Brand Name
Impavido
Generic Name
Miltefosine
View Brand Information FDA approval date: October 29, 2015
Classification: Antileishmanial
Form: Capsule
What is Impavido (Miltefosine)?
IMPAVIDO capsules are indicated in adults and pediatric patients 12 years of age and older weighing greater than or equal to 30 kg for the treatment of: Visceral leishmaniasis caused by Leishmania donovani [see Clinical Trials ( 1.
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Brand Information
IMPAVIDO (miltefosine)
WARNING: EMBRYO-FETAL TOXICITY
- Pregnancy: IMPAVIDO is contraindicated in pregnancy. Based on animal data, miltefosine may cause fetal harm [see Contraindications (.
- Females of Reproductive Potential: Verify pregnancy status prior to initiating IMPAVIDO. To prevent pregnancy, females of reproductive potential should use effective contraception during treatment and for 5 months after the last dose [see Dosage and Administration (
1INDICATIONS AND USAGE
IMPAVIDO (miltefosine) capsules are indicated in adults and pediatric patients 12 years of age and older weighing greater than or equal to 30 kg (66 lbs) for the treatment of:
- Visceral leishmaniasis caused by
- Cutaneous leishmaniasis caused by
- Mucosal leishmaniasis caused by
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
- The efficacy of IMPAVIDO in the treatment of other
2DOSAGE AND ADMINISTRATION
Verify pregnancy status prior to initiating IMPAVIDO in females of reproductive potential
The treatment duration is 28 consecutive days. Administer with food to ameliorate gastrointestinal adverse reactions.
3DOSAGE FORMS AND STRENGTHS
IMPAVIDO
4ADVERSE 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.
4.1Clinical 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 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, Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 diarrhea (≥10 stools per day) and CTCAE Grade 4 hyperbilirubinemia (≥10x upper limit of normal ULN).
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 and older 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 and older 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.
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.
Adverse Effects on Semen Quality and Spermatogenesis
In an open-label, uncontrolled, single-center study that assessed the effects of IMPAVIDO on sperm parameters, a total of 58 Bolivian adult males with cutaneous or mucosal leishmaniasis were administered IMPAVIDO for 28 days at a target dose of 2.5 mg/kg/day. Patients underwent repeat semen analysis testing at baseline (prior to treatment), at the end of treatment (Day 25 to 28 of treatment), and at 3 months after completing treatment. If sperm concentrations were markedly reduced at 3 months, per protocol, one additional semen sample was collected at 6 months after completing treatment.
The primary safety endpoint was determined at the end of treatment and included the number and percentage of patients with abnormal sperm parameters and clinically relevant changes from baseline in semen volume, total sperm count, sperm concentration, sperm motility and sperm morphology as shown in Table 5. The secondary safety endpoints included: mean changes from baseline in semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology. Mean changes from baseline in serum testosterone and FSH concentrations were also evaluated.
A total of 53 patients completed the study. The median patient age was 34 years (range 18 to 51 years). The majority of patients (70.7%) had cutaneous leishmaniasis, while 24.1% had mucosal leishmaniasis, and 5.2% had both forms.
Treatment with IMPAVIDO was associated with reductions in all sperm parameters at the end of treatment (see
Table 5 shows the results for the primary safety endpoint, the number and percentage of patients with abnormal sperm parameters at the end of treatment and in the post-treatment follow-up period, including assessments at 3 months or 6 months after treatment completion.
Semen analyses were not conducted beyond 6 months in any patient; therefore, the duration of effect of IMPAVIDO on sperm concentration after treatment is unknown.
Table 6 shows the results for the secondary safety endpoints, mean sperm parameters at baseline, end of treatment, and 3 and 6 months after treatment completion.
No clinically meaningful changes were observed in serum testosterone or FSH concentrations at the end of treatment or 3 months after treatment.
4.2Postmarketing Experience
The following adverse reactions have been identified during use of IMPAVIDO or miltefosine 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.
