WARNING
EMBRYO-FETAL TOXICITY
IMPAVIDO MAY CAUSE FETAL HARM. FETAL DEATH AND TERATOGENICITY OCCURRED IN ANIMALS ADMINISTERED MILTEFOSINE AT DOSES LOWER THAN THE RECOMMENDED HUMAN DOSE. DO NOT ADMINISTER IMPAVIDO TO PREGNANT WOMEN. OBTAIN A SERUM OR URINE PREGNANCY TEST IN FEMALES OF REPRODUCTIVE POTENTIAL PRIOR TO PRESCRIBING IMPAVIDO. FEMALES OF REPRODUCTIVE POTENTIAL SHOULD BE ADVISED TO USE EFFECTIVE CONTRACEPTION DURING IMPAVIDO THERAPY AND FOR 5 MONTHS AFTER THERAPY [SEE CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS AND NONCLINICAL TOXICOLOGY].
INDICATIONS
IMPAVIDO (MILTEFOSINE) CAPSULES ARE INDICATED IN ADULTS AND ADOLESCENTS ? 12 YEARS OF AGE WEIGHING ? 30 KG FOR THE TREATMENT OF:
" VISCERAL LEISHMANIASIS CAUSED BY LEISHMANIA DONOVANI [SEE CLINICAL TRIALS].
" CUTANEOUS LEISHMANIASIS CAUSED BY LEISHMANIA BRAZILIENSIS, LEISHMANIA GUYANENSIS, AND LEISHMANIA PANAMENSIS [SEE CLINICAL TRIALS].
" MUCOSAL LEISHMANIASIS CAUSED BY LEISHMANIA BRAZILIENSIS [SEE CLINICAL TRIALS].
LIMITATIONS OF USE
" LEISHMANIA SPECIES STUDIED IN CLINICAL TRIALS EVALUATING IMPAVIDO WERE BASED ON EPIDEMIOLOGIC DATA [SEE CLINICAL TRIALS].
" THERE MAY BE GEOGRAPHIC VARIATION IN CLINICAL RESPONSE OF THE SAME LEISHMANIA SPECIES TO IMPAVIDO [SEE CLINICAL TRIALS].
" THE EFFICACY OF IMPAVIDO IN THE TREATMENT OF OTHER LEISHMANIA SPECIES HAS NOT BEEN EVALUATED.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
IMPAVIDO® (MILTEFOSINE) ORAL CAPSULES ARE OPAQUE, RED, HARD GELATIN CAPSULES WITH "PLB" IMPRINTED ON THE CAPSULE BODY AND "MILT 50" IMPRINTED ON THE CAP USING A WHITE INK. EACH CAPSULE CONTAINS 50 MG MILTEFOSINE [SEE DESCRIPTION, STORAGE AND HANDLING].
STORAGE AND HANDLING
EACH IMPAVIDO CAPSULE CONTAINS 50 MG MILTEFOSINE IN AN OPAQUE, RED, HARD GELATIN CAPSULE. IMPAVIDO CAPSULES ARE SUPPLIED IN A FOLDED PEEL/PUSH-THROUGH BLISTER CARD. EACH BLISTER CARD CONTAINS 14 CAPSULES. EACH CARTON CONTAINS TWO BLISTER CARDS (NDC 61744-050-01).
STORE AT 20-25°C (68-77 °F); EXCURSIONS PERMITTED TO 15-30°C (59 - 86°F). [SEE USP CONTROLLED ROOM TEMPERATURE]. PROTECT FROM MOISTURE.
DISPENSE ONLY IN THE ORIGINAL CARTON.
DISTRIBUTED BY: PALADIN THERAPEUTICS INC., CORPORATION TRUST CENTER, 1209 ORANGE STREET, WILMINGTON, DE 19801. REVISED: MARCH 2014
SIDE EFFECTS
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
CLINICAL TRIALS EXPERIENCE
VISCERAL LEISHMANIASIS
ONE PHASE 3 TRIAL WAS CONDUCTED IN PATIENTS ? 12 YEARS OF AGE IN INDIA. TWO-HUNDRED AND NINETYNINE (299) PATIENTS (211 MEN AND 88 WOMEN) RECEIVED ORAL IMPAVIDO AT A TARGET DOSE OF 2.5 MG/KG/DAY FOR 28 DAYS (50 MG CAPSULE ONCE DAILY IF WEIGHT WAS LESS THAN 25 KG AND 50 MG CAPSULE TWICE DAILY IF WEIGHT WAS 25 KG OR GREATER). PATIENTS RANGED BETWEEN 12 AND 64 YEARS OF AGE. WEIGHT RANGED BETWEEN 15 AND 67 KG (MEAN WEIGHT 38.6 KG) AND BMI RANGED BETWEEN 8.2 AND 24 (MEAN 16.1). NINETY-NINE (99) PATIENTS RECEIVED 1 MG/KG/DAY AMPHOTERICIN B DEOXYCHOLATE INTRAVENOUSLY EVERY OTHER DAY FOR 15 DOSES. A STATISTICALLY SIGNIFICANT HIGHER PERCENTAGE OF MEN RECEIVED IMPAVIDO COMPARED TO AMPHOTERICIN B.
