LUPANETA PACK SIDE EFFECTS
- Generic Name: lupaneta pack leuprolide acetate for depot suspension; norethindrone acetate tablets
- Brand Name: Lupaneta Pack
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.
The safety of co-administering leuprolide acetate for depot suspension and norethindrone acetate was evaluated in two clinical studies in which a total of 242 women 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) and 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 leuprolide acetate for depot suspension alone or with leuprolide acetate for depot suspension and norethindrone acetate. The other study was an open-label single arm clinical study in 136 women of one year of treatment with leuprolide acetate for depot suspension and 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 leuprolide acetate and 18% of patients treated monthly with leuprolide acetate plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly hot flashes (6%) and insomnia (4%) in the leuprolide acetate alone group and hot flashes and emotional lability (4% each) in the leuprolide acetate and norethindrone group.
In the open label study, 13% of patients treated monthly with leuprolide acetate plus norethindrone acetate discontinued therapy due to adverse reactions, most commonly depression (4%) and acne (2%).
Common Adverse Reactions
Table 1 lists the adverse reactions observed in at least 5% of patients in any treatment group, during the first 6 months of treatment in the add-back clinical studies, in which patients were treated with monthly leuprolide acetate for depot suspension 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 1: Adverse Reactions Occurring in the First Six Months of Treatment in ≥ 5% of Patients with Endometriosis
| Adverse Reactions | Controlled Study | Open Label Study | ||||
| LA-Only* N=51 |
LA/N† N=55 |
LA/N† N=136 |
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| N | % | N | % | N | % | |
| Any Adverse Reaction | 50 | 98 | 53 | 96 | 126 | 93 |
| Body as a Whole | ||||||
| Asthenia | 18 | 18 | 11 | |||
| Headache/Migraine | 65 | 51 | 46 | |||
| Injection Site Reaction | 2 | 9 | 3 | |||
| Pain | 24 | 29 | 21 | |||
| Cardiovascular System | ||||||
| Hot flashes/Sweats | 98 | 87 | 57 | |||
| Digestive System | ||||||
| Altered Bowel Function (constipation, diarrhea) | 14 | 15 | 10 | |||
| Changes in Appetite | 4 | 0 | 6 | |||
| GI Disturbance (dyspepsia, flatulence) | 4 | 7 | 4 | |||
| Nausea/Vomiting | 25 | 29 | 13 | |||
| Edema | 0 | 9 | 7 | |||
| Weight Gain | 12 | 13 | 4 | |||
| Nervous System | ||||||
| Depression/Emotional Lability | 31 | 27 | 34 | |||
| Dizziness/Vertigo | 16 | 11 | 7 | |||
| Insomnia/Sleep Disorder | 31 | 13 | 15 | |||
| Decreased Libido | 10 | 4 | 7 | |||
| Memory Disorder | 6 | 2 | 4 | |||
| Nervousness/Anxiety | 8 | 4 | 11 | |||
| Neuromuscular Disorder (leg cramps, paresthesia) | 2 | 9 | 3 | |||
| Skin and Appendages | ||||||
| Androgen-Like Effects (acne, alopecia) | 4 | 5 | 18 | |||
| Skin/Mucous Membrane Reaction | 4 | 9 | 11 | |||
| Urogenital System | ||||||
| Breast Changes/Pain/Tenderness | 6 | 13 | 8 | |||
| Menstrual Disorders | 2 | 0 | 5 | |||
| Vaginitis | 20 | 15 | 8 | |||
| * LA-Only = leuprolide acetate 3.75 mg † LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg |
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In the controlled clinical trial, 50 of 51 (98%) patients in the leuprolide acetate alone group and 48 of 55 (87%) patients in the leuprolide acetate and norethindrone group reported experiencing hot flashes on one or more occasions during treatment. Table 2 presents hot flash data in the sixth month of treatment.
Table 2: 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 of Hot Flashes in 24 Hours | |||
| N | (%) | N2 | Mean | N2 | Mean | ||
| Week 24 | LA-Only* | 32/37 | 86 | 37 | 19 | 36 | 5.8 |
| LA/N† | 22/38 | 581 | 38 | 71 | 38 | 1.91 | |
| * LA-Only = leuprolide acetate 3.75 mg † LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg 1Statistically significantly less than the LA-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
In the two clinical trials of women with endometriosis, 4 of 191 patients receiving leuprolide acetate and 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
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 leuprolide acetate for depot suspension was a decrease in serum HDL cholesterol and an increase in the LDL/HDL ratio.
Table 3: Serum Lipids: Mean Percent Changes from Baseline Values at Treatment Week 24
| leuprolide acetate 3.75 mg | leuprolide acetate for depot suspension 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 (105 of 158 patients) returned to pretreatment values.
Table 4: Percent of Patients with Serum Lipid Values Outside of the Normal Range
| Controlled Study (n=41) |
Open Label Study (n=117) |
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| Baseline | Wk 24* | Baseline | Wk 24* | |
| Total Cholesterol (>240 mg/dL) | 15% | 20% | 6% | 7% |
| HDL Cholesterol (<40 mg/dL) | 15% | 44% | 15% | 41% |
| LDL Cholesterol (>160 mg/dL) | 5% | 7% | 9% | 11% |
| LDL/HDL Ratio (>4.0) | 2% | 15% | 7% | 21% |
| Triglycerides (>200 mg/dL) | 12% | 10% | 5% | 9% |
| *Includes all patients regardless of baseline value. | ||||
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of leuprolide acetate for depot suspension or norethindrone acetate. 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.
Leuprolide Acetate For Depot Suspension
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 events, 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 .