DRUGS & SUPPLEMENTS

Miltex

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Miltex uses


WARNING: EMBRYO-FETAL TOXICITY

Miltex may cause fetal harm. Fetal death and teratogenicity occurred in animals administered Miltex at doses lower than the recommended human dose. Do not administer Miltex to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing Miltex. Females of reproductive potential should be advised to use effective contraception during Miltex therapy and for 5 months after therapy .

WARNING: EMBRYO-FETAL TOXICITY

See full prescribing information for complete boxed warning.

Miltex may cause fetal harm. Fetal death and teratogenicity, occurred in animals administered Miltex at doses lower than the recommended human dose. Do not administer Miltex to pregnant women. Obtain a serum or urine pregnancy test in females of reproductive potential prior to prescribing Miltex.

Advise females of reproductive potential to use effective contraception during therapy and for 5 months after therapy (4.1, 5.1, 8.1, 8.8, 13.1).

1 INDICATIONS AND USAGE

Miltex (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 .
  • Cutaneous leishmaniasis caused by Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis .
  • Mucosal leishmaniasis caused by Leishmania braziliensis .

Limitations of Use:

  • Leishmania species studied in clinical trials evaluating Miltex were based on epidemiologic data .
  • There may be geographic variation in clinical response of the same Leishmania species to Miltex .
  • The efficacy of Miltex in the treatment of other Leishmania species has not been evaluated.

Miltex is an antileishmanial drug indicated in adults and adolescents ≥12 years of age weighing ≥30 kg (66 lbs) for treatment of:

  • Visceral leishmaniasis due to Leishmania donovani (1).
  • Cutaneous leishmaniasis due to Leishmania braziliensis, Leishmania guyanensis, and Leishmania panamensis (1).
  • Mucosal leishmaniasis due to Leishmania braziliensis (1).

Limitations of use: Leishmania species evaluated in clinical trials were based on epidemiologic data. There may be geographic variation in the response of the same Leishmania species to Miltex (1, 14). The efficacy of Miltex in the treatment of other Leishmania species has not been evaluated.

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2 DOSAGE AND ADMINISTRATION

The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.


Weight


Dosage and Administration


30 kg to 44 kg


One 50 mg capsule twice daily with food (breakfast and dinner)


45 kg or greater


One 50 mg capsule three times daily with food (breakfast, lunch, and dinner)


Administer with food to ameliorate gastrointestinal adverse reactions.

  • 30 to 44 kg: one 50 mg capsule twice daily for 28 consecutive days (2).
  • 45 kg or greater: one 50 mg capsule three times daily for 28 consecutive days (2).
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3 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 Miltex .

Each Miltex capsule for oral use contains 50 mg Miltex (3).

4 CONTRAINDICATIONS

  • Pregnancy.
  • Sjögren-Larsson-Syndrome (4.2, 12.3).
  • Hypersensitivity to Miltex or any of its excipients (4.3).

4.1 Pregnancy

Miltex may cause fetal harm. Miltex is contraindicated in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Miltex .

4.2 Sjögren-Larsson-Syndrome

Miltex is contraindicated in patients who have Sjögren-Larsson-Syndrome .

4.3 Hypersensitivity

Miltex is contraindicated in patients who are hypersensitive to Miltex or any Miltex excipients.

5 WARNINGS AND PRECAUTIONS

  • Embryo-Fetal Toxicity. Do not use in pregnant women. Obtain a urine or serum pregnancy test prior to initiation of therapy. Advise use of effective contraception in females of reproductive potential.
  • Reproductive effects. Miltex caused testicular atrophy and impaired fertility in male rats and impaired fertility in female rats. Advise patients of reproductive toxicities in animal studies and that the potential effects on human fertility have not been adequately evaluated (13.1).
  • Renal Effects. Monitor serum creatinine during therapy and for 4 weeks after end of therapy (5.3, 6.1).
  • Hepatic Effects. Monitor transaminases and bilirubin during therapy (5.4, 6.1).
  • Gastrointestinal Effects. Encourage fluid intake (5.5).
  • Thrombocytopenia. Monitor platelet count during therapy for visceral leishmaniasis (5.6, 6.1).
  • Absorption of Oral Contraceptives. Advise use of alternative method of contraception if vomiting and/or diarrhea occur (5.7).
  • Stevens-Johnson syndrome. Discontinue Miltex (5.8).