Adverse Reactions from Postmarketing Spontaneous Reports
Blood and Lymphatics Disorders: thrombocytopenia, agranulocytosis
Eye Disorders: keratitis, keratopathy, and acute scleritis; uveitis
Gastrointestinal Disorders: melena
General Disorders: generalized edema, peripheral edema
Hepatobiliary Disorders: jaundice
Nervous System Disorders: seizure
Vascular Disorders: epistaxis
Adverse Reactions from Observational Studies
Reproductive System and Breast Disorders: scrotal pain, decreased ejaculate volume, absent ejaculation.
Investigations: uric acid elevations
Musculoskeletal disorders: acute gout
Reduced Ejaculate Volume and Scrotal Tenderness
Among 33 young male patients treated with miltefosine at a single Dutch center, 21 (64%) reported diminution of ejaculate volume and 2 (6%) reported temporary absence of ejaculate. In addition, 4 patients (12%) reported scrotal tenderness and 1 (3%) was diagnosed with epididymitis. These adverse reactions resolved in all patients upon completion of their miltefosine therapy.
5DRUG INTERACTIONS
In vitro and animal metabolism studies showed that miltefosine did not markedly induce or inhibit the activity of the major human cytochrome P450 enzymes [see Clinical Pharmacology (. The potential of miltefosine to interact with drug transporters has not been evaluated.
6OVERDOSAGE
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.
7DESCRIPTION
IMPAVIDO capsules contain the active ingredient miltefosine, an antileishmanial agent. The chemical name of miltefosine is 2-[[(hexadecyloxy)hydroxyphosphenyl]oxy]-N,N,N-trimethylethylammonium inner salt. Miltefosine 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 C
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.
8HOW SUPPLIED/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 child-resistant blister card. Each blister card contains 14 capsules. Each carton contains two blister cards (NDC 69051-300-01).
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.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (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.
Embryo-fetal Toxicity
- Advise pregnant women and females of reproductive potential that IMPAVIDO may cause fetal harm. Advise females to inform their healthcare provider of a known of suspected pregnancy
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to IMPAVIDO during pregnancy
Lactation
- Advise women not to breastfeed during treatment with IMPAVIDO and for 5 months after the last dose
Females and Males of Reproductive Potential
- Advise women of reproductive potential to use effective contraception during treatment with IMPAVIDO and for 5 months after the last dose
- Advise women who use oral contraceptives to use an additional non-oral method of effective contraception during IMPAVIDO therapy, if vomiting and/or diarrhea occurs
- Advise women who become pregnant while being treated with IMPAVIDO, to discontinue treatment with IMPAVIDO and seek counseling from their healthcare provider about the potential risk to the fetus
- Advise male patients that semen quality and sperm parameters may be adversely affected by treatment with IMPAVIDO. Advise male patients that the effects of IMPAVIDO on spermatogenesis may persist for an unknown duration of time
- Advise females and males of reproductive potential that IMPAVIDO may impair fertility.
- Advise male patients that diminution in ejaculate volume, including temporary absence of ejaculate, and scrotal tenderness may occur during treatment with IMPAVIDO. Male patients should report any concerning genitourinary symptoms to their healthcare provider
Distributed by:
PR033-04
10PRINCIPAL DISPLAY PANEL - Carton
NDC 69051-300-01 28 Capsules
Impavido
(miltefosine) capsules
50 mg per Capsule
(miltefosine) capsules
50 mg per Capsule
Rx only PROFOUNDA
Contains 2 blister cards, 14 blisters per card, 1 capsule per blister.
Active ingredient: miltefosine
Inactive ingredients: colloidal silicon dioxide, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, talc. The capsule shell
contains gelatin, titanium dioxide, ferric oxide and purified water.
magnesium stearate, microcrystalline cellulose, talc. The capsule shell
contains gelatin, titanium dioxide, ferric oxide and purified water.
Usual dosage: see enclosed package insert for complete
prescribing information.
prescribing information.
Keep out of reach of children.
Store at 20-25 °C (68-77 °F); excursions permitted
Distributed by:
Impavido(miltefosine) capsules
50 mg per Capsule
50 mg per Capsule
NDC 69051-300-01
28 Capsules
Lot:
Exp. Date: