LUPRON DEPOT 3.75 mg is a gonadotropin-releasing hormone (GnRH) agonist indicated for: Endometriosis Management of endometriosis, including pain relief and reduction of endometriotic lesions. ( 1.1 ) In combination with a norethindrone acetate for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. ( 1.1 ) Limitations of Use: The total duration of therapy with LUPRON DEPOT 3.75 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density.
( 1.1 , 2.1 , 5.1 ) Uterine Leiomyomata (Fibroids) Concomitant use with iron therapy for preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. ( 1.2 ) Limitations of Use: LUPRON DEPOT 3.75 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids.
( 1.2 )
1.1Endometriosis Monotherapy
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. In Combination with Norethindrone Acetate LUPRON DEPOT 3.75 mg in combination with norethindrone acetate is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms. Use of norethindrone acetate in combination with LUPRON DEPOT 3.75 mg is referred to as add-back therapy, and is intended to reduce the loss of bone mineral density (BMD) and reduce vasomotor symptoms associated with use of LUPRON DEPOT 3.75 mg.
Limitations of Use : The total duration of therapy with LUPRON DEPOT 3.75 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 ) ] .
1.2Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg, used concomitantly with iron therapy, is indicated for the preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary. Consider a one-month trial period on iron alone, as some women will respond to iron alone [see Clinical Studies ( 14.2 )] . LUPRON DEPOT 3.75 mg may be added if the response to iron alone is considered inadequate.
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Limitations of Use : LUPRON DEPOT 3.75 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids [see Dosage and Administration ( 2.1 )] .
Contraindications
LUPRON DEPOT 3.75 mg is contraindicated in women with the following: Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist analogs, including leuprolide acetate, or any of the excipients in LUPRON DEPOT 3.75 mg [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2 ) ] Undiagnosed abnormal uterine bleeding Pregnancy [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.1 ) ] When norethindrone acetate is administered with LUPRON DEPOT 3.75 mg, the contraindications to the use of norethindrone acetate also apply to this combination regimen.
Refer to the norethindrone acetate prescribing information for a list of contraindications for norethindrone acetate. Hypersensitivity to GnRH, GnRH agonist analogs, including leuprolide acetate, or any of the excipients in LUPRON DEPOT 3.75 mg. ( 4 , 5.4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Pregnancy. ( 4 , 8.1 ) If LUPRON DEPOT 3.75 mg is administered with norethindrone acetate, the contraindications for norethindrone acetate also apply.
( 4 )
Warnings and precautions
Loss of bone mineral density (BMD): Duration of treatment is limited by risk of bone mineral density. When using for management of endometriosis: combination use with norethindrone acetate is effective in reducing loss of BMD; do not retreat without combination norethindrone acetate. Assess BMD before retreatment. ( 1.1 , 1.2 , 5.1 ) Embryo-Fetal Toxicity: May cause fetal harm. Exclude pregnancy before initiating treatment if clinically indicated and discontinue use if pregnancy occurs.
Use non-hormonal methods of contraception only. ( 5.2 ) Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), occurred in patients treated with LUPRON DEPOT. Discontinue LUPRON DEPOT 3.75 mg if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.3 ) Hypersensitivity reactions, including anaphylaxis, have been reported with LUPRON DEPOT 3.75 mg.
( 5.4 ) If LUPRON is administered with norethindrone acetate, the warnings and precautions for norethindrone acetate apply to the combination regimen. ( 5.8 )
5.1Loss of Bone Mineral Density
LUPRON DEPOT 3.75 mg induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible after stopping treatment. In women with major risk factors for decreased BMD such as chronic alcohol use (> 3 units per day), tobacco use, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD, such as anticonvulsants or corticosteroids, use of LUPRON DEPOT 3.75 mg may pose an additional risk.
Carefully weigh the risks and benefits of LUPRON DEPOT 3.75 mg use in these populations. The duration of LUPRON DEPOT 3.75 mg treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration ( 2.1 )] . When using LUPRON DEPOT 3.75 mg for the management of endometriosis, combination use of norethindrone acetate (add-back therapy) is effective in reducing the loss of BMD that occurs with leuprolide acetate [see Clinical Studies ( 14.2 )] .
Do not retreat with LUPRON DEPOT 3.75 mg without combination norethindrone acetate. Assess BMD before retreatment.
5.2Embryo-Fetal Toxicity Based
on animal reproduction studies and the drug’s mechanism of action, LUPRON DEPOT 3.75 mg may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPRON DEPOT 3.75 mg if clinically indicated. Discontinue LUPRON DEPOT 3.75 mg 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, LUPRON DEPOT 11.25 mg usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking LUPRON DEPOT 11.25 mg. If contraception is indicated, advise women to use non-hormonal methods of contraception while on treatment with LUPRON DEPOT 3.75 mg.
5.3Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCARs) have been reported in patients receiving GnRH agonists, including LUPRON DEPOT. These reactions include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions ( 6.2 )] .
