Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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.

LAMPRENE (NDA-019500)

(CLOFAZIMINE)

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

Download Data

Expand all

01/31/2019 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 QT Prolongation

Additions and/or revisions underlined:

QT prolongation has also been reported in patients who were receiving concomitant LAMPRENE and bedaquiline at the recommended dosages. Monitor ECGs in patients taking LAMPRENE and bedaquiline concomitantly, and discontinue LAMPRENE …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Adverse Reactions Occurring in More Than 1% of Patients

Ocular: Diminished vision, conjunctival …

7 Drug Interactions

Addition of the following two subsections:

7.1 Effect of LAMPRENE on Substrates of CYP3A

Concomitant use of LAMPRENE may increase concentrations of drugs that are substrates of CYP3A4/5 which may increase the risk of toxicity of these drugs. Monitor for toxicities of these drugs when used concomitantly with LAMPRENE.

7.2 Drugs that Prolong QT Interval

QT prolongation and Torsade de Pointes have been reported in patients receiving LAMPRENE in combination with QT prolonging medications, such as bedaquiline. Monitor ECGs for QT prolongation when LAMPRENE is administered with other drugs known to prolong the QT interval.

8 Use in Specific Populations

Addition of the two following subsections:

8.7 Renal Impairment

No LAMPRENE dosage adjustments are recommended in patients with mild to moderate renal impairment. Use caution in patients with severe renal impairment.

8.8 Hepatic Impairment

Avoid LAMPRENE in patients with hepatic impairment (Child-Pugh Class A, B, and C) unless the benefit outweighs the risk.

07/08/2016 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

LAMPRENE is contraindicated in patients with known hypersensitivity to clofazimine or any of the excipients of LAMPRENE (addition).

5 Warnings and Precautions

Abdominal Obstruction and Other Gastrointestinal Adverse Reactions (new heading)

Clofazimine may accumulate in various organs as crystals, including the mesenteric lymph nodes and histiocytes at the lamina propria of the intestinal mucosa, spleen and liver. Deposition in the intestinal mucosa may lead to intestinal obstruction that may necessitate exploratory laparotomy. Splenic infarction, gastrointestinal bleeding, and death have been reported. If a patient complains of pain in the abdomen, nausea, vomiting, or diarrhea, initiate appropriate medical investigations and reduce the daily dose of LAMPRENE, or increase the dosing interval or discontinue the drug. Doses of LAMPRENE of more than 100 mg daily should be given for as short a period as possible (less than 3 months) and only under close medical supervision.

Psychological Effects of Skin Discoloration

Skin discoloration due to LAMPRENE therapy has been reported to result in depression and suicide. Advise patients regarding skin discoloration and monitor for depression or suicidal ideation during LAMPRENE therapy.

QT prolongation

Cases of Torsades de Pointes with QT prolongation have been reported in patients receiving dosage regimens containing higher than 100 mg daily dose of LAMPRENE or in combination with QT prolonging medications. For QT prolongation and Torsades de Pointes cases, the patient must remain under medical surveillance. In all these patients, monitor trocardiograms (ECGs) for QT prolongation and cardiac rhythm disturbances.
QT prolongation has also been reported in patients who were receiving LAMPRENE with bedaquiline at the recommended dosage regimen for each drug. Monitor ECGs if LAMPRENE is coadministered to patients receiving bedaquiline, and discontinue LAMPRENE if clinically significant ventricular arrhythmia is noted or if the QTcF interval is 500 ms or greater. If syncope occurs, obtain an ECG to detect QT prolongation.

Skin and Body Fluid Discoloration and Other Skin Reactions

LAMPRENE causes orange-pink to brownish-black discoloration of the skin, as well as discoloration of the conjunctivae, tears, sweat, sputum, urine and feces in 75-100% of patients. Advise patients that skin discoloration is likely to occur and that it may take several months or years to reverse after the conclusion of therapy. Other skin reactions associated with LAMPRENE therapy include ichthyosis, dry skin and pruritus

6 Adverse Reactions

The following adverse reactions associated with the use of LAMPRENE were identified. Because these adverse reactions are reported from different studies, these adverse reactions 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 Less Than 1% of Patients

Ocular: addition of maculopathy (bull’s eye retinopathy).

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

Abdominal Obstruction and Gastrointestinal Adverse Reactions
QT Prolongation
Skin and Body Fluid Discoloration and Other Skin Reactions
Psychological Effects of Skin Discoloration

8 Use in Specific Populations

Females and Males of Reproductive Potential (PLLR Conversion)

Pregnancy testing

Sexually-active females of reproductive potential should have a pregnancy test prior to starting treatment with LAMPRENE.

