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.
LUPANETA PACK (NDA-203696)
(LEUPROLIDE ACETATE; NORETHINDRONE ACETATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
08/09/2023 (SUPPL-5)
5 Warnings and Precautions
5.1 Loss of Bone Mineral DensityAdditions and/or revisions underlined:
Leuprolide acetate for depot suspension induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible after stopping treatment.
…
Total treatment duration with LUPANETA PACK should not exceed 12 months. The duration of LUPANETA PACK treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration (2.1)].
When using LUPANETA PACK for the
management of endometriosis, the norethindrone acetate component of the
LUPANETA PACK reduces the BMD loss that occurs with leuprolide acetate use
alone [see Clinical Studies (14)]. Do
not retreat with leuprolide acetate for depot suspension alone. Assess BMD
after 6 months of treatment before retreatment.
Additions and/or revisions underlined:
Based on animal reproduction studies and the drug’s mechanism of action, leuprolide acetate for depot suspension may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPANETA PACK if clinically indicated. Discontinue LUPANETA PACK if the woman becomes pregnant during treatment and inform the woman of potential risk to the fetus [see Contraindications (4) and Use in Specific Populations (8.1)]. Advise women to notify their healthcare provider if they believe they may be pregnant.
When used at the recommended dose and dosing interval, leuprolide acetate for depot suspension usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking leuprolide acetate for depot suspension. If contraception is indicated, advise women to use nonhormonal methods of contraception while on treatment with LUPANETA PACK.
Additions and/or revisions underlined:
Based on animal reproduction studies and the drug’s mechanism of action, leuprolide acetate for depot suspension may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPANETA PACK if clinically indicated. Discontinue LUPANETA PACK if the woman becomes pregnant during treatment and inform the woman of potential risk to the fetus [see Contraindications (4) and Use in Specific Populations (8.1)]. Advise women to notify their healthcare provider if they believe they may be pregnant.
When used at the recommended dose and dosing interval, leuprolide acetate for depot suspension usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking leuprolide acetate for depot suspension. If contraception is indicated, advise women to use nonhormonal methods of contraception while on treatment with LUPANETA PACK
Additions and/or revisions underlined:
Hypersensitivity reactions, including
anaphylaxis, have been reported with LUPANETA PACK use. LUPANETA PACK is
contraindicated in women with a history of hypersensitivity to gonadotropin-releasing
hormone (GnRH), GnRH agonist analogs, or norethindrone acetate [see Adverse Reactions (6.2)].
…
6 Adverse Reactions
Addition of the following bulleted line listing:
The following clinically significant adverse reactions are described elsewhere in the labeling:
Loss of Bone Mineral Density [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Initial Flare of Symptoms [see Warnings and Precautions (5.5)]
Convulsions [see Warnings and Precautions (5.6)]
Clinical Depression [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Extensive additions and/or revisions, please refer to label for complete information.
7 Drug Interactions
Additions and/or revisions underlined:
Leuprolide Acetate for Depot Suspension
No drug-drug interaction studies have been conducted with leuprolide acetate for depot suspension. However, leuprolide acetate is a peptide that is not degraded by cytochrome P-450 enzymes; hence, drug interactions associated with cytochrome P-450 enzymes would not be expected to occur.
Norethindrone Acetate
No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate have been conducted. Drugs or herbal products that induce or inhibit certain enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone, respectively.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
Safety and effectiveness of LUPANETA PACK for management of endometriosis have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. The safety and effectiveness of LUPANETA PACK for these indications have not been established in premenarcheal pediatric patients.
8.1 Pregnancy
PLLR conversion:
Risk Summary
LUPANETA PACK is contraindicated in pregnancy [see Contraindications (4)].
Leuprolide acetate for depot suspension may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are limited human data on the use of LUPANETA PACK in pregnant women. Based on animal reproduction studies, leuprolide acetate for depot suspension 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].
