IMPAVIDO (miltefosine 50 mg) Dailymed

• • Impaired Semen Quality and Spermatogenesis: Advise male patients that semen quality may be adversely affected after treatment with IMPAVIDO and that effects on spermatogenesis may persist for an unknown duration of time. IMPAVIDO may impair male fertility (5.2, 6.1, 8.3).
• • Female Reproductive Effects: IMPAVIDO caused impaired fertility in female rats. Advise females of reproductive potential of the reproductive toxicities found in animal studies. The potential effects of IMPAVIDO on female fertility have not been adequately evaluated (5.3, , 13.1)
• • Absorption of Oral Contraceptives: Advise females to use an additional non-oral method of effective contraception if vomiting and/or diarrhea occur (5.4,).
• • Renal Effects: Monitor serum creatinine during therapy and for 4 weeks after end of therapy (5.5, 6.1).
• • Hepatic Effects: Monitor transaminases and bilirubin during therapy (5.6, 6.1).
• • Gastrointestinal Effects: Encourage fluid intake (5.7).
• • Thrombocytopenia: Monitor platelet count during therapy for visceral leishmaniasis (5.8, 6.1).
• • Stevens-Johnson Syndrome: Discontinue IMPAVIDO (5.9).

5.1 Embryo-Fetal Toxicity

IMPAVIDO is contraindicated in patients who are pregnant. Based on animal data, miltefosine may cause fetal harm. Embryo-fetal toxicity, including death and fetal malformations, 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). Advise females of reproductive potential of the potential risk to a fetus. Verify pregnancy status prior to initiating IMPAVIDO in females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with IMPAVIDO and for 5 months after the last dose [see Boxed Warning, Contraindications (4.1) and Use in Specific Populations (8.1, 8.3)].

5.2 Impaired Semen Quality and Impaired Spermatogenesis

IMPAVIDO may impair male fertility. Reductions in semen parameters (ejaculate volume, total sperm count, sperm concentration, sperm morphology, sperm motility) were observed in a clinical study evaluating the effects of IMPAVIDO on spermatogenesis. For all parameters, except sperm concentration, the observed reductions were reversible in most affected patients and improved within 3 to 6 months. Reductions in sperm concentration of > 50% persisted in up to 26% of patients. Reductions up to the lower limit of normal in sperm concentration (< 20 million/ mL) persisted in up to 8% of patients. Per protocol, semen parameters were not assessed beyond 6 months in any patient. The effect of IMPAVIDO on spermatogenesis may persist for an unknown duration. [see Adverse Reactions (6.1) and Use in Specific Populations (8.3)].

Reductions in ejaculate volume, temporary absence of ejaculate, and scrotal tenderness were reported in an observational study of male patients who received IMPAVIDO. These adverse reactions resolved in all patients upon completion of IMPAVIDO therapy [see Adverse Reactions (6.2)].

5.3 Female Reproductive Effects

IMPAVIDO caused impaired fertility in female rats and follicular atresia and reversible anestrus/diestrus in dogs at doses approximately 1.0 and 0.2 times the MRHD based on body surface area comparisons, respectively [see Nonclinical Toxicology (13.1)]. The effects of IMPAVIDO on human female fertility have not been formally studied [see Use in Specific Population (8.3)].

5.4 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 an additional non-oral method of effective contraception [see Boxed Warning, Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

5.5 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 (6.1)].

5.6 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 (6.1)].

5.7 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 (6.1)].

5.8 Thrombocytopenia

Thrombocytopenia during therapy has been reported in patients treated for visceral leishmaniasis. Monitor platelet count during therapy for visceral leishmaniasis [see Adverse Reactions (6.1, 6.2)].

5.9 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 (6.1)].

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 (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Knight at 1-844-483-5636 , 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 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).

Table 2: Treatment Emergent Adverse Reactions Occurring in ≥2% of Visceral Leishmaniasis Patients Receiving IMPAVIDO

System Organ ClassPreferred Term	IMPAVIDON = 299	Amphotericin B DeoxycholateN = 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 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.

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 ClassAdverse Reaction	IMPAVIDON = 89	PlaceboN = 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 ClassAdverse Reaction	IMPAVIDON = 120	MeglumineN = 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.

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). All sperm parameter reductions, except for sperm concentration, recovered on follow-up assessments at 3 and 6 months after treatment completion. For sperm concentration, small mean decreases persisted on follow-up assessments at 3 and 6 months after treatment completion, with approximately 26% of subjects showing post-treatment sperm concentrations reductions of ≥ 50%, and 8% showing reductions to the lower limit of normal (< 20 million/ mL), on their last observed assessment.

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.

Table 5: Number (%) of Subjects with Abnormal Sperm Parameters, Based on Last Observation, n=55

Sperm Parameter	End of Treatment	Follow-up Period(Last observation Last observation=Patient’s final semen analysis at either 3 months or 6 months after treatment completion )
Semen volume
< 1.5 mL	41/55 (75%)	8/53 (15%)
Total sperm count
≥ 50% reduction from baseline	28/52 (54%)	10/53 (19%)
< 39 million	17/52 (33%)	3/53 (6%)
Sperm concentration
≥ 50% reduction from baseline	11/52 (21%)	14/53 (26%)
< 20 million sperm/mL	6/52 (12%)	4/53 (8%)
Sperm motility
≥ 25% reduction from baseline	28/55 (51%)	5/53 (9%)
< 40% with total motility	18/55 (33%)	3/53 (6%)
Sperm morphology
≥ 25% reduction from baseline	17/55 (31%)	8/53 (15%)
< 4% normal forms	0/55 (0%)	0/53 (0%)

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.

Table 6: Mean Sperm Parameters Over Time

* If sperm concentrations were markedly reduced at 3 months, per protocol, one additional semen sample was collected at 6 months after completing treatment.** Mean and SD of log(X+1) transformed data are calculated and transformed back to original unit using exp(X)-1 to derive Geometric Mean and Geometric SD in this table.
		n	Geometric Mean (SD)**
Semen	Baseline	55	2.3 (0.4)
Volume	End of Treatment	55	1.0 (0.4)
(mL)	3 Months	49	2.1 (0.3)
	6* Months	18	2.3 (0.4)
Total Sperm	Baseline	55	169 (1.0)
Count	End of Treatment	52	74 (3.8)
(millions)	3 Months	49	128 (1.3)
	6* Months	18	129 (1.9)
Sperm	Baseline	55	79 (1.2)
Concentration	End of Treatment	52	74 (2.8)
(million/mL)	3 Months	49	65 (1.3)
	6* Months	18	59 (1.5)
		n	Mean (SD)
Sperm Motility	Baseline	55	59 (8.8)
(%)	End of Treatment	55	39 (15.2)
	3 Months	49	57 (10.4)
	6* Months	18	54 (10.6)
Sperm Morphology	Baseline	55	7 (4.2)
(%)	End of Treatment	52	15 (5.1)
	3 Months	49	18 (5.7)
	6* Months	18	16 (5.5)

No clinically meaningful changes were observed in serum testosterone or FSH concentrations at the end of treatment or 3 months after treatment.

6.2 Postmarketing 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

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.

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.