Version May 2024
Note: Lupaneta Pack has been discontinued in the United States for >1 year.
Endometriosis: Note: Treatment consists of an oral norethindrone tablet used in conjunction with an IM leuprolide injection. The initial therapy should be limited to 6 months duration; a single re-treatment of not more than 6 additional months may be administered if symptoms recur. Maximum total duration of therapy is 12 months. Due to the specific release characteristics, the 1-month and 3-month depot formulations are not equivalent and cannot be substituted for one another
1 month:
Injection: IM: Leuprolide 3.75 mg as a single dose administered by healthcare provider once every month for up to 6 doses (maximum initial therapy: 6 months; maximum cumulative therapy: 12 months).
Tablet: Oral: Norethindrone 5 mg once daily for up to 6 months (maximum initial therapy: 6 months; maximum cumulative therapy: 12 months).
3 month:
Injection: IM: Leuprolide 11.25 mg as a single dose administered by healthcare provider once every 3 months for up to 2 doses (maximum initial therapy: 6 months; maximum cumulative therapy: 12 months).
Tablet: Oral: Norethindrone 5 mg once daily for up to 6 months (maximum initial therapy: 6 months; maximum cumulative therapy: 12 months).
No dosage adjustment provided in manufacturer's labeling (has not been studied).
No dosage adjustment provided in manufacturer's labeling (has not been studied). Use is contraindicated with hepatic tumors or disease.
Not for use in postmenopausal patients.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults. Also see individual agents.
>10%:
Dermatologic: Acne vulgaris (≤18%), alopecia (≤18%), dermatological reaction (≤11%), diaphoresis (≤87%)
Endocrine & metabolic: Decreased HDL cholesterol (41% to 44%), hot flash (≤87%), hypercholesterolemia (7% to 20%), increased LDL cholesterol (7% to 11%), weight gain (4% to 13%)
Gastrointestinal: Constipation (≤15%), diarrhea (≤15%), mucous membrane abnormality (≤11%), nausea and vomiting (13% to 29%)
Genitourinary: Breast changes (≤13%), breast tenderness (≤13%), mastalgia (≤13%), vaginitis (8% to 15%)
Nervous system: Anxiety (≤11%), asthenia (11% to 18%), depression (≤34%), dizziness (≤11%), emotional lability (≤34%), headache (≤51%), insomnia (≤15%), migraine (≤51%), nervousness (≤11%), pain (21% to 29%), sleep disturbance (≤15%), vertigo (≤11%)
1% to 10%:
Cardiovascular: Edema (7% to 9%)
Endocrine & metabolic: Decreased libido (4% to 7%), increased serum triglycerides (9% to 10%), menstrual disease (5%)
Gastrointestinal: Change in appetite (6%), dyspepsia (≤7%), flatulence (≤7%)
Genitourinary: Urinary tract infection (2%)
Hepatic: Increased gamma-glutamyl transferase (1%), increased serum alanine aminotransferase (≥2 × ULN: 2%)
Local: Injection-site reaction (3% to 9%)
Nervous system: Memory impairment (2% to 4%), paresthesia (≤9%)
Neuromuscular & skeletal: Lower limb cramp (≤9%)
<1%: Renal: Nephrolithiasis
Postmarketing:
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, nonimmune anaphylaxis)
Respiratory: Asthma
Hypersensitivity to leuprolide, gonadotropin-releasing hormone (GnRH), GnRH-agonist analogs, norethindrone acetate, or any component of the formulation; undiagnosed abnormal uterine bleeding; breast cancer or other hormone-dependent neoplasms (current or a history of); hepatic tumors or disease; thrombotic or thromboembolic disorder (current or history of); pregnancy.
Concerns related to adverse effects:
• Allergic reactions: Anaphylactoid reactions and asthma exacerbations have been reported with therapy in patients with histories of asthma, sinusitis, or environmental or drug allergies.
• Decreased bone density: Leuprolide depot suspension may cause an irreversible loss in bone mineral density (BMD). Norethindrone reduces this loss; however, use of this combination should be limited in duration. The initial therapy should be limited to 6 months duration; a single re-treatment of not more than 6 additional months may be administered if symptoms recur. BMD should be measured prior to re-treatment. Maximum total duration of therapy is 12 months. Use caution in patients with additional risk factors for bone loss (eg, chronic alcohol or tobacco use, strong family history of osteoporosis, chronic use of medications that may decrease BMD such as corticosteroid therapy).