5.1 Embryo-Fetal Toxicity

Miltex may cause fetal harm. Embryo-fetal toxicity, including death and teratogenicity, was observed in animals administered Miltex prior to mating, during early pregnancy, and during organogenesis at doses lower than the maximum recommended human dose (MRHD). Do not use Miltex in pregnant women. Obtain a urine or serum pregnancy test prior to prescribing Miltex to females of reproductive potential. Advise females of reproductive potential to use effective contraception during Miltex therapy and for 5 months after completion of therapy .

5.2 Reproductive Effects

Females

Miltex caused impaired fertility in rats and reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD based on body surface area comparisons . Effects on human female fertility have not been formally studied.

Males

Miltex caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD [see Nonclinical Toxicology (13.1 )]. A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended.

Scrotal pain and decreased or absent ejaculation during therapy have been reported during Miltex therapy [see Adverse Reactions (6.2 )]. The effects of Miltex on human male fertility have not been adequately studied.

Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Miltex therapy in humans has not been adequately evaluated.

5.3 Renal Effects

Elevations of serum creatinine (Cr) were noted in clinical trials evaluating Miltex in the treatment of cutaneous, mucosal and visceral leishmaniasis. Monitor renal function weekly in patients receiving Miltex during therapy and for 4 weeks after end of therapy .

5.4 Hepatic Effects

Elevations in liver transaminases and bilirubin were noted in clinical trials evaluating Miltex in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving Miltex .

5.5 Gastrointestinal Effects

Vomiting and/or diarrhea commonly occur during Miltex administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion .

5.6 Thrombocytopenia

Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis .

5.7 Absorption of Oral Contraceptives

Vomiting and/or diarrhea occurring during Miltex therapy may affect the absorption of oral contraceptives, and therefore compromise their efficacy. If vomiting and/or diarrhea occur during Miltex therapy, advise females to use additional non-hormonal or alternative method(s) of effective contraception.

5.8 Stevens-Johnson Syndrome

Stevens-Johnson syndrome has been reported during Miltex therapy. Discontinue Miltex if an exfoliative or bullous rash is noted during therapy .

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6 ADVERSE REACTIONS

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.

  • Adverse reactions occurring in ≥2% of patients include nausea, vomiting, diarrhea, headache, decreased appetite, dizziness, abdominal pain, pruritus, somnolence, elevated transaminases, and elevated creatinine.

To report SUSPECTED ADVERSE REACTIONS, contact Paladin Therapeutics Inc. at 1-888-550-6060 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Visceral Leishmaniasis

One Phase 3 trial was conducted in patients ≥ 12 years of age in India. Two-hundred and ninety-nine (299) patients (211 men and 88 women) received oral Miltex 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 Miltex compared to amphotericin B.

Less than 1% of patients who received Miltex died (2/299) and no patient who received amphotericin B died. Serious adverse reactions were reported in 2% of Miltex 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 Miltex included Stevens-Johnson syndrome, melena and thrombocytopenia, arthritis and skin rash, CTCAE Common Terminology Criteria for Adverse Events Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).


System Organ Class

Preferred Term


Miltex

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%)


In this study, creatinine (Cr) elevations ≥ 1.5 times above baseline occurred in approximately 10% of Miltex 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 Miltex recipient discontinued therapy due to Cr elevation.

Elevations of transaminases during therapy occurred in up to half of Miltex 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 Miltex recipients and 54% and 2% of amphotericin B recipients had platelet count < 150,000 and < 50,000 respectively.