Data
Animal Data
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate produced a dose-related increase in major fetal abnormalities. 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 for depot suspension in either animal or human milk, the effects on the breastfed infants, or the effects on milk production. Detectable amounts of progestins have been identified in the milk of mothers receiving them.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPANETA PACK and any potential adverse effects on the breastfed infant from LUPANETA PACK 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 LUPANETA PACK if clinically indicated [see Warnings and Precautions (5.2)].
Contraception
Females
Based on animal reproduction studies and the drug’s mechanism of action, the leuprolide acetate component of LUPANETA PACK may cause embryo-fetal harm when administered during pregnancy. LUPANETA PACK is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPANETA PACK [see Warnings and Precautions (5.2)].
Infertility
Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPANETA PACK. 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 (12.1)].
There is no evidence that pregnancy rates are affected following discontinuation of LUPANETA PACK.
Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
See FDA-approved patient labeling (Patient Information)
Loss of Bone Density
Advise patients about the risk of loss of bone mineral density and that treatment duration is limited [see Dosage and Administration (2.1)]. Advise patients about other factors that can increase and decrease their risk of bone mineral density loss [see Warnings and Precautions (5.1)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the possible risk to a fetus. Advise patients to inform healthcare provider if they believe they may be pregnant [see Warnings and Precautions (5.2) and Use in Special Populations (8.1)].
If contraception is indicated, advise females of reproductive potential to use non-hormonal contraception during treatment with LUPANETA PACK [see Use in Special Populations (8.3)].
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including anaphylaxis, have been reported with LUPANETA PACK. Advise patients to seek appropriate medical care if symptoms of hypersensitivity reactions occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].
…
Initial Flare of Symptoms
Advise patients that they may experience an increase in symptoms during the initial days of therapy. Advise patients that these symptoms should dissipate with continued therapy [see Warnings and Precautions (5.5)]. Advise patients to notify their healthcare provider if they develop new or worsened symptoms after beginning treatment.
Convulsions
Inform patients that convulsions have been reported in patients who have received LUPANETA PACK. Advise patients to seek medical attention in the event of a convulsion [see Warnings and Precautions (5.6)].
…
Visual Abnormalities
Advise patients to discontinue norethindrone acetate and seek medical attention if they develop sudden loss of vision, double vision or sudden migraine [see Warnings and Precautions (5.8)].
PATIENT INFORMATION
Extensive additions and/or revisions, please refer to label for complete information.
08/09/2023 (SUPPL-6)
5 Warnings and Precautions
5.1 Loss of Bone Mineral DensityAdditions and/or revisions underlined:
Leuprolide acetate for depot suspension induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible after stopping treatment.
…
Total treatment duration with LUPANETA PACK should not exceed 12 months. The duration of LUPANETA PACK treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration (2.1)].
When using LUPANETA PACK for the
management of endometriosis, the norethindrone acetate component of the
LUPANETA PACK reduces the BMD loss that occurs with leuprolide acetate use
alone [see Clinical Studies (14)]. Do
not retreat with leuprolide acetate for depot suspension alone. Assess BMD
after 6 months of treatment before retreatment.
Additions and/or revisions underlined:
Based on animal reproduction studies and the drug’s mechanism of action, leuprolide acetate for depot suspension may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPANETA PACK if clinically indicated. Discontinue LUPANETA PACK if the woman becomes pregnant during treatment and inform the woman of potential risk to the fetus [see Contraindications (4) and Use in Specific Populations (8.1)]. Advise women to notify their healthcare provider if they believe they may be pregnant.
When used at the recommended dose and dosing interval, leuprolide acetate for depot suspension usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking leuprolide acetate for depot suspension. If contraception is indicated, advise women to use nonhormonal methods of contraception while on treatment with LUPANETA PACK.
Additions and/or revisions underlined:
Hypersensitivity reactions, including
anaphylaxis, have been reported with LUPANETA PACK use. LUPANETA PACK is
contraindicated in women with a history of hypersensitivity to gonadotropin-releasing
hormone (GnRH), GnRH agonist analogs, or norethindrone acetate [see Adverse Reactions (6.2)].
