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Impavido

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Impavido

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryo-Fetal Toxicity

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

Reproductive Effects

Females

Miltefosine 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 [see Nonclinical Toxicology].

Effects on human female fertility have not been formally studied.

Males

Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD [see Nonclinical Toxicology]. 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 IMPAVIDO therapy [see ADVERSE REACTIONS]. The effects of IMPAVIDO 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 IMPAVIDO therapy in humans has not been adequately evaluated.

Renal Effects

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

Hepatic Effects

Elevations in liver transaminases (ALT, AST) and bilirubin were noted in clinical trials evaluating IMPAVIDO in the treatment of visceral leishmaniasis. Monitor liver transaminases (ALT, AST) and bilirubin during therapy in patients receiving IMPAVIDO [see ADVERSE REACTIONS].

Gastrointestinal Effects

Vomiting and/or diarrhea commonly occur during IMPAVIDO administration and may result in volume depletion. Encourage fluid intake to avoid volume depletion [see ADVERSE REACTIONS].

Thrombocytopenia

Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis [see ADVERSE REACTIONS].

Absorption Of Oral Contraceptives

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

Stevens-Johnson Syndrome

Stevens-Johnson syndrome has been reported during IMPAVIDO therapy. Discontinue IMPAVIDO if an exfoliative or bullous rash is noted during therapy [see ADVERSE REACTIONS].

Patient Counseling Information

See the FDA-approved Medication Guide

Dosing Instructions
  • IMPAVIDO 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 IMPAVIDO 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.
Females and Males of Reproductive Potential
  • Advise women of reproductive potential to use effective contraception during IMPAVIDO therapy and for 5 months after therapy ends [see BOXED WARNING and Use In Specific Populations].
  • Advise women who use oral contraceptives to use additional non-hormonal or alternative method(s) of effective contraception during IMPAVIDO therapy if vomiting and/or diarrhea occurs [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Advise nursing mothers not to breastfeed during IMPAVIDO therapy and for 5 months after therapy is completed [see Use in Specific Populations].
  • Advise women and men that IMPAVIDO 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 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Mutagenicity/Carcinogenicity: Miltefosine tested negative in the AMES-Salmonella test, DNAamplification 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 miltefosine (1.0 times the MRHD based on BSA comparison). The carcinogenic potential of miltefosine 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

IMPAVIDO may cause fetal harm. Human pregnancy data are not available, however, embryofetal toxicity including death and teratogenicity, was observed in embryo-fetal studies in rats and rabbits administered oral miltefosine 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 miltefosine prior to mating through day 7 of pregnancy at doses 0.3 times the MRHD. Do not administer IMPAVIDO 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

Miltefosine 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 miltefosine 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 miltefosine 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, miltefosine 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. [see CONTRAINDICATIONS, Nonclinical Toxicology].

Nursing Mothers

It is not known whether IMPAVIDO 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 IMPAVIDO, 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 IMPAVIDO therapy.

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 [see INDICATIONS AND USAGE].

Geriatric Use

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

Renal Impairment

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

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. Miltefosine pharmacokinetics have not been studied in patients with hepatic impairment.

Females And Males Of Reproductive Potential

Contraception

IMPAVIDO may cause fetal harm when used during pregnancy. Advise females of reproductive potential to use effective contraception during IMPAVIDO therapy and for 5 months after therapy is completed [see BOXED WARNING, WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Vomiting and/or diarrhea occurring during IMPAVIDO 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 IMPAVIDO therapy if vomiting and/or diarrhea occurs during therapy [see WARNINGS AND PRECAUTIONS].

Infertility

Females

Miltefosine 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 [see WARNINGS AND PRECAUTIONS, Nonclinical Toxicology]. The effects of IMPAVIDO on human female fertility have not been formally studied.

Males

Miltefosine caused reduced viable sperm counts and impaired fertility in rats at doses approximately 0.4 times the MRHD [see WARNINGS AND PRECAUTIONS, Nonclinical Toxicology]. 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 IMPAVIDO 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 IMPAVIDO therapy has not been adequately evaluated.

Last reviewed on RxList: 3/31/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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