• Endometriosis: Due to the physiologic effects of the drug, exacerbation of endometriosis symptoms may occur after the first dose of leuprolide.
• Seizures: Convulsions have been observed with leuprolide in postmarketing reports in patients with and without concurrent medications and comorbid conditions.
• Visual disturbances: Discontinue norethindrone pending examination if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue this combination permanently if papilledema or retinal vascular lesions are observed on examination.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with risk factors for arterial disease or venous thromboembolism (VTE) (eg, hypertension, hypercholesterolemia, obesity, diabetes, family history of VTE, or patients who smoke). Manage risk factors prior to therapy; monitor closely.
• Depression: Use with caution in patients with depression. Depression may occur or worsen during therapy; discontinue if serious depression recurs.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes, or cardiac or renal dysfunction.
Special populations:
• Older adult: Not for post menopause.
• Pediatric patients: Not for use prior to menarche.
Dosage form specific issues:
• Injection: Due to differing release characteristics, the 1-month and 3-month depot formulations of leuprolide are not equivalent and cannot be substituted for one another.
Lupaneta Pack has been discontinued in the United States for >1 year.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Kit, Combination:
Lupaneta Pack: 1-month kit: leuprolide acetate 3.75 mg depot suspension for injection (1) and norethindrone acetate 5 mg oral tablets (30) [DSC], 3-month kit: leuprolide acetate 11.25 mg depot suspension for injection (1) and norethindrone acetate 5 mg oral tablets (90) [DSC] [contains polysorbate 80]
No
Kit (Lupaneta Pack Combination)
3.75 & 5 mg (per each): $1,779.83
11.25 & 5 mg (per each): $5,339.53
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
IM: Leuprolide: Administer IM in the gluteal area, anterior thigh, or deltoid. Alternate injection sites. Do not use if a blood vessel is accidently penetrated (will be able to see aspirated blood below the transparent luer lock).
Oral: Tablet: Norethindrone: Administer orally.
Hazardous agent (NIOSH 2016 [groups 1 and 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules. Double gloving and a protective gown are recommending during IM administration (NIOSH 2016).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Lupaneta Pack: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/203696s005s006lbl.pdf#page=30
Endometriosis: Management of initial and recurrent painful symptoms of endometriosis
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Choline C 11: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Corifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Leuprolide and Norethindrone. Specifically, norethindrone concentrations may be decreased. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Leuprolide and Norethindrone. Specifically, concentrations of norethindrone may increase. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flotufolastat F18: Androgen Deprivation Therapy Agents may diminish the diagnostic effect of Flotufolastat F18. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of flotufolastat F18 in prostate cancer. The impact of ADT on the performance of flotufolastat F18 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gallium Ga 68 PSMA-11: Androgen Deprivation Therapy Agents may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact of ADT on the performance of gallium Ga 68 PSMA-11 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Piflufolastat F18: Androgen Deprivation Therapy Agents may diminish the diagnostic effect of Piflufolastat F18. Management: Androgen deprivation therapy (ADT) may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of ADT on the performance of piflufolastat F18 is unknown, but use of alternative agents should be considered. Risk D: Consider therapy modification
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Pregnancy must be excluded prior to the start of treatment. Although leuprolide usually inhibits ovulation and stops menstruation, contraception is not ensured and a nonhormonal contraceptive should be used during therapy.
Fertility suppression observed with other leuprolide formulations is reversible following discontinuation of therapy. This formulation is indicated to treat pain associated with endometriosis; in infertile patients with endometriosis, it does not necessarily improve the ability to conceive (ACOG 2010; Practice Committee ASRM 2012).
Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to leuprolide and norethindrone may cause fetal harm.
Use is contraindicated in patients who are pregnant; discontinue if pregnancy occurs during treatment.
Also refer to individual monographs for additional information.
It is not known if leuprolide is present in breast milk. Small amounts of progestins can be detected in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Also refer to individual monographs.
In clinical trials, patients were given supplemental elemental calcium 1 g/day.
Pregnancy test (prior to therapy); bone mineral density (prior to re-treatment); endometrial-related pain; serum lipids; signs of depression.
Leuprolide administration inhibits the production of estrogen through negative feedback of pituitary gonadotropins. This in turn decreases endometrial implants and symptoms of endometriosis such as pain. Norethindrone is used to decrease adverse events observed with the hypoestrogenic state caused by leuprolide and possibly mitigate bone mineral density loss (Surrey, 2010).
See individual monographs.
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