Cutaneous Leishmaniasis

The efficacy of Miltex 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 Miltex 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 Miltex 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.


System Organ Class

Preferred Term


Miltex

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


System Organ Class

Preferred Term


Miltex

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%) Miltex 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 Miltex or pentavalent antimony had Cr elevations above baseline at 3 and 6 months after therapy (approximately 5%). Approximately 25% of Miltex 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 Miltex and placebo recipients (approximately 5%).

Other adverse events seen at <2% incidence in the Miltex 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during use of Miltex 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

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7 DRUG INTERACTIONS

In vitro and animal metabolism studies showed that Miltex did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes . The potential of Miltex to interact with drug transporters has not been evaluated.

  • Miltex did not inhibit human cytochrome P450 enzymes in vitro.
  • Miltex did not induce cytochrome 3A activity in rats (7, 12.3).

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Miltex should not be used during pregnancy. Obtain a urine or serum pregnancy test in females of reproductive potential prior to prescribing.
  • Nursing Mothers: Discontinue drug or nursing depending on importance of drug to mother. Avoid breastfeeding for 5 months after Miltex therapy (8.3).
  • Females and Males of Reproductive Potential: Advise females to use effective contraception during therapy and for 5 months after therapy. Advise patients of reproductive toxicities in animals, and that the potential for impaired fertility in humans has not been adequately evaluated (5.1, 5.2, 8.8).

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Miltex may cause fetal harm. Human pregnancy data are not available, however, embryo-fetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral Miltex during organogenesis at doses that were respectively 0.06 and 0.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparison. Numerous visceral and skeletal fetal malformations were observed in a fertility study in female rats administered Miltex prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer Miltex to pregnant women.

Clinical Considerations

During pregnancy, visceral leishmaniasis may be life-threatening for the mother and may result in adverse fetal outcomes, including spontaneous abortion, congenital disease due to vertical transmission, small for gestational age newborn, and severe anemia. During pregnancy, cutaneous leishmaniasis may manifest with larger and atypical appearing lesions and may be associated with increased risk for adverse fetal outcomes, including preterm births and stillbirths.

Animal Data

Miltex administration in rat embryo-fetal toxicity studies during early embryonic development (Day 6 to Day 15 of gestation) caused embryo-fetal toxicity including death and teratogenicity at dosages of ≥ 1.2 mg/kg/day (0.06 times the MRHD based on BSA comparison). Teratogenic effects included undeveloped cerebrum, hemorrhagic fluid filling the lumina of the skull, cleft palate and generalized edema. Embryo-fetal toxicity was also observed in rabbits after oral administration of Miltex during organogenesis (Day 6 to Day 18 of gestation) at doses ≥ 2.4 mg/kg/day (0.2 times the MRHD based on BSA comparison). In both rats and rabbits, there were no viable litters at Miltex doses ≥ 6.0 mg/kg/day (0.3 or 0.6 times the MRHD based on BSA comparisons for rats and rabbits respectively).

In a separate female fertility study in rats, Miltex doses ≥ 6.81 mg/kg/day (0.3 times the MRHD based on BSA comparison) administered for four weeks before mating and up to Day 7 of pregnancy produced numerous visceral (misshapen cerebral structures, dilated ventricles filled with brown masses, misshapen spinal cord, misshapen and malpositioned eyes, hypophysis, and absent inner ear) and skeletal (cleft palate, dumbbell-shaped ossification of thoracic vertebral centers, markedly enlarged skull bones, and markedly dilated suturae) fetal malformations. .

8.3 Nursing Mothers

It is not known whether Miltex is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Miltex, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Breastfeeding should be avoided for 5 months after Miltex therapy.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients < 12 years have not been established. Juvenile rats were more sensitive to the miltefosine-induced effects, especially retinal and kidney effects, than adult rats .

8.5 Geriatric Use

Clinical studies of Miltex did not include sufficient numbers of subjects 65 years of age and over to determine if they respond differently than younger subjects.

