Lupaneta Pack

You should not use this medication if you are allergic to leuprolide or norethindrone, or if you have:

• abnormal vaginal bleeding that has not been checked by a doctor;

• past or present hormone-related cancer such as breast or uterine cancer;

• uncontrolled or untreated high blood pressure;

• heart disease (coronary artery disease, heart valve disorder, history of heart attack, stroke, or blood clot);

• a blood-clotting disorder or circulation problems;

• liver disease or liver cancer; or

• if you are pregnant or breast-feeding.

You may need to have a negative pregnancy test before starting this treatment.

To make sure leuprolide and norethindrone is safe for you, tell your doctor if you have:

• risk factors for coronary artery disease (such as diabetes, menopause, smoking, being overweight, having high blood pressure or high cholesterol, having a family history of coronary artery disease, history of hysterectomy);

• low bone mineral density (or risk factors such as smoking, drinking more than 3 alcoholic beverages per day, having a family history of osteoporosis, or long-term use of certain medicines);

• epilepsy;

• migraine headaches;

• kidney disease;

• a history of depression; or

• if you may become pregnant.

FDA pregnancy category X. Leuprolide can harm an unborn baby or cause birth defects. Do not use if you are pregnant. Stop taking the norethindrone tablets and tell your doctor right away if you become pregnant during treatment.

Leuprolide is likely to cause you not to ovulate or have menstrual periods during the 6-month treatment period. However, you may still be able to get pregnant.

Use an intrauterine device (IUD) or a barrier form of birth control (condom or diaphragm with spermicide). Hormonal contraception (birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

It is not known whether leuprolide and norethindrone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not give norethindrone to anyone under 18 years old without medical advice.

Take the missed norethindrone dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Call your doctor for instructions if you miss an appointment for your leuprolide injection.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with leuprolide and norethindrone, especially:

• seizure medication; or

• steroids (prednisone and others).

Other drugs may interact with leuprolide and norethindrone, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

In the U.S.

• Lupaneta Pack

Available Dosage Forms:

• Powder for Suspension, 3 Month
• Tablet
• Powder for Suspension, 1 Month

• It is used to treat endometriosis.
• It may be given to you for other reasons. Talk with the doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Lupaneta Pack or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Lupaneta Pack. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

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.

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.

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.

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.

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.

7.1 Drug-Drug Interactions

Leuprolide Acetate for Depot Suspension

No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprolide acetate for depot suspension. However, drug interactions associated with cytochrome P-450 enzymes or protein binding would not be expected to occur [see Clinical Pharmacology (12.3)].

Norethindrone Acetate

No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate have been conducted. Drugs or herbal products that induce or inhibit certain enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone.

Drug/Laboratory Test Interactions

Leuprolide Acetate for Depot Suspension

Administration of leuprolide acetate for depot suspension in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored within three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three months after discontinuation of leuprolide acetate for depot suspension may be affected.

Applies to leuprolide / norethindrone: oral and injectable kit

General

The most common adverse reactions leading to discontinuation of therapy included hot flashes (4%), emotional lability (4%), depression (4%) and acne (2%).
The most common adverse reaction observed were hot flashes and headaches.[Ref]

Cardiovascular

Leuprolide-Norethindrone:
Very common (10% or more): Hot flashes/sweats (up to 87%)

Leuprolide:
Very common (10% or more): Hot flashes/sweats (98%)
Postmarketing reports: Hypotension, hypertension, serious venous and arterial thrombotic and thromboembolic events (deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, transient ischemic attack[Ref]

Dermatologic

Leuprolide-Norethindrone:
Very common (10% or more): Androgen-like effects (acne, alopecia) (up to 18%), skin/mucous membrane reaction (up to 11%)

Leuprolide:
Common (1% to 10%): Androgen-like effects (acne, alopecia) (4%), skin/mucous membrane reaction (4%)[Ref]

Gastrointestinal

Leuprolide-Norethindrone:
Very common (10% or more): Altered bowel function (constipation, diarrhea) (up to 15%), nausea/vomiting (up to 29%)
Common (1% to 10%): GI disturbances (dyspepsia, flatulence) (up to 7%), changes in appetite (6%)

