13%).

CL caused by L. braziliensis in Brazil has a similar cure rate when treated with antimony or miltefosine. Considering that the oral administration of miltefosine is an advantage compared with the parenteral route used for antimony standard treatment in the rural area, our data suggests that miltefosine may be considered for the treatment of CL caused by L. braziliensis in Brazil.

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APPENDIX II: CURRENT APPROVED PRODUCT INSERT

1. NAME OF THE MEDICINAL PRODUCT Impavido 10 mg capsules Impavido 50 mg capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 capsule contains: Impavido 10 mg capsules--10 mg Miltefosine. Impavido 50 mg capsules--50 mg Miltefosine. For excipients, see 6.1.

3. PHARMACEUTICAL FORM Capsules

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of visceral Leishmaniasis caused by Leishmania donovani .

Treatment of cutaneous Leishmaniasis caused by Leishmania brasiliensis complex or Leishmania mexicana complex.

4.2 Posology and method of administration Impavido capsules are for oral use. The dosage of Impavido capsules depends on body weight.

Cutaneous leishmaniasis

The daily dosage for children aged 12 years and older and a body weight of at least 30 kg, adolescents and adults with a body weight of lower than 45 kg is 100 mg miltefosine (2 capsules Impavido 50 mg).

Patients with a bodyweight higher than 45 kg receive 150 mg miltefosine daily (3 capsules Impavido50 mg).

No data from clinical studies are available for patients with a bodyweight lower than 30 kg. A therapy may be considered using the dosages recommended for visceral leishmaniasis.

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The capsules should be taken with meals. Dosages of 2 - 8 capsules per day should be divided into 2 -- 3 individual doses to be taken either in the morning and in the evening or in the morning, at noon and in the evening.

The duration of treatment is 28 days. Immunocompromised patients may require prolonged treatment (see 4.4.)

4.3 Contra-indications · Hypersensitivity to the active substance or any of the excipients. · Pre-existing severe damage of liver or kidney function (see 4.4 “Special Warnings and Precautions for use”). · Sjögren-Larsson-Syndrome. · Pregnancy and women of childbearing potential who do not use a reliable contraception during and up to 3 months after treatment.

4.4 Special warnings and special precautions for use In immunocompromised patients Impavido may only be used after failure of standard therapy as only limited experience is available on therapeutic use of Impavido in such patients. In 39 HIV co-infected patients with a mean body weight of 59 kg (range 43 – 99 kg) Impavido was used at a dosage of 100 mg per day for treatment of visceral Leishmaniasis that was recurrent after or refractory to drug therapy. After a mean treatment duration of 55 days (median: 30 days, range 4 – 732 days) 25 patients (65 %) responded to therapy; of these, 16 patients (43 %) showed negative parasitology. 22 patients received at least one further treatment course with similar response rate and tolerability.

The results of a clinical study in cutaneous Leishmaniasis caused by Leishmania brasiliensis indicate, that the efficacy of Impavido against this pathogen may be somewhat lower than against other Leishmania species.

Patients with severe damage of liver and kidney functions were not investigated (see also 4.3 “Contraindications”).

Sufficient data of patients with mild and moderate impairment of liver and kidney function are not available. Patients with liver values (GOT, GPT, alkaline phosphatase) 3 times and kidney values (serum creatinine, BUN) 1.5 times above the normal range, were excluded from the clinical study.

Toxicological studies have shown an impairment of reproductive function in male rats (see 5.3). Data on reproductive performance of 300 male patients who were treated in clinical studies with up to 200 mg Impavido per day for 4 weeks did not indicate an effect on fertility.

Treatment with Impavido may lead to an increase in serum creatinine and liver enzymes. Liver and kidney function must be controlled in weekly intervals. In patients with clinically significant abnormality in kidney function monitoring should be continued until normalisation.

Vomiting and diarrhea are possible side effects of a therapy with Impavido (see 4.8). The patients must be instructed that in case of prolonged persistence of these symptoms a sufficient fluid intake must be ensured, to avoid dehydration and consequently the risk of an impaired renal function.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

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4.5 Interaction with other medicinal products and other forms of interaction In vitro investigations have shown that interactions are unlikely with medications that are metabolized by cytochrome P450 or glucuronised or conjugated otherwise. However, the possibility of interactions with commonly used medicinal products cannot entirely be excluded.

4.6 Pregnancy and lactation Pregnancy There are no adequate data from the use of miltefosine in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). Impavido is contraindicated in pregnancy (see 4.3). Women of childbearing potential have to use effective contraception during and up to 3 months after treatment. Vomiting and diarrhoea are very common side effects of therapy with Impavido and can compromise the efficacy of oral contraception. The patient must be informed by her physician, accordingly. If necessary, suitable alternative methods of contraception must be used. The patient has to be advised to immediately contact her physician for pregnancy testing as soon as there is any suspicion of pregnancy. If the test is positive, the physician and patient must discuss the risks associated with this pregnancy.

Lactation It is not known whether miltefosine is excreted in the milk. Impavido must not be used during lactation; otherwise breast feeding must be stopped.

4.7 Effects on ability to drive and use machines Impavido may cause undesirable effects such as nausea which may impair the patients ability to concentrate and react properly. In such cases patients should refrain from driving cars and using machines.

