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.
LUPRON DEPOT-PED KIT (NDA-020263)
(LEUPROLIDE ACETATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/14/2023 (SUPPL-53)
04/22/2022 (SUPPL-50)
03/11/2021 (SUPPL-44)
4 Contraindications
Additions underlined
Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOT- PED. Anaphylactic reactions to synthetic GnRH or GnRH agonists have been reported [see Adverse Reactions (6.2)].
…
5 Warnings and Precautions
5.1 Initial Rise of Gonadotropins and Sex Steroid LevelsAdditions underlined
During the early phase of therapy or after subsequent doses, gonadotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug [see Clinical Pharmacology (12.2)]. Therefore, an increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses [see Adverse Reactions (6)].
6 Adverse Reactions
Additions underlined
following serious adverse reactions are described here and elsewhere in the label:
Initial rise in gonadotropin and sex steroid levels [see Warnings and Precautions (5.1)].
Psychiatric Events [see Warnings and Precautions (5.2)].
Convulsions [see Warnings and Precautions (5.3)].
6.1 Clinical Trials Experience
Additions underlined…
LUPRON DEPOT-PED for 1-month administration
LUPRON DEPOT-PED 1-month administration was evaluated in a pivotal, open label, multicenter study in which 55 (49 female and 6 male) pediatric patients with central precocious puberty were enrolled. The age ranged from 1 to 8 years of age at the beginning of treatment; the mean age for females was 6.8 years (range: 1 to 9 years) and the mean age for males was 7.5 years (range: 4 to 9 years); 61.8% were Caucasian; 20% Black; 1.8% Oriental; and 16.4% Hispanic.
Adverse reactions that occurred in greater than or equal to 2% of patients are shown in Table 2.
Please refer to label to view Table 2.
…
LUPRON DEPOT-PED for 3-month administration
LUPRON DEPOT-PED for 3-month administration was evaluated in a pivotal, open-label, multicenter, clinical study with 84 randomized pediatric patients with central precocious puberty; 76 (90.5%) were females and 8 (9.5%) were males. The age ranged from 1 to 11 years age at the beginning of treatment; 80/84 (95.2%) were 5 years or older, and female patients were younger than male; the mean age for 11.25 mg and 30 mg groups for females was 7.6 and 7.7 years, and for males 9.3 and 9.4 years, respectively; 58.3% were Caucasian; 22.6% were Black; 7.1% were Asian; 1.2% were Native Hawaiian or Other Pacific Islander; and 10.7% were Multi-race.
Adverse reactions that occurred in Greater than or equal to 2% of patients are shown in Table 3.
Please refer to label to view Table 3.
…
6.2 Postmarketing Experience
Additions underlined
The following adverse events have been observed with post-approval use of leuprolide acetate in pediatric patients. 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.
Allergic reactions: anaphylactic, rash, urticaria, and photosensitivity reactions.
General: chest pain, weight increase, decreased appetite, fatigue.
Laboratory Abnormalities: decreased WBC.
Metabolic: diabetes mellitus.
Musculoskeletal and Connective Tissue: tenosynovitis-like symptoms, severe muscle pain, arthralgia, epiphysiolysis, muscle spasms, myalgia.
Published literature and postmarketing reports indicate that bone mineral density may decrease during GnRH therapy in pediatric patients with central precocious puberty. Published studies indicate that after discontinuation of therapy, subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected.
Neurologic: neuropathy peripheral, convulsion, insomnia.
…
Reproductive System: vaginal bleeding, breast enlargement.
Respiratory: dyspnea.
Skin and Subcutaneous Tissue: injection site reactions including induration and abscess, flushing, hyperhidrosis.
Vascular Disorders: hypertension, hypotension.
8 Use in Specific Populations
8.1 PregnancyPLLR conversion
Risk Summary
LUPRON DEPOT-PED is contraindicated in pregnancy [see Contraindications (4)].
