Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

IMPAVIDO (NDA-204684)

(MILTEFOSINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/25/2021 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

4.1 Pregnancy

(Additions and/or revisions underlined)

IMPAVIDO is contraindicated in patients who are pregnant. Based on animal data, miltefosine may cause fetal harm. [see Boxed Warning, Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

5 Warnings and Precautions

5.1 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

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

(Newly Added Subsection)

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

(Additions and/or revisions underlined)

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

(Additions and/or revisions underlined)

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)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

astrointestinal 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.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; extensive revisions – please refer to labeling)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions underlined)

Risk Summary

There are no data on the presence of miltefosine in human or animal milk, the effects on the breastfed infants, or the effects on milk production. Because of the potential for serious adverse reactions, breastfeeding is not recommended during treatment with IMPAVIDO and for 5 months after the last dose.

8.3 Females and Males of Reproductive Potential

(Extensive changes; please refer to labeling)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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 [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to IMPAVIDO during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women not to breastfeed during treatment with IMPAVIDO and for 5 months after the last dose [see Use in Specific Populations (8.2)].

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 [see Boxed Warning, and Use in Specific Populations (8.1, 8.3)].
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 [see Warnings and Precautions (5.7) and Use in Specific Populations (8.3)].
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 [see Boxed Warning and Use in Specific Populations (8.1)].

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 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)].

Advise females and males of reproductive potential that IMPAVIDO may impair fertility. [see Warnings and Precautions (5.2, 5.3),Use in Specific Populations (8.3), and Nonclinical Toxicology (13.1)].

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 [see Warnings and Precautions (5.2), Adverse Reactions (6.2), and Use in Specific Populations (8.3)].