Drug Safety-related Labeling Changes (SrLC)

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LUPRON DEPOT-PED KIT (NDA-020263)

(LEUPROLIDE ACETATE)

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

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04/22/2022 (SUPPL-50)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Pseudotumor Cerebri (Idiopathic Intracranial Hypertension)

Newly added subsection

Pseudotumor cerebri (idiopathic intracranial hypertension) have been reported in pediatric patients receiving GnRH agonists, including LUPRON DEPOT-PED. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

  • Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [see Warnings and Precautions (5.4)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of leuprolide acetate or LUPRON DEPOT-PED 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, pseudotumor cerebri (idiopathic intracranial hypertension).

Psychiatric Disorders: emotional lability, such as crying, irritability, impatience, anger, and aggression. Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.

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.

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

MEDICATION GUIDE

Extensive changes; please refer to label

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pseudotumor Cerebri (Idiopathic Intracranial Hypertension)

Inform patients and caregivers that reports of pseudotumor cerebri (idiopathic intracranial hypertension) have been observed in pediatric patients receiving GnRH agonists, including LUPRON DEPOT-PED. Advise patients and caregivers to monitor for headache and vision issues such as blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement, ringing in the ears, dizziness, and nausea. Advise patients and caregivers to contact their healthcare provider if the patient develops any of these symptoms [see Warnings and Precautions (5.4)].

03/11/2021 (SUPPL-44)

Approved Drug Label (PDF)

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 Levels

Additions 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 Pregnancy

PLLR 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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

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.

8.4 Pediatric Use

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 GUIDE

Additions 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.

PATIENT COUNSELING INFORMATION

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)].

03/11/2021 (SUPPL-47)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

Additions 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.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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