8.6 Renal Impairment

Patients with serum creatinine or BUN levels ≥1.5 times the upper limit of normal were excluded from the clinical studies. Miltex pharmacokinetics have not been studied in patients with renal impairment.

8.7 Hepatic Impairment

Patients with serum levels of ALT or AST ≥3 times the upper limit of normal and bilirubin levels ≥2 times the upper limit of normal were excluded from the clinical studies. Miltex pharmacokinetics have not been studied in patients with hepatic impairment.

8.8 Females and Males of Reproductive Potential

Contraception

Miltex may cause fetal harm when used during pregnancy. Advise females of reproductive potential to use effective contraception during Miltex therapy and for 5 months after therapy is completed .

Vomiting and/or diarrhea occurring during Miltex therapy may affect absorption of oral contraceptives and therefore may compromise their efficacy. Advise females who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during Miltex therapy if vomiting and/or diarrhea occurs during therapy .

Infertility

Females

Miltex caused impaired fertility in rats and caused reversible follicular atresia and diestrus in dogs at doses approximately 1.0 and 0.2 times respectively the MRHD . The effects of Miltex on human female fertility have not been formally studied.

Males

Miltex caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD . A higher dose in rats, approximately 1.0 times the MRHD, caused testicular atrophy and impaired fertility that did not fully reverse 10 weeks after drug administration ended. The effects of Miltex on human male fertility have not been adequately studied.

Advise women and men of the animal fertility findings, and that the potential for impaired fertility with Miltex therapy has not been adequately evaluated.

10 OVERDOSAGE

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 Miltex is only slightly excreted in the urine, forced diuresis will not increase Miltex excretion. Gastrointestinal lavage is of unknown value. A specific antidote to treat Miltex overdose is not known.

11 DESCRIPTION

Miltex capsules contain the active ingredient Miltex, an antileishmanial agent. The chemical name of Miltex is 2-[[(hexadecyloxy)hydroxyphosphenyl]oxy]-N,N,N-trimethylethylammonium inner salt. Miltex is a white powder that is freely soluble in water, 0.1 N HCl or NaOH, methanol, and ethanol. It has the empirical formula of C21H46NO4P with a molecular weight of 407.6 and the following structural formula:

The inactive ingredients are colloidal silicon dioxide, microcrystalline cellulose, lactose monohydrate, talc, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, ferric oxide, and purified water.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Miltex is an anti-leishmanial agent .

12.3 Pharmacokinetics

The pharmacokinetic parameters of Miltex in patients with visceral and cutaneous leishmaniasis treated for 28 days with Miltex are listed in Table 5. Due to the long half-life of Miltex (> 6 days), trough plasma concentrations did not appear to reach a steady state at the end of treatment (i.e., Day 28).

a: Adolescent (≥12 years)/Adults, mean dose per kg was 3.1 mg/kg/day

b: Adolescent (≥12 years)/Adults, mean dose per kg was 3.6 mg/kg/day

c: Adults, mean dose per kg was 1.8 mg/kg/day

d: median (range)

e: AUC0-12h for BID, AUC0-8h for TID

f: t1/2,α = distribution phase half-life; t1/2,β = terminal elimination phase half-life

g: Estimates based on a population PK model

h: mean (% standard error)


Dose


Cmax

(µg/mL)


Tmax d

(hr)


AUCtau e

(µg∙hr/mL)


t1/2,α f

(day)


t1/2,β g

(day)


Visceral Leishmaniasis

(on Day 23)


50 mg BID (4 wks)a


66.2 (28.5)


7(2-12)


636 (26.7)


6.4 (31.1)


50 mg BID (1 wk)/

50 mg TID (3 wks)b


75.9 (17.6)


4 (2-8)


486 (18.1)


8.5 (28.9)


Cutaneous Leishmaniasisc

(on Day 27)


50 mg TID (4 wks)


37.3 (22)f


295 (22)f


6.8 (5.8)g,h


30.7 (18.3)g,h


Absorption

Absolute bioavailability of Miltex has not been determined. In patients with visceral leishmaniasis, maximum Miltex concentrations following oral administration of Miltex capsules were reached right before the next dose in many patients, indicating that the absorption of Miltex may proceed throughout the dosing interval.