4.8 Undesirable effects The most commonly reported adverse drug reactions are transient gastrointestinal discomfort, vomiting, diarrhoea, and elevation of liver enzymes and serum creatinine. These effects are usually mild to moderate and transient or reversible at the end of treatment and therefore do not require discontinuation of treatment or dosage reduction. In clinical trials and during therapeutic use at the recommended dosages the following undesirable effects were observed:

4.9 Overdose A specific antidote against miltefosine is not known.

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Overdose. Adverse effects on liver, kidney, and retinal function cannot be excluded in case of substantial overdose.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiprotozoal, ATC code: P01CX Miltefosine has a marked direct antileishmanial activity in vitro and in animal models. Leishmania donovani was the most sensitive species in promastigote and amastigote test systems, with the ED50 concentrations around 1 µmol/l. For promastigotes the sensitivity decreased in the following order: Leishmania donovani > Leishmania aethiopica > Leishmania tropica > Leishmania panamensis > Leishmania mexicana > Leishmania major . For amastigotes the ranking was: Leishmania donovani > Leishmania aethiopica > Leishmania tropica > Leishmania mexicana > Leishmania panamensis > Leishmania major .

The specific mode of action of miltefosine in leishmaniasis is unknown. Among others, miltefosine can inhibit the metabolism of phospholipids in cell membranes of parasites.

5.2 Pharmacokinetic properties Due to the hemolytic nature of miltefosine no study in humans with intravenous administration can be performed to assess the bioavailability after oral use. In rats and dogs, however, an absolute bioavailability of 82% and 94%, respectively, has been shown with tmax values ranging from 4 to 48 h. Miltefosine is widely distributed in the body, however, without evidence of melanin binding in pigment containing tissues. Placental transfer and excretion into milk have not been investigated but can be assumed. No data are available from pharmacokinetic studies in healthy subjects. The following table summarizes the results of studies in patients with visceral leishmaniasis. Because of the severity of the disease only limited blood sampling was feasible, particularly in children. Therefore, only a subset of the typical pharmacokinetic parameters could be determined.

After repeated dosing accumulation of plasma concentration was lower in children than in adults. No relevant sex differences of pharmacokinetic parameters were observed. Distribution studies in rats, using radioactively labelled miltefosine, showed highest uptake of radioactivity in kidney, liver and spleen. Slow elimination of radioactivity from tissues (half lives 8-16 days) is partially explained by metabolism of miltefosine and incorporation of the labelled choline fragment into physiological lipids. No oxidative metabolism by 15 different cytochrome P450 isozymes was observed in vitro. No CYP3A induction by miltefosine was found in vivo, in rats. Thus, no interaction has to be expected between miltefosine and drugs, like contraceptive hormones, that are metabolised by CYP3A. A slow metabolic breakdown could be shown in human hepatocytes, resulting in the release of choline by Phospholipase D like cleavage of the miltefosine molecule. The fatty alcohol containing fragment of miltefosine can enter the metabolism of fatty acids after being oxidized to palmitic acid. This Oxidation is blocked in patients with Sjögren-Larrson syndrome, which is caused by a genetic defect in fatty aldeyhde dehydrogenase activity. Preclinical and clinical studies suggest that only a very minor part of the administered dose will be excreted as the unchanged drug substance. Instead, choline and choline-containing metabolites are the most likely excretion products.

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5.3 Preclinical safety data Toxicological studies with miltefosine have been performed in mice, rats, dogs and rabbits. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Acute and chronic toxicity The oral administration of miltefosine in rats was associated with regressive and/or progressive lesions especially affecting the eyes (retinal degeneration), kidneys (acute resp. chronic nephropathy) and organs with rapidly dividing cell tissues (atrophy/hyperplasia), as well as reproductive organs (atrophy). These alterations were observed after 8 weeks treatment at doses of 10 mg/kg/day which led to plasma drug levels of about 52 µg/ml. Juvenile rats were more sensitive than adult rats to the miltefosine induced effects, especially on eyes and kidneys.

Reproduction toxicity Testicular atrophy and impaired fertility were observed in rats following daily oral doses of 8.25 mg/kg. These findings were reversible within a recovery period of 10 weeks. Reproductive toxicity studies in rats during the early embryonic development (up to day 7 of pregnancy) indicate an embryotoxic, fetotoxic and teratogenic risk following miltefosine dosages of 1.2 mg/kg/day and higher. Embryo- and fetotoxic findings were also observed in rabbits after oral administration of miltefosine during the phase of organogenesis (2.4 mg/kg/day and higher).

Mutagenicity / Carcinogenicity Miltefosine tested negative in 6 of 7 of mutagenicity tests (AMES-Salmonella test, DNA- amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, oral mouse- micronucleus test in vivo). The V 79 mammalian cell HPRT gene mutation test showed an increase in mutant frequency without dose dependency. In view of all mutagenicity test results, the single positive finding in the V 79 HPRT test is considered to be not of toxicological relevance with respect to a mutagenic risk to humans. The results of the mutagenicity tests ruled out a genotoxicity-mediated carcinogenic potential of miltefosine. Carcinogenicity studies were not performed.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Collodial anhydrous silica, microcrystalline cellulose, lactose monohydrate, talc, magnesium stearate, gelatin, titanium dioxide, ferric oxide, purified water.

6.2 Incompatibilities Not applicable.

6.3 Shelf life 5 years.

6.4 Special precautions for storage Store in the original container in order to protect from moisture.

6.5 Nature and content of container Impavido 10 mg Pack with 56 capsules sealed in 8 aluminium/aluminium blister stripes, each containing 7 capsules.

Impavido 50 mg

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Packs with 28 and 56 capsules sealed in 4 and 8 aluminium/aluminium blister stripes, respectively, each containing 7 capsules.

6.6 Instructions for use and handling, and disposal Any unused product or waste material should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER Paladin Labs Ireland Inc. Matsack Trust Limited of 70 Sir John Rogerson's Quay Dublin 2, Ireland

8. MARKETING AUTHORISATION NUMBERS Impavido 10 mg: 56589.00.00 Impavido 50 mg: 56589.01.00

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 19th November 2004

10. DATE OF REVISION OF THE TEXT September 2009

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