Drug Safety-related Labeling Changes (SrLC)
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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.
RAPAMUNE (NDA-021083)
(SIROLIMUS)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/22/2022 (SUPPL-69)
08/22/2022 (SUPPL-70)
07/15/2019 (SUPPL-64)
5 Warnings and Precautions
5.15 Embryo-Fetal Toxicity(additions underlined)
Based on animal studies and the mechanism of action , Rapamune can cause fetal harm when administered to a pregnant woman. In animal studies, sirolimus caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using Rapamune and for 12 weeks after ending treatment.
(new subsection added)
Azoospermia or
oligospermia may be observed.
Rapamune is an anti-proliferative drug and affects rapidly dividing cells like the germ cells.
(addition underlined)
Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor.
(new subsection added)
The use of live vaccines should be avoided during treatment with Rapamune; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Immunosuppressants may affect response to vaccination. Therefore, during treatment with Rapamune, vaccination may be less effective.
6 Adverse Reactions
(additions underlined)
...
Embryo-fetal toxicity
Male infertility
…
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion)
Risk Summary
Based on animal studies and the mechanism of action, Rapamune can cause fetal harm when administered to a pregnant woman [see Data, Clinical Pharmacology (12.1)]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [see Data]. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Sirolimus crossed the placenta and was toxic to the conceptus.
In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6-15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose
of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone.
In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6-18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of
0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e., embryo-fetal abortion or early resorption). Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg).
In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20). An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At
0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.
(PLLR conversion)
Risk Summary
It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known.
Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rapamune and any potential adverse effects on the breastfed child from Rapamune.
(PLLR conversion)
Contraception
Females should not be pregnant or become pregnant while receiving Rapamune. Advise females of reproductive potential that animal studies have been shown Rapamune to be harmful to the developing fetus. Females of reproductive potential are recommended to use highly effective contraceptive method. Effective contraception must be initiated before Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped.
Infertility
Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment with Rapamune . Ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) have been reported in females with the use of Rapamune. Azoospermia has been reported in males with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(additions underlined)
What should I tell my doctor before taking RAPAMUNE?
…
are pregnant or are a female who can become pregnant. RAPAMUNE can harm your unborn baby…
It is not known whether RAPAMUNE passes into breast milk; however, there is a risk of serious side effects in breastfed infants. You and your doctor should decide about the best way to feed your baby if you take RAPAMUNE.
…
What should I avoid while taking RAPAMUNE?
…
Limit your time in sunlight and UV light. Cover your skin with clothing and use a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer with RAPAMUNE.
…
What are the possible side effects of RAPAMUNE? RAPAMUNE may cause serious side effects, including:
…
Possible harm to your unborn baby. RAPAMUNE can harm your unborn baby. You should not become pregnant during treatment with RAPAMUNE and for 12 weeks after ending treatment with RAPAMUNE. See “What should I tell my doctor before taking RAPAMUNE?”.
…
Other side effects that may occur with RAPAMUNE:
RAPAMUNE may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.
RAPAMUNE may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.
(additions underlined)
17.2 Skin Cancer Events
Advise patients that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor because of the increased risk for skin cancer.
17.3 Pregnancy and Lactation
Advise female patients of reproductive potential to avoid becoming pregnant throughout treatment and for 12 weeks after Rapamune therapy has stopped. Rapamune can cause fetal harm if taken during pregnancy.
Advise a pregnant woman of the potential risk to her fetus. Before making a decision to breastfeed, inform the patient that the effects of breastfeeding in infants while taking this drug are unknown, but there is potential for serious adverse effects.
17.4 Infertility
Inform male and female patients that Rapamune may impair fertility