LESS THAN 1% OF PATIENTS WHO RECEIVED IMPAVIDO DIED (2/299) AND NO PATIENT WHO RECEIVED AMPHOTERICIN B DIED. SERIOUS ADVERSE REACTIONS WERE REPORTED IN 2% OF IMPAVIDO RECIPIENTS (6/299) AND 1% OF AMPHOTERICIN B RECIPIENTS (1/99). APPROXIMATELY 3% OF PATIENTS DISCONTINUED TREATMENT IN EACH TREATMENT ARM DUE TO AN ADVERSE REACTION. SERIOUS ADVERSE REACTIONS AND ADVERSE REACTIONS LEADING TO DRUG DISCONTINUATION THAT WERE THOUGHT TO BE RELATED OR POSSIBLY RELATED TO IMPAVIDO INCLUDED STEVENS-JOHNSON SYNDROME, MELENA AND THROMBOCYTOPENIA, ARTHRITIS AND SKIN RASH, CTCAE1 GRADE 4 DIARRHEA ( ? 10 STOOLS PER DAY) AND CTCAE GRADE 4 HYPERBILIRUBINEMIA ( ? 10X UPPER LIMIT OF NORMAL ULN).
TABLE 2: TREATMENT EMERGENT ADVERSE REACTIONS OCCURRING IN ? 2% OF VISCERAL LEISHMANIASIS PATIENTS RECEIVING IMPAVIDO
SYSTEM ORGAN CLASS PREFERRED TERM IMPAVIDO
N = 299 AMPHOTERICIN B DEOXYCHOLATE
N = 99
GASTROINTESTINAL DISORDERS
DIARRHEA 61 (20.4%) 6 (6.1%)
VOMITING 113 (37.8%) 20 (20.0%)
GENERAL DISORDERS
ASTHENIA 19 (6.3%) 4 (4.0%)
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE 69 (23.1%) 22 (22.2%)
1 COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS
IN THIS STUDY, CREATININE (CR) ELEVATIONS ? 1.5 TIMES ABOVE BASELINE OCCURRED IN APPROXIMATELY 10% OF IMPAVIDO RECIPIENTS AND IN 40% OF AMPHOTERICIN B RECIPIENTS AT THE END OF THERAPY. TEN PERCENT OF SUBJECTS IN EACH ARM HAD CR ELEVATIONS ? 1.5 TIMES ABOVE BASELINE AT 6 MONTHS FOLLOW UP. NO IMPAVIDO RECIPIENT DISCONTINUED THERAPY DUE TO CR ELEVATION.
ELEVATIONS OF TRANSAMINASES DURING THERAPY OCCURRED IN UP TO HALF OF IMPAVIDO RECIPIENTS AND UP TO A THIRD OF AMPHOTERICIN B RECIPIENTS. THE ELEVATIONS WERE MILD ( < 3X ULN) OR MODERATE (3-5X ULN) IN 94% AND 6% RESPECTIVELY OF IMPAVIDO-TREATED PATIENTS WHO EXPERIENCED AN ELEVATION. NO PATIENT DISCONTINUED THERAPY DUE TO ELEVATIONS IN TRANSAMINASES.
AT THE END OF THERAPY, 62% AND 2.4% OF IMPAVIDO RECIPIENTS AND 54% AND 2% OF AMPHOTERICIN B RECIPIENTS HAD PLATELET COUNT < 150,000 AND < 50,000 RESPECTIVELY.