Leuprolide:
Very common (10% or more): Nausea/vomiting (25%), altered bowel function (constipation, diarrhea) (14%)
Common (1% to 10%): Changes in appetite (4%)%), GI disturbances (dyspepsia, flatulence) (4%)[Ref]

Genitourinary

Leuprolide-Norethindrone:
Very common (10% or more): Vaginitis (up to 15%%), breast changes/pain/tenderness (up to 13%)
Common (1% to 10%): Menstrual disorders (5%)
Frequency not reported: Urinary tract infection

Leuprolide:
Very common (10% or more): Vaginitis (20%)
Common (1% to 10%): Breast changes/pain/tenderness (6%), menstrual disorders (2%)[Ref]

Hematologic

Leuprolide:
Postmarketing reports: Decreased white blood count[Ref]

Hepatic

Leuprolide:
Postmarketing reports: Serious liver injury
Leuprolide-Norethindrone:
Common (1% to 10%): Elevated SGPT (at least twice the upper limit) (2%), elevated GGT (1.5%)[Ref]

Hypersensitivity

Leuprolide-Norethindrone:
Postmarketing reports: Allergic reactions (anaphylactic, rash, urticaria, photosensitivity)[Ref]

Local

Leuprolide-Norethindrone:
Common (1% to 10%): Injection site reaction (up to 9%)

Leuprolide:
Common (1% to 10%): Injection site reaction (2%)
Postmarketing reports: Localized reactions including induration and abscess at the site of injection[Ref]

Metabolic

Leuprolide-Norethindrone:
Very common (10% or more): Weight gain (up to 13%)
Common (1% to 10%): Edema (up to 9%), elevated SGPT (at least twice the upper limit) (2%), elevated GGT (1.5%)
Frequency not reported: Increased total cholesterol (greater than 240 mg/dL), decreased HDL cholesterol (less than 40 mg/dL), increased LDL cholesterol (greater than 160 mg/dL), increased LDL/HDL ratio (greater than 4), increased triglycerides (greater than 200 mg/dL)

Leuprolide:
Common (1% to 10%): Weight gain (12%)[Ref]

Musculoskeletal

Leuprolide:
Postmarketing reports: Spinal fracture, tenosynovitis-like symptoms, symptoms consistent with fibromyalgia[Ref]

Nervous system

Leuprolide-Norethindrone:
Very common (10% or more): Headache/migraine (up to 51%), insomnia/sleep disorders (up to 15%), dizziness/vertigo (up to 11%)
Common (1% to 10%): Neuromuscular disorder (leg cramps, paresthesia) (up to 9%), decreased libido (up to 7%), memory disorder (up to 4%)

Leuprolide:
Very common (10% or more): Headache/migraine (65%), insomnia/sleep disorders (31%), dizziness/vertigo (16%), decreased libido (10%)
Common (1% to 10%): Memory disorder (6%), neuromuscular disorder (leg cramps, paresthesia) (2%)
Postmarketing reports: Pituitary apoplexy, convulsion, peripheral neuropathy, paralysis[Ref]

Other

Leuprolide-Norethindrone:
Very common (10% or more): Pain (up to 29%), asthenia (up to 18%)

Leuprolide:
Very common (10% or more): Pain (24%), asthenia (18%)

Psychiatric

Leuprolide-Norethindrone:
Very common (10% or more): Depression/emotional lability (up to 34%), nervousness/anxiety (up to 11%)

Leuprolide:
Very common (10% or more): Depression/emotional lability (31%)
Common (1% to 10%): Nervousness/anxiety (8%)
Postmarketing reports: Mood swings, suicidal ideation and attempt[Ref]

Renal

Leuprolide-Norethindrone:
Frequency not reported: Renal calculus[Ref]

Respiratory

Leuprolide:
Postmarketing reports: Symptoms consistent with an asthmatic process[Ref]

Some side effects of Lupaneta Pack may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.