LUPRON DEPOT 11.25 SIDE EFFECTS
- Generic Name: leuprolide acetate for depot suspension
- Brand Name: Lupron Depot 11.25 mg
SIDE EFFECTS
Clinical 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 (Monotherapy)
The safety of LUPRON DEPOT 11.25 mg for the endometriosis and fibroids indications was established based on adequate and well-controlled adult studies of LUPRON DEPOT 3.75 mg for 1-month administration and on a single trial of LUPRON DEPOT 11.25 mg. 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 patients treated with LUPRON DEPOT 3.75 mg discontinued prematurely due to hot flashes.
Common Adverse Reactions
LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse reactions reported in ≥ 5% of patients in either of these populations are noted in the following tables.
Table 1: Adverse Reactions Reported in ≥ 5% of Patients Taking LUPRON DEPOT-Endometriosis (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 patients 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; Hemic and Lymphatic System –Ecchymosis; Nervous System -Anxiety*, Insomnia/Sleep disorders*, Delusions, Memory disorder, Personality disorder; Skin and Appendages –Alopecia, Hair disorder; Special Senses –Ophthalmologic disorders*; Urogenital System –Dysuria*, Lactation. * = Possible effect of decreased estrogen. |
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Table 2: Adverse Reactions Reported in ≥ 5% of Patients -Uterine Fibroids (4 Studies)
| 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 patients included: Body as a Whole –Body odor, Flu syndrome, Injection site reactions; Cardiovascular System –Tachycardia; Digestive System –Appetite changes, Dry mouth; Endocrine System –Androgen-like effects; Nervous System –Anxiety*, Insomnia/Sleep disorders*; Respiratory System –Rhinitis; Skin and Appendages –Nail disorder; Special Senses –Conjunctivitis, Taste perversion; Urogenital System –Menstrual disorders. * = Possible effect of decreased estrogen. |
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In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Adverse reactions seen with this dose that were not seen at the lower dose included galactorrhea, pyelonephritis, and urinary incontinence. Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
In a pharmacokinetic trial involving 20 healthy female subjects receiving LUPRON DEPOT 11.25 mg, a few adverse reactions were reported with this formulation that were not reported previously, including face edema.
In a phase 4 study involving endometriosis patients receiving LUPRON DEPOT 3.75 mg (N=20) or LUPRON DEPOT 11.25 mg (N=21), similar adverse reactions were reported by the two groups of patients. In general the safety profiles of the two formulations were comparable in this study.
LUPRON DEPOT With Norethindrone Acetate Add-back Therapy
The safety of co-administering LUPRON DEPOT 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 leuprolide acetate 3.75 mg (13 injections) alone or monthly IM injections of leuprolide acetate 3.75 mg (13 injections) plus 5 mg norethindrone acetate daily. The population age range was 17-43 years old. The majority of patients were Caucasian (87%).
One study was a controlled clinical trial in which 106 women were randomized to one year of treatment with LUPRON DEPOT alone or with LUPRON DEPOT and norethindrone acetate. The other study was an open-label single arm clinical study in 136 women of one year of treatment with LUPRON DEPOT 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 patients treated monthly with LUPRON DEPOT and 18% of patients treated monthly with LUPRON DEPOT plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly hot flashes (6%) and insomnia (4%) in the LUPRON DEPOT alone group and hot flashes and emotional lability (4% each) in the LUPRON DEPOT plus norethindrone group.
In the open label study, 13% of patients treated monthly with LUPRON DEPOT plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%).
Common Adverse Reactions
Table 3 lists the adverse reactions observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the two add-back clinical studies, in which patients were treated with monthly LUPRON DEPOT 3.75 mg with or without norethindrone acetate co-treatment. The most frequently-occurring adverse reactions observed in these studies were hot flashes and headaches.
Table 3: Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Patients with Endometriosis
| Adverse Reactions | Controlled Study | Open Label Study | |
| LD-Only* N=51 % |
LD/N† N=55 % |
LD/N† N=136 % |
|
| 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 |
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In the controlled clinical trial, 50 of 51 (98%) patients in the LUPRON DEPOT 3.75 mg arm and 48 of 55 (87%) patients in the LUPRON DEPOT 3.75 mg plus norethindrone acetate arm reported experiencing hot flashes on one or more occasions during treatment.
Table 4 presents hot flash data in the last month of treatment.