CUTANEOUS LEISHMANIASIS
THE EFFICACY OF IMPAVIDO IN THE TREATMENT OF CUTANEOUS LEISHMANIASIS WAS EVALUATED IN ONE PLACEBO-CONTROLLED TRIAL CONDUCTED IN COLOMBIA AND GUATEMALA AND IN TWO COMPARATIVE TRIALS CONDUCTED IN BOLIVIA AND BRAZIL RESPECTIVELY. IN THE PLACEBO-CONTROLLED TRIAL, EIGHTY-NINE (89) PATIENTS ? 12 YEARS OF AGE RECEIVED A TARGET IMPAVIDO DOSE OF 2.5 MG/KG/DAY FOR 28 DAYS AND FORTY-FOUR (44) RECEIVED PLACEBO. IN THE COMPARATIVE TRIALS, ONE HUNDRED AND TWENTY (120) PATIENTS ? 12 YEARS OF AGE RECEIVED A TARGET IMPAVIDO DOSE OF 2.5 MG/KG/DAY FOR 28 DAYS AND FIFTY EIGHT (58) PATIENTS RECEIVED 20 MG/KG/DAY PENTAVALENT ANTIMONY (MEGLUMINE) PARENTERALLY FOR 20 DAYS.
TABLE 3: ADVERSE REACTIONS OCCURRING IN ? 2% OF IMPAVIDO-TREATED PATIENTS ? 12 YEARS OF AGE WITH CUTANEOUS LEISHMANIASIS IN THE PLACEBO-CONTROLLED TRIAL
SYSTEM ORGAN CLASS PREFERRED TERM IMPAVIDO
N = 89 PLACEBO
N = 44
EAR AND LABYRINTH DISORDERS
MOTION SICKNESS 26 (29.2%) 10 (22.7%)
GASTROINTESTINAL DISORDERS
ABDOMINAL PAIN 10 (11.2%) 3 (6.8%)
DIARRHEA 7 (7.9%) 2 (4.5%)
NAUSEA 32 (35.9%) 5 (11.1%)
VOMITING 4 (4.5%) 0
GENERAL AND ADMINISTRATION SITE DISORDERS
MALAISE 3 (3.4%) 1 (2.3%)
PYREXIA 5 (5.6%) 2 (4.5%)
NERVOUS SYSTEM DISORDERS
DIZZINESS 4 (4.5%) 0
HEADACHE 25 (28.1%) 10 (22.7%)
SOMNOLENCE 3 (3.4%) 0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PRURITUS 4 (4.5%) 0
TABLE 4: ADVERSE REACTIONS OCCURRING IN ? 2% OF IMPAVIDO-TREATED PATIENTS ? 12 YEARS OF AGE WITH CUTANEOUS LEISHMANIASIS IN TWO COMPARATIVE TRIALS
SYSTEM ORGAN CLASS PREFERRED TERM IMPAVIDO
N = 120 MEGLUMINE
N = 58
GASTROINTESTINAL DISORDERS
ABDOMINAL PAIN 9 (7.5%) 3 (5.2%)
DIARRHEA 18 (15.0%) 3 (5.2%)
NAUSEA 50 (41.7%) 3 (5.2%)
VOMITING 33 (27.5%) 0
INFECTIONS AND INFESTATIONS
LYMPHANGITIS 7 (5.8%) 0
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE 13 (10.8%) 4 (5.8%)
NERVOUS SYSTEM DISORDERS
DIZZINESS 15 (12.5%) 4 (6.9%)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PRURITUS 7 (5.8%) 0
IN THE PLACEBO CONTROLLED TRIAL, 12/89 (13.4%) IMPAVIDO SUBJECTS HAD CR INCREASES OF 1.5-3 TIMES ABOVE BASELINE, COMPARED TO 2/44 (4.5%) PLACEBO SUBJECTS AT END OF THERAPY. IN THE COMPARATIVE TRIAL, A SIMILAR PERCENTAGE OF SUBJECTS WHO RECEIVED IMPAVIDO OR PENTAVALENT ANTIMONY HAD CR ELEVATIONS ABOVE BASELINE AT 3 AND 6 MONTHS AFTER THERAPY (APPROXIMATELY 5%). APPROXIMATELY 25% OF IMPAVIDO SUBJECTS AND 11% OF PENTAVALENT ANTIMONY SUBJECTS HAD CR ELEVATIONS 1.5-3 TIMES ABOVE BASELINE AT THE END OF THERAPY IN THE TWO ACTIVE CONTROLLED TRIALS. THE FREQUENCY OF AST AND ALT INCREASE ABOVE UPPER LIMIT OF NORMAL AT END OF THERAPY WAS SIMILAR IN IMPAVIDO AND PLACEBO RECIPIENTS (APPROXIMATELY 5%). OTHER ADVERSE EVENTS SEEN AT < 2% INCIDENCE IN THE IMPAVIDO GROUP INCLUDED ANEMIA, LYMPHADENOPATHY, ABDOMINAL DISTENSION, CONSTIPATION, DYSPHAGIA, FLATULENCE, FATIGUE, MALAISE, ABSCESS, CELLULITIS, ECTHYMA, PARESTHESIA, TESTICULAR PAIN, TESTICULAR SWELLING, STEVENS-JOHNSON SYNDROME, URTICARIA, RASH, PYODERMA.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING USE OF IMPAVIDO WORLDWIDE. BECAUSE THESE REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