LUPRON DEPOT-PED may cause fetal harm, when administered to a pregnant woman, based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. The available data from published clinical studies and case reports and from the pharmacovigilance database on exposure to LUPRON DEPOT-PED during pregnancy are insufficient to assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on animal reproduction studies, LUPRON DEPOT-PED may be associated with an increased risk of pregnancy complications, including early pregnancy loss and fetal harm. In animal reproduction studies, subcutaneous administration of leuprolide acetate to rabbits during the period of organogenesis caused embryo-fetal toxicity, decreased fetal weights and a dose-dependent increase in major fetal abnormalities in animals at doses less than the recommended human dose based on body surface area using an estimated daily dose. A similar rat study also showed increased fetal mortality and decreased fetal weights but no major fetal abnormalities at doses less than the recommended human dose based on body surface area using an estimated daily dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US 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
When administered on day 6 of pregnancy at test dosages of 0.00024 mg/kg, 0.0024 mg/kg, and
0.024 mg/kg (doses less than the recommended human dose) to rabbits, leuprolide acetate produced a dose-related increase in malformations comprised primarily of segmental and fusion defects of the skeleton and skull. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was increased fetal mortality and decreased fetal weights with the two higher doses of leuprolide acetate in rabbits and with the highest dose (0.024 mg/kg) in rats.
PLLR conversion
Risk Summary
There are no data on the presence of leuprolide acetate in either animal or human milk, the effects on the breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPRON DEPOT-PED and any potential adverse effects on the breastfed infant from LUPRON DEPOT-PED or from the underlying maternal condition.
PLLR conversion
Pregnancy Testing
Exclude pregnancy in women of reproductive potential prior to initiating LUPRON DEPOT- PED if clinically indicated [see Use in Specific Populations (8.1)].
Contraception
Females
LUPRON DEPOT-PED may cause embryo-fetal harm when administered during pregnancy. LUPRON DEPOT-PED is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPRON DEPOT-PED [see Use in Specific Populations (8.1)].
Infertility
Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPRON DEPOT-PED. Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks [see Clinical Pharmacology (12.2)].
There is no evidence that pregnancy rates are affected following discontinuation of LUPRON DEPOT-PED.
Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.
Subsection revised, additions and/or underlined
The safety and effectiveness of LUPRON DEPOT-PED for the treatment of CPP has been established in pediatric patients 1 years of age and older. Use of LUPRON DEPOT-PED for this indication is supported by evidence from two pivotal, open label clinical studies of 139 pediatric patients with central precocious puberty with an age range of 1 to 11 years [see Clinical Studies (14)]. The safety and effectiveness of LUPRON DEPOT-PED have not been established in pediatric patients less than 1 year old.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions underlined
…
How will your child receive LUPRON DEPOT-PED?
• Your child’s doctor should do tests to make sure your child has CPP before treating them
with LUPRON DEPOT-PED.
• LUPRON DEPOT-PED is injected given as a single-dose injection into your child’s muscle
each month or every 3 months by a doctor or trained nurse. Your doctor will decide how
often your child will receive the injection.
…
Additions underlined
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Symptoms After Initial LUPRON DEPOT-PED Administration
Inform patients and caregivers that during the early phase of therapy with LUPRON DEPOT- PED, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms of puberty may be observed. Instruct patients and caregivers to notify the physician if these symptoms continue beyond the second month after LUPRON DEPOT-PED administration [see Warnings and Precautions (5.1)].
…
Injection Site Reactions
Inform patients and caregivers that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and redness. Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see Adverse Reactions (6.1)].
Pregnancy
LUPRON DEPOT-PED is contraindicated in pregnancy. If the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to the fetus [see Use in Specific Populations (8.1)].
Compliance with the Dosing Schedule
Inform caregivers about the importance of adherence to the LUPRON DEPOT-PED dosing schedule [see Dosage and Administration (2.2, 2.3)].