Distribution

The distribution of Miltex has not been studied in humans. Human plasma protein binding of Miltex, evaluated by an ultracentrifugation method, was 98% over the drug concentration range from 0.1 to 10 µg/mL. In rats, radioactivity of [14C] Miltex 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 Miltex molecule. The fatty alcohol-containing fragment of Miltex 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. Miltex is contraindicated in patients who have Sjögren-Larsson-Syndrome .

There was little or no evidence of time or metabolism dependent inhibition of the cytochrome P450 enzymes examined at up to approximately 40 µg/mL Miltex.

Oral administration of Miltex 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.

12.4 Microbiology

Mechanism of Action

The specific mode of action of Miltex against Leishmania species is unknown. The mechanism of action of Miltex 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

Miltex has anti-leishmanial activity in vitro and in clinical infections . Sensitivity of different Leishmania species as well as different strains of a Leishmania species to Miltex may vary in different geographic regions.

Drug Resistance

In vitro studies show a potential for development of resistance to Miltex. Some strains of L. braziliensis with intrinsic resistance to Miltex have been identified. However, the clinical relevance of these observations is not known.

Drug resistance could be due to a decrease in Miltex 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 Miltex transport machinery that consists of the Miltex 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenicity/Carcinogenicity: Miltex tested negative in the AMES-Salmonella test, DNA-amplification test, chromosomal aberration test in vitro, UDS-test in vivo/in vitro, and 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.

Carcinogenicity studies were not performed. In a 52-week oral rat toxicity study, testicular Leydig cell adenoma was observed in 3 of 30 male rats with daily administration of 21.5 mg/kg/day Miltex. The carcinogenic potential of Miltex in humans is unknown.

In a Segment I fertility study in male rats, testicular atrophy, reduced numbers of viable sperm, and impaired fertility were observed in rats following daily oral doses of ≥ 8.25 mg/kg (0.4 times the MRHD based on BSA comparison). These findings were reversible within a recovery period of 10 weeks except at the highest dose tested, 21.5 mg/kg/day (1.0 times the MRHD based on BSA comparison), where effects were not fully reversible.

In a female fertility study in rats, estrus cycle arrest in the metestrus or diestrus phases occurred with the high-dose of 21.5 mg/kg (1.0 times the MRHD based on BSA comparison). At doses of 6.81 and 21.5 mg/kg (0.3 and 1.0 times the MRHD respectively based on BSA comparison) increased numbers of embryonic and fetal resorptions and dead fetuses were observed. In a 52-week toxicology study in dogs, increased numbers of atretic follicles in the ovaries, and cycle arrest in the uterus, vagina, and mammary gland with morphology consistent with anestrus or diestrus was observed at doses ≥ 1 mg/kg/day (0.2 times the MRHD based on BSA comparison). The effects in dogs were fully reversible after a recovery period of 6 weeks.

13.2 Animal Toxicology and/or Pharmacology

Toxicological studies with Miltex 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 Miltex 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).

14 CLINICAL STUDIES

14.1 Treatment of Visceral Leishmaniasis

One randomized, open-label, active-controlled study was conducted to evaluate the efficacy of Miltex 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 confirmed by the presence of Leishmania amastigotes in aspirates of spleen or bone marrow were randomized to receive oral Miltex or intravenous amphotericin B deoxycholate in a 3:1 ratio. Patients weighing ≥ 25 kg received an Miltex 50 mg capsule with meals twice a day. Patients weighing < 25 kg received an Miltex 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 Miltex 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%) Miltex 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 Miltex 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 Miltex and amphotericin B were 94% and 97%, respectively.