BLOOD AND LYMPHATICS DISORDERS: THROMBOCYTOPENIA, AGRANULOCYTOSIS
GASTROINTESTINAL DISORDERS: MELENA
GENERAL DISORDERS: GENERALIZED EDEMA, PERIPHERAL EDEMA
HEPATOBILIARY DISORDERS: JAUNDICE
NERVOUS SYSTEM DISORDERS: SEIZURE
REPRODUCTIVE SYSTEM AND BREAST DISORDERS: SCROTAL PAIN, DECREASED EJACULATE VOLUME, ABSENT EJACULATION.
VASCULAR DISORDERS: EPISTAXIS
READ THE IMPAVIDO (MILTEFOSINE CAPSULES) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THE COMMON ADVERSE EFFECTS OF VOMITING, DIARRHEA, AND ABDOMINAL PAIN ARE LIKELY IN CASE OF OVERDOSE. INSTITUTE ADEQUATE HYDRATION TO PREVENT THE RISK OF IMPAIRED RENAL FUNCTION, AND REPLACE ELECTROLYTES AS NECESSARY. BECAUSE MILTEFOSINE IS ONLY SLIGHTLY EXCRETED IN THE URINE, FORCED DIURESIS WILL NOT INCREASE MILTEFOSINE EXCRETION. GASTROINTESTINAL LAVAGE IS OF UNKNOWN VALUE. A SPECIFIC ANTIDOTE TO TREAT MILTEFOSINE OVERDOSE IS NOT KNOWN.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
MILTEFOSINE IS AN ANTI-LEISHMANIAL AGENT.
PHARMACOKINETICS
THE PHARMACOKINETIC PARAMETERS OF MILTEFOSINE IN PATIENTS WITH VISCERAL AND CUTANEOUS LEISHMANIASIS TREATED FOR 28 DAYS WITH IMPAVIDO ARE LISTED IN TABLE 5. DUE TO THE LONG HALF-LIFE OF MILTEFOSINE ( > 6 DAYS), TROUGH PLASMA CONCENTRATIONS DID NOT APPEAR TO REACH A STEADY STATE AT THE END OF TREATMENT (I.E., DAY 28).
TABLE 5: MEAN (%CV) PHARMACOKINETIC PARAMETERS FOR MILTEFOSINE FOLLOWING ORAL CAPSULE ADMINISTRATION TO ADULT PATIENTS WITH VISCERAL AND CUTANEOUS LEISHMANIASIS
ABSORPTION
ABSOLUTE BIOAVAILABILITY OF MILTEFOSINE HAS NOT BEEN DETERMINED. IN PATIENTS WITH VISCERAL LEISHMANIASIS, MAXIMUM MILTEFOSINE CONCENTRATIONS FOLLOWING ORAL ADMINISTRATION OF IMPAVIDO CAPSULES WERE REACHED RIGHT BEFORE THE NEXT DOSE IN MANY PATIENTS, INDICATING THAT THE ABSORPTION OF MILTEFOSINE MAY PROCEED THROUGHOUT THE DOSING INTERVAL.
DISTRIBUTION
THE DISTRIBUTION OF MILTEFOSINE HAS NOT BEEN STUDIED IN HUMANS. HUMAN PLASMA PROTEIN BINDING OF MILTEFOSINE, EVALUATED BY AN ULTRACENTRIFUGATION METHOD, WAS 98% OVER THE DRUG CONCENTRATION RANGE FROM 0.1 TO 10 ?G/ML. IN RATS, RADIOACTIVITY OF [14C] MILTEFOSINE IS WIDELY DISTRIBUTED AFTER BOTH SINGLE AND REPEATED ORAL ADMINISTRATION WITH HIGHEST UPTAKE OF RADIOACTIVITY IN KIDNEY, LIVER, AND SPLEEN. PLACENTAL TRANSFER AND EXCRETION INTO MILK HAVE NOT BEEN INVESTIGATED.
