LUPRON DEPOT Powder for solution for injection Ref.[109539] Active ingredients: Leuprorelin

5.1 Loss 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.

5.2 Embryo-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.

5.3 Hypersensitivity Reactions

Acute Hypersensitivity

Acute 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.

Delayed Hypersensitivity

Delayed hypersensitivity reactions including the severe cutaneous adverse reactions (SCAR) of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been very rarely reported post-marketing in association with leuprolide-containing therapy [see Adverse Reactions (6.2)]. Discontinue future leuprolide therapy at first signs or symptoms of a delayed hypersensitivity reaction, and treat patients according to current treatment guidelines.

5.4 Initial 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.

5.5 Convulsions

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.

5.6 Clinical 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.

5.7 Risks 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.

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 with Management of Endometriosis [see Warnings and Precautions (5.4)]
• Convulsions [see Warnings and Precautions (5.5)]
• Clinical Depression [see Warnings and Precautions (5.6)]

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

Table 3. Adverse Reactions Reported in ≥ 5% of Women with Uterine Fibroids (4 Studies) Taking LUPRON DEPOT 3.75 mg

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

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 (Controlled Study)

Serious Adverse Reactions

Urinary tract infection (1.9%), renal calculus (0.7%), depression (0.7%)

Changes in Laboratory Values during Treatment

Liver Enzymes

Three percent of women with uterine fibroids treated with LUPRON DEPOT 3.75 mg, manifested post-treatment transaminase values that were at least twice the baseline value and above the upper limit of the normal range.

In the two clinical trials of women with endometriosis, 2% (4 of 191) women receiving leuprolide acetate plus norethindrone acetate for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT and 1% (2 of 136) developed an elevated GGT. Among these six women with increased liver tests, the increases in five were observed beyond 6 months of treatment. None were associated with an elevated bilirubin concentration.

Lipids

Triglycerides were increased above the upper limit of normal in 12% of the women with endometriosis who received LUPRON DEPOT 3.75 mg.

Of those women with endometriosis and women with uterine fibroid whose pretreatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to +17 mg/dL in women with endometriosis and +11 mg/dL to +29 mg/dL in women with uterine fibroids. In the women with endometriosis, increases from the pretreatment values were statistically significant (p<0.03). There was essentially no increase in the LDL/HDL ratio in women from either population receiving LUPRON DEPOT 3.75 mg.

Percent changes from baseline for serum lipids and percentages of women with serum lipid values outside of the normal range in the two studies of LUPRON DEPOT 3.75 mg and norethindrone acetate are summarized in Table 6 and Table 7 below. The major impact of adding norethindrone acetate to treatment with LUPRON DEPOT 3.75 mg was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio.

Table 6. Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24

Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from women with follow-up data returned to pretreatment values.

Table 7. Percentage of Women with Serum Lipids Values Outside of the Normal Range

The following adverse reactions have been identified during post-approval use of LUPRON DEPOT monotherapy or LUPRON DEPOT with norethindrone acetate add-back therapy. 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.

During postmarketing surveillance which includes other dosage forms and other populations, the following adverse reactions were reported:

• Body as a whole: Hypersensitivity reactions including anaphylaxis, localized reactions including induration and abscess at the site of injection
• Nervous/Psychiatric System: Mood swings, including depression; suicidal ideation and attempt; convulsion, peripheral neuropathy, paralysis
• Hepato-biliary system: Serious liver injury
• Skin reactions: erythema multiforme, dermatitis bullous, dermatitis exfoliative, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
• Injury, poisoning and procedural complications: Spinal fracture
• Investigations: Decreased white blood count
• Musculoskeletal and connective tissue system: Tenosynovitis-like symptoms
• Vascular system: Hypotension, hypertension, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, transient ischemic attack
• Respiratory system: Symptoms consistent with an asthmatic process
• Multi-system disorders: Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath), individually and collectively.

Pituitary apoplexy

During postmarketing surveillance, cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of leuprolide acetate and other GnRH agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.

No drug-drug interaction studies have been conducted with LUPRON DEPOT 3.75 mg.

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 ⅓ 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.

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 3.75 mg and any potential adverse effects on the breastfed infant from LUPRON DEPOT 3.75 mg or from the underlying maternal condition.

Pregnancy Testing

Exclude pregnancy in women of reproductive potential prior to initiating LUPRON DEPOT 3.75 mg if clinically indicated [see Warnings and Precautions (5.2)].

Contraception

Females

LUPRON DEPOT 3.75 mg may cause embryo-fetal harm when administered during pregnancy. LUPRON DEPOT 3.75 mg 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 3.75 mg [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 LUPRON DEPOT 3.75 mg. 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 LUPRON DEPOT 3.75 mg.

Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.

Safety and effectiveness of LUPRON DEPOT 3.75 mg for management of endometriosis and the preoperative hematologic improvement of women with anemia caused by fibroids 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 LUPRON DEPOT 3.75 mg for these indications have not been established in premenarcheal pediatric patients.

LUPRON DEPOT 3.75 mg is not indicated in postmenopausal women and has not been studied in this population.