Monitor patients for the signs and symptoms of SCARs such as fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy. Advise patients of the signs and symptoms of SCARs. If a SCAR is suspected, discontinue LUPRON DEPOT 3.75 mg. Consult with a healthcare provider with expertise in the diagnosis and management of SCARs. If a diagnosis of SCAR is confirmed, permanently discontinue LUPRON DEPOT 3.75 mg.
5.4Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, have been reported with LUPRON DEPOT use. LUPRON DEPOT 3.75 mg is contraindicated in women with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH) or GnRH agonist analogs [ see Contraindications ( 4 ) and Adverse Reactions ( 6.2 )] . In clinical trials of LUPRON DEPOT 3.75 mg, adverse events of asthma were reported in women with pre-existing histories of asthma, sinusitis, and environmental or drug allergies.
Symptoms consistent with an anaphylactoid or asthmatic process have been reported postmarketing.
5.5Initial Flare of Symptoms Following
the first dose of LUPRON DEPOT 3.75 mg, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in symptoms may be observed during the initial days of therapy, but these should dissipate with continued therapy.
5.6Convulsions
There have been postmarketing reports of convulsions in women on GnRH agonists, including leuprolide acetate. These included women with and without concurrent medications and comorbid conditions.
5.7Clinical Depression
Depression may occur or worsen during treatment with GnRH agonists including LUPRON DEPOT 3.75 mg [see Adverse Reactions ( 6.1 )] . Carefully observe women for depression, especially those with a history of depression and consider whether the risks of continuing LUPRON DEPOT 3.75 mg outweigh the benefits. Women with new or worsening depression should be referred to a mental health professional, as appropriate.
5.8Risks Associated with Norethindrone Combination Treatment If
LUPRON DEPOT 3.75 mg is administered with norethindrone acetate, the warnings and precautions for norethindrone acetate apply to this regimen. Refer to the norethindrone acetate prescribing information for a full list of the warnings and precautions for norethindrone acetate.
Interactions
No drug-drug interaction studies have been conducted with LUPRON DEPOT 3.75 mg.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
LUPRON DEPOT 3.75 mg is contraindicated in pregnancy [see Contraindications ( 4 ) ] . LUPRON DEPOT 3.75 mg 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 LUPRON DEPOT in pregnant women. Based on animal reproduction studies, LUPRON DEPOT 3.75 mg 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 mg/kg, 0.0024 mg/kg, 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 LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Loss of Bone Mineral Density [see Warnings and Precautions ( 5.1 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 ) ] Initial Flare of Symptoms with Management of Endometriosis [see Warnings and Precautions ( 5.5 ) ] Convulsions [see Warnings and Precautions ( 5.6 ) ] Clinical Depression [see Warnings and Precautions ( 5.7 ) ] Most common adverse reactions (>10%) in clinical trials were hot flashes/sweats, headache/migraine, vaginitis, depression/emotional lability, general pain, weight gain/loss, nausea/vomiting, decreased libido, and dizziness.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. LUPRON DEPOT 3.75 mg (Monotherapy) The safety of LUPRON DEPOT 3.75 mg for the endometriosis and fibroids indications was established based on adequate and well-controlled adult studies.
The safety of LUPRON DEPOT 3.75 mg was evaluated in six clinical studies in which a total of 332 women were treated for up to six months. Women were treated with monthly IM injections of LUPRON DEPOT 3.75 mg. The population age range was 18 to 53 years old. Adverse Reactions (>1%) Leading to Study Discontinuation In the six studies 1.8% of women treated with LUPRON DEPOT 3.75 mg discontinued prematurely due to hot flashes.
Common Adverse Reactions The safety of LUPRON DEPOT 3.75 mg was evaluated in controlled clinical trials in 166 women with endometriosis and 166 women with uterine fibroids. Adverse reactions reported in ≥ 5% of women in either of these populations are noted in Tables 2 and 3 , below. Table 2. Adverse Reactions Reported in ≥ 5% of Women with Endometriosis Taking LUPRON DEPOT 3.75 mg - 2 Studies LUPRON DEPOT 3.75 mg N=166 Danazol N=136 Placebo N=31 % % % Hot flashes/sweats* 84 57 29 Headache* 32 22 6 Vaginitis* 28 17 0 Depression/emotional lability* 22 20 3 General pain 19 16 3 Weight gain/loss 13 26 0 Nausea/vomiting 13 13 3 Decreased libido* 11 4 0 Dizziness 11 3 0 Acne 10 20 0 Skin reactions 10 15 3 Joint disorder* 8 8 0 Edema 7 13 3 Paresthesias 7 8 0 GI disturbances* 7 6 3 Neuromuscular disorders* 7 13 0 Breast changes/tenderness/pain* 6 9 0 Nervousness* 5 8 0 In these same studies, symptoms reported in < 5% of women included: Body as a Whole - Injection site reactions Cardiovascular System - Palpitations, syncope, tachycardia Digestive System - Appetite changes, dry mouth, thirst Endocrine System - Androgen-like effects, lactation Blood and Lymphatic System - Ecchymosis Nervous/Psychiatric System - Anxiety*, insomnia/sleep disorders*, delusions, memory disorder, personality disorder Dermal System - Alopecia, hair disorder Ocular system - Ophthalmologic disorders* Urogenital System - Dysuria*. * = Possible effect of decreased estrogen.