METABOLISM AND EXCRETION
NO IN VITRO OXIDATIVE METABOLISM BY 15 DIFFERENT HUMAN CYTOCHROME P450 ENZYMES (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, AND 4A1) WAS OBSERVED.
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 ALCOHOLCONTAINING FRAGMENT OF MILTEFOSINE CAN ENTER THE METABOLISM OF FATTY ACIDS AFTER BEING OXIDIZED TO PALMITIC ACID. THIS OXIDATION IS BLOCKED IN PATIENTS WITH SJÖGREN-LARSSON SYNDROME, WHICH IS CAUSED BY A GENETIC DEFECT IN FATTY ALDEHYDE DEHYDROGENASE ACTIVITY. IMPAVIDO IS CONTRAINDICATED IN PATIENTS WHO HAVE SJÖGREN-LARSSON-SYNDROME [SEE CONTRAINDICATIONS].
THERE WAS LITTLE OR NO EVIDENCE OF TIME OR METABOLISM DEPENDENT INHIBITION OF THE CYTOCHROME P450 ENZYMES EXAMINED AT UP TO APPROXIMATELY 40 ?G/ML MILTEFOSINE.
ORAL ADMINISTRATION OF MILTEFOSINE DID NOT MARKEDLY INDUCE THE CONTENT OF HEPATIC CYP3A ASSAYED BY DEMETHYLATION ACTIVITY OF ERYTHROMYCIN IN RATS.
IN VISCERAL LEISHMANIASIS PATIENTS, < 0.2% OF THE ADMINISTERED DOSE WAS EXCRETED INTO THE URINE.
MICROBIOLOGY
MECHANISM OF ACTION
THE SPECIFIC MODE OF ACTION OF MILTEFOSINE AGAINST LEISHMANIA SPECIES IS UNKNOWN. THE MECHANISM OF ACTION OF MILTEFOSINE IS LIKELY TO INVOLVE INTERACTION WITH LIPIDS (PHOSPHOLIPIDS AND STEROLS), INCLUDING MEMBRANE LIPIDS, INHIBITION OF CYTOCHROME C OXIDASE (MITOCHONDRIAL FUNCTION), AND APOPTOSIS-LIKE CELL DEATH.
ACTIVITY IN VITRO AND IN VIVO
MILTEFOSINE HAS ANTI-LEISHMANIAL ACTIVITY IN VITRO AND IN CLINICAL INFECTIONS [SEE CLINICAL STUDIES]. SENSITIVITY OF DIFFERENT LEISHMANIA SPECIES AS WELL AS DIFFERENT STRAINS OF A LEISHMANIA SPECIES TO MILTEFOSINE MAY VARY IN DIFFERENT GEOGRAPHIC REGIONS.
DRUG RESISTANCE
IN VITRO STUDIES SHOW A POTENTIAL FOR DEVELOPMENT OF RESISTANCE TO MILTEFOSINE. SOME STRAINS OF L. BRAZILIENSIS WITH INTRINSIC RESISTANCE TO MILTEFOSINE HAVE BEEN IDENTIFIED. HOWEVER, THE CLINICAL RELEVANCE OF THESE OBSERVATIONS IS NOT KNOWN.