Table 4: Hot Flashes in the Month Prior to the Assessment Visit (Controlled Study)
| Assessment Visit | Treatment Group | Number of Patients Reporting Hot Flashes | Number of Days with Hot Flashes | Maximum Number Hot Flashes in 24 Hours | |||
| N | (%) | N2 | Mean | N2 | Mean | ||
| Week 24 | LD-Only* | 32/37 | 86 | 37 | 19 | 36 | 5.8 |
| LD/N† | 22/38 | 581 | 38 | 71 | 38 | 1.91 | |
| * LD-Only = LUPRON DEPOT 3.75 mg † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg 1Statistically significantly less than the LD-Only group (p<0.01) 2Number of patients assessed. |
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Serious Adverse Reactions
Urinary tract infection, renal calculus, depression
Changes In Laboratory Values during Treatment
Liver Enzymes
Three percent of uterine fibroid patients treated with LUPRON DEPOT 3.75 mg for 1-month administration, manifested post-treatment transaminase values that were at least twice the baseline value and above the upper limit of the normal range. None of the laboratory increases were associated with clinical symptoms.
In the two clinical trials of women with endometriosis, 4 of 191 patients receiving leuprolide acetate plus norethindrone acetate for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT and 2 of 136 developed an elevated GGT. Five of the 6 increases were observed beyond 6 months of treatment. None was associated with an elevated bilirubin concentration.
Lipids
Triglycerides were increased above the upper limit of normal in 12% of the endometriosis patients who received LUPRON DEPOT 3.75 mg and in 32% of the subjects receiving LUPRON DEPOT 11.25 mg.
Of those endometriosis and uterine fibroid patients whose pretreatment cholesterol values were in the normal range, mean change following therapy was +16 mg/dL to +17 mg/dL in endometriosis patients and +11 mg/dL to +29 mg/dL in uterine fibroid patients. In the endometriosis patients, increases from the pretreatment values were statistically significant (p<0.03). There was essentially no increase in the LDL/HDL ratio in patients from either population receiving LUPRON DEPOT 3.75 mg.
Percent changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the normal range in the two studies of leuprolide acetate and norethindrone acetate are summarized in the tables below. The major impact of adding norethindrone acetate to treatment with LUPRON DEPOT was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio.
Table 5: Serum Lipids: Mean Percent Changes From Baseline Values at Treatment Week 24
| LUPRON DEPOT 3.75 mg | LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily | |||||
| Controlled Study (n=39) |
Controlled Study (n=41) |
Open Label Study (n=117) |
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| Baseline Value* | Wk 24 % Change | Baseline Value* | Wk 24 % Change | Baseline Value* | Wk 24 % Change | |
| Total Cholesterol | 170.5 | 9.2% | 179.3 | 0.2% | 181.2 | 2.8% |
| HDL Cholesterol | 52.4 | 7.4% | 51.8 | -18.8% | 51.0 | -14.6% |
| LDL Cholesterol | 96.6 | 10.9% | 101.5 | 14.1% | 109.1 | 13.1% |
| LDL/HDL Ratio | 2.0† | 5.0% | 2.1† | 43.4% | 2.3† | 39.4% |
| Triglycerides | 107.8 | 17.5% | 130.2 | 9.5% | 105.4 | 13.8% |
| * mg/dL † ratio |
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Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients with follow up data returned to pretreatment values.
Table 6: Percentage of Patients with Serum Lipids Values Outside of the Normal Range
| LUPRON DEPOT 3.75 mg | LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily | |||||
| Controlled Study (n=39) |
Controlled Study (n=41) |
Open Label Study (n=117) |
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| Wk 0 | Wk 24* | Wk 0 | Wk 24* | Wk 0 | Wk 24* | |
| Total Cholesterol (>240 mg/dL) | 15% | 23% | 15% | 20% | 6% | 7% |
| HDL Cholesterol (<40 mg/dL) | 15% | 10% | 15% | 44% | 15% | 41% |
| LDL Cholesterol (>160 mg/dL) | 0% | 8% | 5% | 7% | 9% | 11% |
| LDL/HDL Ratio (>4.0) | 0% | 3% | 2% | 15% | 7% | 21% |
| Triglycerides (>200 mg/dL) | 13% | 13% | 12% | 10% | 5% | 9% |
| * Includes all patients regardless of baseline value. | ||||||
Postmarketing Experience
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 with other dosage forms and in the same or different populations, the following adverse reactions were reported:
- Allergic reactions (anaphylactic, rash, urticaria, and photosensitivity reactions)
- Mood swings, including depression
- Suicidal ideation and attempt
- Symptoms consistent with an anaphylactoid or asthmatic process
- Localized reactions including induration and abscess at the site of injection
- Symptoms consistent with fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath), individually and collectively
Other adverse reactions reported are:
Hepato-biliary disorder –Serious liver injury
Injury, poisoning and procedural complications –Spinal fracture
Investigations –Decreased white blood count
Musculoskeletal and connective tissue disorder –Tenosynovitis-like symptoms
Nervous System disorder –Convulsion, peripheral neuropathy, paralysis
Vascular disorder –Hypotension, Hypertension
Serious venous and arterial thrombotic and thromboembolic reactions have been reported, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack
Pituitary Apoplexy
During post-marketing 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.
SRC: NLM .