Miltex

N = 299


Amphotericin B Deoxycholate

N = 99


End of therapy


Initial Cure


293 (98%)


97 (98%)


6 months after therapy


Final CureThe 95% exact confidence interval for the difference (IV Amphotericin B – Miltex) in final cure is (-3.0%, 6.8%).


282 (94%)


96 (97%)


Treatment Failure


9 (3%)


0 (0)


Not Assessable


8 (3%)


3 (3%)

14.2 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 Miltex or placebo in a 2:1 allocation. Patients who weighed < 45 kg received Miltex 50 mg capsule twice a day, and patients who weighed ≥45 kg received Miltex 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 Miltex was statistically significantly higher than the cure rate for placebo.


Miltex


Placebo


Definite CureThe difference (95% CI) between groups is 36.8% (20.1%, 53.4%) with P-value<0.0001.


59/89 (66%)


13/44 (30%)


Colombia


40/49 (82%)


9/24 (38%)


Guatemala


19/40 (48%)


4/20 (20%)


An additional study of Miltex 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 Miltex orally for 28 days. Miltex 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 re-epithelialization 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.

14.3 Treatment of Mucosal Leishmaniasis

A single arm study was conducted to evaluate the efficacy of Miltex 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 Miltex 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Miltex capsule contains 50 mg Miltex in an opaque, red, hard gelatin capsule. Miltex 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).. Protect from moisture.

Dispense only in the original carton.

17 PATIENT COUNSELING INFORMATION

See the FDA-approved Medication Guide

17.1 Dosing Instructions

  • Miltex is administered with food to ameliorate gastrointestinal side effects.
  • Instruct the patient to swallow the capsule whole and not to chew it or break it apart. Instruct the patient to complete the full course of therapy.
  • Inform the patient that abdominal pain, nausea, vomiting, and diarrhea are common side effects of therapy with Miltex and instruct the patient to inform their healthcare provider if these gastrointestinal side effects are severe or persistent. Instruct the patient to consume sufficient fluids to avoid dehydration and, consequently, the risk of kidney injury.

17.2 Females and Males of Reproductive Potential

  • Advise women of reproductive potential to use effective contraception during Miltex therapy and for 5 months after therapy ends .
  • Advise women who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during Miltex therapy if vomiting and/or diarrhea occurs .
  • Advise nursing mothers not to breastfeed during Miltex therapy and for 5 months after therapy is completed .
  • Advise women and men that Miltex caused infertility in male rats, impaired fertility in female rats, and caused atresia in ovarian follicles in female dogs. Advise patients that the potential of impaired fertility in humans has not been adequately evaluated .

Distributed by:

Paladin Therapeutics Inc.

Corporation Trust Center

1209 Orange Street

Wilmington, DE 19801

USA

Medication Guide

IMPAVIDO® (Im-PA-vee-do)

(miltefosine)

Capsules

Read this Medication Guide before you receive Miltex. This information does not take the place of talking to your healthcare provider about you medical condition or treatment.

What is the most important information I should know about Miltex?

Miltex may cause serious risks to pregnancy:

  • Do not take Miltex if you are pregnant. If you take Miltex during pregnancy, your baby is at risk for death or serious birth defects.
  • Women who can become pregnant should use effective birth control (contraception) during Miltex treatment and for 5 months after stopping Miltex treatment. Discuss with your healthcare provider which birth control method is right for you.
  • If you become pregnant while taking Miltex, tell your healthcare provider right away. Talk to your healthcare provider about taking part in the Miltex Pregnancy Registry. This is a study to learn how Miltex affects pregnancy and babies. You can enroll in this registry by calling xxxxxxx.

What is Miltex?

Miltex is prescription medicine used to treat certain types of leishmaniasis:

  • visceral leishmaniasis (affecting your internal organs)
  • cutaneous leishmaniasis (affecting the skin)
  • mucosal leishmaniasis (affecting the nose, mouth and throat)

It is not known if Miltex is safe and effective in children under 12 years of age.