DRUG RESISTANCE COULD BE DUE TO A DECREASE IN MILTEFOSINE ACCUMULATION WITHIN LEISHMANIA PARASITE WHICH IS THOUGHT TO BE DUE TO EITHER AN INCREASE IN DRUG EFFLUX, MEDIATED BY THE OVEREXPRESSION OF THE ABC TRANSPORTER P-GLYCOPROTEIN AND/OR A DECREASE IN DRUG UPTAKE BY THE INACTIVATION OF THE MILTEFOSINE TRANSPORT MACHINERY THAT CONSISTS OF THE MILTEFOSINE TRANSPORTER AND ITS BETA SUBUNIT. MUTATION IN THE TRANSPORTER GENE WAS REPORTED IN THE ISOLATES FROM A RELAPSED PATIENT IN ONE STUDY. HOWEVER, THE CLINICAL RELEVANCE OF THESE FINDINGS IS NOT KNOWN.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
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 LESIONS AFFECTING THE EYES (RETINAL DEGENERATION). RETINAL DEGENERATION WAS OBSERVED AFTER 8- WEEKS TREATMENT AT DOSES OF 10 MG/KG/DAY (0.5 TIMES THE MRHD BASED ON BSA COMPARISON). JUVENILE RATS WERE MORE SENSITIVE TO THE MILTEFOSINE-INDUCED EFFECTS, ESPECIALLY ON EYES AND KIDNEYS, THAN ADULT RATS WITH RETINAL DEGENERATION OCCURRING AT DOSES ? 2.15 MG/KG/DAY (0.1 TIMES THE MRHD BASED ON BSA COMPARISON), AND REVERSIBLE DAMAGE TO PROXIMAL TUBULE EPITHELIUM OCCURRING AT DOSES ? 4.64 MG/KG/DAY (0.2 TIMES THE MRHD BASED ON BSA COMPARISON).
CLINICAL STUDIES
TREATMENT OF VISCERAL LEISHMANIASIS
ONE RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY WAS CONDUCTED TO EVALUATE THE EFFICACY OF IMPAVIDO IN THE TREATMENT OF VISCERAL LEISHMANIASIS IN BIHAR, INDIA, AN AREA WHERE L. DONOVANI IS KNOWN EPIDEMIOLOGICALLY TO BE THE PREVALENT INFECTING SPECIES. PATIENTS ? 12 YEARS OF AGE WITH CLINICAL SIGNS AND SYMPTOMS COMPATIBLE WITH VISCERAL LEISHMANIASIS (FEVER, SPLENOMEGALY, AND CYTOPENIA) CONFIRMED BY THE PRESENCE OF LEISHMANIA AMASTIGOTES IN ASPIRATES OF SPLEEN OR BONE MARROW WERE RANDOMIZED TO RECEIVE ORAL IMPAVIDO OR INTRAVENOUS AMPHOTERICIN B DEOXYCHOLATE IN A 3:1 RATIO. PATIENTS WEIGHING ? 25 KG RECEIVED AN IMPAVIDO 50 MG CAPSULE WITH MEALS TWICE A DAY. PATIENTS WEIGHING < 25 KG RECEIVED AN IMPAVIDO 50 MG CAPSULE WITH MEALS ONCE A DAY IN THE MORNING. WEIGHT RANGED BETWEEN 15 AND 67 KG (MEAN WEIGHT 38.6 KG) AND BMI RANGED BETWEEN 8.2 AND 24 (MEAN 16.1). NO PATIENT WEIGHED MORE THAN 70KG. AMPHOTERICIN B WAS ADMINISTERED INTRAVENOUSLY OVER 6 CONTINUOUS HOURS AT 1 MG/KG EVERY OTHER DAY FOR 15 DOSES. PATIENTS WERE HOSPITALIZED FOR THE DURATION OF THERAPY.
EXCLUSION CRITERIA INCLUDED PLATELET COUNT < 50 × 109/L, WHITE CELL COUNT < 1 × 109/L, HEMOGLOBIN < 6 G/100 ML, AST OR ALT ? 3 TIMES UPPER LIMIT OF THE NORMAL RANGE, BILIRUBIN ? 2 TIMES UPPER LIMIT OF THE NORMAL RANGE, SERUM CREATININE OR BUN > 1.5 TIMES UPPER LIMIT OF THE NORMAL RANGE, PROTHROMBIN TIME > 5 SECONDS ABOVE CONTROL, AND ANY NON-COMPENSATED OR UNCONTROLLED CONDITION INCLUDING HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION. WOMEN OF REPRODUCTIVE POTENTIAL WERE REQUIRED TO USE EFFECTIVE CONTRACEPTION FOR THE DURATION OF THERAPY AND FOR 2 MONTHS POST THERAPY.
FINAL CURE WAS DEFINED AS INITIAL CURE AT END OF THERAPY PLUS ABSENCE OF SIGNS AND SYMPTOMS OF VISCERAL LEISHMANIASIS AT 6 MONTHS FOLLOW UP. INITIAL CURE AT THE END OF THERAPY WAS EVALUATED BY REPEAT SPLEEN OR BONE MARROW ASPIRATION. PATIENTS WITH INITIAL PARASITOLOGIC CURE WERE FOLLOWED FOR 6 MONTHS; PATIENTS WITHOUT ABSENCE OF CLINICAL SIGNS AND SYMPTOMS OF VISCERAL LEISHMANIASIS WERE TO BE EVALUATED WITH REPEAT SPLEEN OR BONE MARROW ASPIRATION TO DETERMINE FINAL CURE.