Contraception

Animal studies have shown LAMPRENE to be harmful to the developing fetus. Advise sexually active females of reproductive potential to use effective contraception (methods that result in less than 1 % pregnancy rates) when using LAMPRENE during treatment and for at least 4 months after stopping treatment with LAMPRENE.
Advise males taking LAMPRENE to use a condom during intercourse while on treatment and for at least 4 months after stopping treatment with LAMPRENE.

Infertility

Impaired female fertility (reduced number of offspring and lower proportion of implantations) was observed in one study in rats receiving LAMPRENE. There are no non-clinical data on male fertility.

Lactation (PLLR Conversion)

Risk Summary

LAMPRENE is excreted in human milk. Skin discoloration has been observed in breast fed neonates of mothers receiving clofazimine.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LAMPRENE and any potential adverse effects on the breastfed infant from LAMPRENE or from the underlying maternal condition.

Patients with HIV Co-infection (addition)

Response to treatment, including treatment of erythema nodosum leprosum reactions, is not altered in HIV-positive and immunocompromised leprosy patients. Dose adjustments of LAMPRENE are not required in these patients.

Pregnancy (PLLR Conversion)

There are no data with LAMPRENE use in pregnant women to inform associated risk. Retardation of fetal skull ossification, increased incidences of abortions and stillbirths, and impaired neonatal survival were observed in mice following prenatal exposure to LAMPRENE at 25 mg/kg, equivalent to the 0.6 times maximum recommended human daily dose (200 mg), based on body surface area comparisons. Advise pregnant women of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/neonatal adverse reactions

The skin of infants born to pregnant mothers who had received LAMPRENE during pregnancy is pigmented at birth. Limited data is available regarding the reversibility of discoloration. Based on previous observations, discoloration gradually faded over the first year.

Data

Human Data

There are no studies of LAMPRENE use in pregnant women. Few cases of clofazimine use during pregnancy have been reported in the literature. These reports indicate that the skin of infants born to women who had received LAMPRENE during pregnancy was deeply pigmented at birth. LAMPRENE should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Animal Data

Embryofetal toxicity studies were conducted in rats, rabbits and mice. In mice LAMPRENE-induced embryotoxicity and fetotoxicity was evident. Retardation of fetal skull ossification, increased incidences of abortions and stillbirths, and impaired neonatal survival were observed following prenatal exposure to LAMPRENE at 25 mg/kg, equivalent to the 0.6 times maximum recommended human daily dose [MRHD] (200 mg), based on body surface area comparisons. The skin and fatty tissue of offspring became discolored approximately 3 days after birth, which was attributed to the presence of clofazimine in the maternal milk. No developmental effects were observed in rat or rabbits orally administered clofazimine during organogenesis at doses up to 50 mg/kg and 15 mg/kg,(equivalent to about 2.4 and 1.5 times the MRHD of 200 mg based on body surface area) respectively. These animal studies were conducted according to the standards at the time of initial drug approval (1986) and not under current regulatory standards

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

PCI - Information for Patients

Inform patients to take LAMPRENE with meals.
Inform patients to report abdominal pain or other gastrointestinal symptoms, such as nausea or vomiting, to their healthcare provider.
Inform patients that LAMPRENE frequently causes a red to brownish-black discoloration of the skin as well as discoloration of the conjunctivae, tears, sweat, sputum, urine, and feces. Advise patients that skin discoloration may take several months or years to resolve after the conclusion of therapy with LAMPRENE.
Inform patients that skin discoloration may result in psychological effects and advise them to report any symptoms of depression or suicidal ideation.
Advise females of reproductive potential to use effective contraception while taking LAMPRENE and for at least 4 months after stopping treatment with LAMPRENE. It is also recommended that they have a pregnancy test prior to starting treatment with LAMPRENE.
Advise males taking LAMRENE to use a condom during intercourse while taking LAMPRENE and for at least 4 months after stopping treatment.
Inform patients of the importance of compliance with the prescribed drug regimen in order to prevent drug resistance. Irregularity in administration of medication and poor compliance can lead to delayed and incomplete cure, and could result in infecting other people. Poor compliance can result in disease progression and ultimately result in the development of disabilities and deformities. Whenever possible, ensure that non-compliant patients receive adequate assessment, health education and supervised treatment.
Instruct patients on the recognition of signs and symptoms of inflammatory reactions and relapses during and following completion of treatment, and instruct them regarding the importance of immediately reporting the earliest manifestations of these signs to their healthcare provider.