…
6 Adverse Reactions
Addition of the following bulleted line listing:
The following clinically significant adverse reactions are described elsewhere in the labeling:
Loss of Bone Mineral Density [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
Initial Flare of Symptoms [see Warnings and Precautions (5.5)]
Convulsions [see Warnings and Precautions (5.6)]
Clinical Depression [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Extensive additions and/or revisions, please refer to label for complete information.
7 Drug Interactions
Additions and/or revisions underlined:
Leuprolide Acetate for Depot Suspension
No drug-drug interaction studies have been conducted with leuprolide acetate for depot suspension. However, leuprolide acetate is a peptide that is not degraded by cytochrome P-450 enzymes; hence, drug interactions associated with cytochrome P-450 enzymes would not be expected to occur.
Norethindrone Acetate
No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate have been conducted. Drugs or herbal products that induce or inhibit certain enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone, respectively.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
Safety and effectiveness of LUPANETA PACK for management of endometriosis have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. The safety and effectiveness of LUPANETA PACK for these indications have not been established in premenarcheal pediatric patients.
8.1 Pregnancy
PLLR conversion:
Risk Summary
LUPANETA PACK is contraindicated in pregnancy [see Contraindications (4)].
Leuprolide acetate for depot suspension may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are limited human data on the use of LUPANETA PACK in pregnant women. Based on animal reproduction studies, leuprolide acetate for depot suspension 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].
Data
Animal Data
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate produced a dose-related increase in major fetal abnormalities. 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 for depot suspension in either animal or human milk, the effects on the breastfed infants, or the effects on milk production. Detectable amounts of progestins have been identified in the milk of mothers receiving them.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPANETA PACK and any potential adverse effects on the breastfed infant from LUPANETA PACK 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 LUPANETA PACK if clinically indicated [see Warnings and Precautions (5.2)].
Contraception
Females
Based on animal reproduction studies and the drug’s mechanism of action, the leuprolide acetate component of LUPANETA PACK may cause embryo-fetal harm when administered during pregnancy. LUPANETA PACK is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPANETA PACK [see Warnings and Precautions (5.2)].
Infertility
Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPANETA PACK. 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 (12.1)].
There is no evidence that pregnancy rates are affected following discontinuation of LUPANETA PACK.
Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.Pediatric Use
Additions and/or revisions underlined:
Safety and effectiveness of LUPANETA PACK for management of endometriosis have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. The safety and effectiveness of LUPANETA PACK for these indications have not been established in premenarcheal pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
See FDA-approved patient labeling (Patient Information)
Loss of Bone Density
Advise patients about the risk of loss of bone mineral density and that treatment duration is limited [see Dosage and Administration (2.1)]. Advise patients about other factors that can increase and decrease their risk of bone mineral density loss [see Warnings and Precautions (5.1)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the possible risk to a fetus. Advise patients to inform healthcare provider if they believe they may be pregnant [see Warnings and Precautions (5.2) and Use in Special Populations (8.1)].
If contraception is indicated, advise females of reproductive potential to use non-hormonal contraception during treatment with LUPANETA PACK [see Use in Special Populations (8.3)].
Hypersensitivity Reactions
Inform patients that hypersensitivity reactions, including anaphylaxis, have been reported with LUPANETA PACK. Advise patients to seek appropriate medical care if symptoms of hypersensitivity reactions occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].
…
Initial Flare of Symptoms
Advise patients that they may experience an increase in symptoms during the initial days of therapy. Advise patients that these symptoms should dissipate with continued therapy [see Warnings and Precautions (5.5)]. Advise patients to notify their healthcare provider if they develop new or worsened symptoms after beginning treatment.
Convulsions
Inform patients that convulsions have been reported in patients who have received LUPANETA PACK. Advise patients to seek medical attention in the event of a convulsion [see Warnings and Precautions (5.6)].
…
Visual Abnormalities
Advise patients to discontinue norethindrone acetate and seek medical attention if they develop sudden loss of vision, double vision or sudden migraine [see Warnings and Precautions (5.8)].
PATIENT INFORMATION
Extensive additions and/or revisions, please refer to label for complete information.