TWO HUNDRED AND NINETY NINE (299) PATIENTS RECEIVED IMPAVIDO AND 99 PATIENTS RECEIVED AMPHOTERICIN B. APPROXIMATELY, 70% OF PATIENTS IN EACH ARM HAD PREVIOUSLY FAILED TREATMENT WITH PENTAVALENT ANTIMONY. INITIAL CURE WAS ACHIEVED IN 98% OF PATIENTS IN EACH TREATMENT ARM. AT 6 MONTHS AFTER THERAPY, 88 (29.5%) IMPAVIDO RECIPIENTS AND 12 (12.1%) AMPHOTERICIN B RECIPIENTS CONTINUED TO HAVE SIGNS AND SYMPTOMS SUGGESTIVE OF VISCERAL LEISHMANIASIS. THESE SIGNS OR SYMPTOMS WERE ATTRIBUTED TO ALTERNATIVE DIAGNOSIS IN 73 PATIENTS. THE REMAINING 27 PATIENTS, ALL IN THE IMPAVIDO ARM, UNDERWENT EVALUATION WITH SPLENIC OR BONE MARROW ASPIRATION, AND 9 (3.0%) WERE POSITIVE FOR LEISHMANIA AMASTIGOTES, INDICATING RELAPSE. THE FINAL CURE RATES FOR IMPAVIDO AND AMPHOTERICIN B WERE 94% AND 97%, RESPECTIVELY.
TABLE 6: EFFICACY OF IMPAVIDO IN VISCERAL LEISHMANIASIS IN PATIENTS ? 12 YEARS OF AGE IN INDIA
IMPAVIDO
N = 299 AMPHOTERICIN B DEOXYCHOLATE
N = 99
END OF THERAPY
INITIAL CURE 293 (98%) 97 (98%)
6 MONTHS AFTER THERAPY
FINAL CURE* 282 (94%) 96 (97%)
TREATMENT FAILURE 9 (3%) 0 (0)
NOT ASSESSABLE 8 (3%) 3 (3%)
* THE 95% EXACT CONFIDENCE INTERVAL FOR THE DIFFERENCE (IV AMPHOTERICIN B - IMPAVIDO) IN FINAL CURE IS (-3.0%, 6.8%).
TREATMENT OF CUTANEOUS LEISHMANIASIS
A PLACEBO CONTROLLED STUDY WAS PERFORMED IN COLOMBIA WHERE L. PANAMENSIS AND L. BRAZILIENSIS ARE EPIDEMIOLOGICALLY KNOWN TO BE THE PREVALENT INFECTING LEISHMANIA SPECIES, AND IN GUATEMALA WHERE L. BRAZILIENSIS IS EPIDEMIOLOGICALLY KNOWN TO BE THE PREVALENT INFECTING SPECIES. THE STUDY INCLUDED MALE AND FEMALE PATIENTS OLDER THAN 12 YEARS OF AGE WHO HAD NEWLY DIAGNOSED OR RELAPSING CUTANEOUS LEISHMANIASIS WITHOUT MUCOSAL INVOLVEMENT, PARASITOLOGICALLY CONFIRMED, PRESENTING WITH AT LEAST ONE SKIN ULCER WITH MINIMUM AREA OF 50 MM². EXCLUSION CRITERIA WERE AST OR ALT ? 2 TIMES UPPER LIMIT OF NORMAL RANGE, BILIRUBIN ? 1.5 TIMES UPPER LIMIT OF NORMAL RANGE, AND SERUM CREATININE OR BUN > 1.5 TIMES UPPER LIMIT OF NORMAL RANGE. WOMEN OF REPRODUCTIVE POTENTIAL WERE REQUIRED TO USE EFFECTIVE CONTRACEPTION FOR THE DURATION OF THERAPY AND FOR 2 MONTHS POST THERAPY.