Who should not take Miltex? Do not take Miltex if you:

  • are pregnant
  • have Sjögren-Larsson-Syndrome
  • are allergic to Miltex or any of the ingredients in Miltex. See the end of this leaflet for a list of the ingredients in Miltex.
  • are a woman who can become pregnant and have not had a pregnancy test. Women who can get pregnant must have a urine or blood pregnancy test before taking Miltex.
  • are a woman who can become pregnant and you are not willing to use effective birth control during Miltex treatment and for 5 months after treatment

Before you take Miltex, tell your healthcare provider about all of your medical conditions, including if you:

  • have kidney or liver problems. Your healthcare provider should do blood tests to check your kidneys and liver before you start, during and after your treatment with Miltex.
  • are pregnant or planning to become pregnant. Miltex may harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Miltex passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Miltex. You should avoid breastfeeding while you take Miltex and for 5 months after you stop taking Miltex.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take Miltex?

  • Take Miltex exactly as your healthcare provider tells you to.
  • Complete your full 28 day Miltex treatment.
  • Take Miltex capsules whole. Do not break, crush, dissolve, or chew Miltex before swallowing.
  • Take Miltex with food to help reduce stomach problems.

What are the possible side effects of Miltex?

Miltex may cause serious side effects, including:

See “What is the most important information I should know about Miltex?”

  • Fertility problems in male and female rats and abnormal menstrual cycle in female dogs. It is not known if Miltex causes fertility problems in men or women
  • Testicular pain and absent or decreased ejaculation
  • Kidney and liver problems
  • Stomach problems. Miltex can cause vomiting, diarrhea, and dehydration. Call your healthcare provider right away if you have severe vomiting and diarrhea that does not go away. Drink a lot of water to help prevent dehydration while you are having vomiting and diarrhea.
  • Decreased effectiveness of oral contraceptive pills. Vomiting and diarrhea may cause your birth control pills to be less effective at preventing pregnancy. Use an extra method of birth control, such as male condoms with spermicide, until you are no longer having vomiting and diarrhea.
  • Decrease in platelets (which are blood cells that help blood clot).
  • Serious Skin Problems. Miltex can cause a serious skin problem called Stevens-Johnson Syndrome. If you develop a skin rash with blisters while taking Miltex, stop taking Miltex right away and call your healthcare provider.

The most common side effects of Miltex include: nausea, vomiting and diarrhea. Other side effects include abdominal pain, decreased appetite, dizziness, headache, sleepiness, skin itching, and abnormalities in liver or kidney tests.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Miltex. For more information, ask your healthcare provider.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store Miltex?

  • Store Miltex at room temperature between 68°F to 77°F (20°C to 25°C).
  • Protect Miltex from moisture.

Keep Miltex and all medicines out of the reach of children.

General information about the safe and effective use of Miltex.

Medicines are sometimes prescribed for purposes other than those listed in this Medication Guide. Do not use Miltex for a condition for which it was not prescribed. This Medication Guide summarizes the most important information about Miltex. If you would like more information, talk to your healthcare provider or pharmacist. You can ask your healthcare or pharmacist for information about Miltex that is written for health professionals. Do not give Miltex to other people, even if they have the same symptoms that you have. For more information, go to www. TRADENAME.com or www.dailymed.nlm.nih.gov, or call 1-XXX-XXX-XXXX.

What are the ingredients in Miltex?

Active ingredient: Miltex

Inactive ingredients: colloidal silicon dioxide, microcrystalline cellulose, lactose monohydrate, talc, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, ferric oxide, and purified water.

Distributed by: Paladin Therapeutics, Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Issued: March 2014

Miltex pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Miltex available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Miltex destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Miltex Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Miltex pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."IMPAVIDO (MILTEFOSINE) CAPSULE [PALADIN THERAPEUTICS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."MILTEFOSINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Miltefosine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Miltex?

Depending on the reaction of the Miltex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Miltex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Miltex addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Miltex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Miltex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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