Table 3. Adverse Reactions Reported in ≥ 5% of Women with Uterine Fibroids (4 Studies) Taking LUPRON DEPOT 3.75 mg LUPRON DEPOT 3.75 mg N=166 Placebo N=163 % % Hot flashes/sweats* 73 18 Headache* 26 18 Vaginitis* 11 2 Depression/emotional lability* 11 4 Asthenia 8 5 General pain 8 6 Joint disorder* 8 3 Edema 5 1 Nausea/vomiting 5 4 Nervousness* 5 1 In these same studies, symptoms reported in < 5% of women included: Body as a Whole - Body odor, flu syndrome, injection site reactions Cardiovascular System - Tachycardia Digestive System - Appetite changes, dry mouth, taste perversion Endocrine System - Androgen-like effects, menstrual disorders Nervous/Psychiatric System - Anxiety*, insomnia/sleep disorders* Respiratory System - Rhinitis Dermal System - Nail disorder Ocular system - Conjunctivitis * = Possible effect of decreased estrogen.
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT 3.75 mg and LUPRON DEPOT 7.5 mg in women diagnosed with uterine fibroids received one injection every 4 weeks for a duration of 12 weeks. Adverse reactions of galactorrhea, pyelonephritis, and urinary incontinence were reported in the 7.5 mg dose group but not in the 3.75 mg dose group. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
LUPRON DEPOT 3.75 mg in combination with Norethindrone Acetate 5 mg The safety of co-administering LUPRON DEPOT 3.75 mg and norethindrone acetate was evaluated in two clinical studies in which a total of 242 women with endometriosis were treated for up to one year. Women were treated with monthly IM injections of LUPRON DEPOT 3.75 mg (13 injections) alone or monthly IM injections of LUPRON DEPOT 3.75 mg (13 injections) plus norethindrone acetate 5 mg daily.
The population age range was 17 to 43 years old. The majority of women were Caucasian (87%). In one study, 106 women were randomized to one year of treatment with LUPRON DEPOT 3.75 mg alone or with LUPRON DEPOT 3.75 mg and norethindrone acetate. The other study was an open-label, single arm clinical study in 136 women on one year of treatment with LUPRON DEPOT 3.75 mg plus norethindrone acetate, with follow-up for up to 12 months after completing treatment.
Adverse Reactions (>1%) Leading to Study Discontinuation In the controlled study, 18% of women treated monthly with LUPRON DEPOT 3.75 mg and 18% of women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly hot flashes (6%) and insomnia (4%) in the LUPRON DEPOT 3.75 mg alone group and hot flashes and emotional lability (4% each) in the LUPRON DEPOT 3.75 mg plus norethindrone group.
In the open-label study, 13% of women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%). Common Adverse Reactions Table 4 lists the adverse reactions observed in at least 5% of women in any treatment group, during the first 6 months of treatment in the two add-back clinical studies, in which women were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate 5 mg daily co-treatment.
The most frequently-occurring adverse reactions observed in these studies were hot flashes and headaches. Table 4. Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Women with Endometriosis Controlled Study Open Label Study LD-Only* LD/N† LD/N† N=51 N=55 N=136 Adverse Reactions % % % Any Adverse Reaction 98 96 93 Hot flashes/Sweats 98 87 57 Headache/Migraine 65 51 46 Depression/Emotional Lability 31 27 34 Insomnia/Sleep Disorder 31 13 15 Nausea/Vomiting 25 29 13 Pain 24 29 21 Vaginitis 20 15 8 Asthenia 18 18 11 Dizziness/Vertigo 16 11 7 Altered Bowel Function (constipation, diarrhea) 14 15 10 Weight Gain 12 13 4 Decreased Libido 10 4 7 Nervousness/Anxiety 8 4 11 Breast Changes/Pain/Tenderness 6 13 8 Memory Disorder 6 2 4 Skin/Mucous Membrane Reaction 4 9 11 GI Disturbance (dyspepsia, flatulence) 4 7 4 Androgen-Like Effects (acne, alopecia) 4 5 18 Changes in Appetite 4 0 6 Injection Site Reaction 2 9 3 Neuromuscular Disorder (leg cramps, paresthesia) 2 9 3 Menstrual Disorders 2 0 5 Edema 0 9 7 * LD-Only = LUPRON DEPOT 3.75 mg † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg In the controlled clinical trial, 50 of 51 (98%) women in the LUPRON DEPOT 3.75 mg arm and 48 of 55 (87%) women in the LUPRON DEPOT 3.75 mg plus norethindrone acetate arm reported experiencing hot flashes on one or more occasions during treatment.
Table 5 presents hot flash data in the last month of treatment. Table 5. Hot Flashes in the Month Prior to the Assessment Visit (Contro
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Composition
Active ingredients
LEUPROLIDE ACETATE 3.75MG/VIAL **Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons**
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
LEUPROLIDE ACETATE 3.75MG/VIAL **Federal Register determination that product was not discontinued or withdrawn for safety or effectiveness reasons** · InjectableThis page
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