PATIENTS WERE RANDOMIZED TO RECEIVE IMPAVIDO OR PLACEBO IN A 2:1 ALLOCATION. PATIENTS WHO WEIGHED < 45 KG RECEIVED IMPAVIDO 50 MG CAPSULE TWICE A DAY, AND PATIENTS WHO WEIGHED ? 45 KG RECEIVED IMPAVIDO 50 MG CAPSULE THREE TIMES A DAY. NO PATIENT WEIGHED MORE THAN 84 KG. DEFINITE CURE WAS DEFINED AS APPARENT (COMPLETE EPITHELIALIZATION OF ALL LESIONS) OR PARTIAL CURE (INCOMPLETE EPITHELIALIZATION, NO ENLARGEMENT BY > 50% IN LESIONS, NO APPEARANCE OF NEW LESIONS, AND NEGATIVE PARASITOLOGY IF DONE) AT 2 WEEKS AFTER END OF THERAPY AND COMPLETE EPITHELIALIZATION OF ALL ULCERS AT 6 MONTHS AFTER END OF THERAPY. THE DEFINITE CURE RATE FOR IMPAVIDO WAS STATISTICALLY SIGNIFICANTLY HIGHER THAN THE CURE RATE FOR PLACEBO.
TABLE 7: EFFICACY OF IMPAVIDO COMPARED TO PLACEBO IN THE TREATMENT OF CUTANEOUS LEISHMANIASIS IN COLOMBIA AND GUATEMALA
IMPAVIDO PLACEBO
DEFINITE CURE* 59/89 (66%) 13/44 (30%)
COLOMBIA 40/49 (82%) 9/24 (38%)
GUATEMALA 19/40 (48%) 4/20 (20%)
* THE DIFFERENCE (95% CI) BETWEEN GROUPS IS 36.8% (20.1%, 53.4%) WITH P-VALUE < 0.0001.
AN ADDITIONAL STUDY OF IMPAVIDO WAS CONDUCTED IN BAHIA AND MANAUS, TWO REGIONS IN BRAZIL WHERE RESPECTIVELY L. BRAZILIENSIS AND L. GUYANENSIS ARE EPIDEMIOLOGICALLY THE PREVALENT INFECTING PATHOGENS. ADOLESCENT/ADULT PATIENTS AGED 12-65 YEARS RECEIVED IMPAVIDO ORALLY FOR 28 DAYS. IMPAVIDO TARGET DOSE WAS 2.5 MG/KG/DAY: PATIENTS WEIGHING 15-29 KG RECEIVED 50 MG ONCE DAILY, PATIENTS WEIGHING 30-45 KG RECEIVED 50 TWICE MG DAILY AND PATIENTS WEIGHING > 46 KG RECEIVED 50 MG THREE TIMES DAILY. THE EFFICACY CRITERIA WERE INITIAL CURE (COMPLETE REEPITHELIALIZATION OF THE ULCER AT 2 MONTHS AFTER THE END OF THERAPY) FOLLOWED BY DEFINITE CURE (COMPLETE RE-EPITHELIALIZATION AT 6 MONTHS AFTER THE END OF THERAPY). DEFINITE CURE RATE IN PATIENTS AGED ? 12 YEARS WAS 27/40 (67.5%) FOR MANAUS, BRAZIL AND 34/40 (85%) FOR BAHIA, BRAZIL.
TREATMENT OF MUCOSAL LEISHMANIASIS
A SINGLE ARM STUDY WAS CONDUCTED TO EVALUATE THE EFFICACY OF IMPAVIDO CAPSULES FOR THE TREATMENT OF MUCOSAL LEISHMANIASIS. THE STUDY WAS CONDUCTED IN BOLIVIA WHERE L. BRAZILIENSIS IS EPIDEMIOLOGICALLY THE PREVALENT SPECIES.
SEVENTY NINE (79) PATIENTS ? 18 YEARS OF AGE WITH A CUTANEOUS LEISHMANIASIS SCAR PLUS PARASITES OBSERVED OR CULTURED FROM LESION MATERIAL OR A POSITIVE SKIN TEST, AND NO CLINICALLY SIGNIFICANT CONCOMITANT DISEASE RECEIVED MILTEFOSINE AT A TARGET DOSE OF 2.5 MG/KG/DAY FOR 28 DAYS. BY 12 MONTHS AFTER THE END OF THERAPY, 49 OF THE PATIENTS (62%) HAD COMPLETE RESOLUTION OF EDEMA, ERYTHEMA, INFILTRATION AND EROSION FROM THE INVOLVED MUCOSAL SITES.