Lupaneta Pack 3.75 mg: Indications, Dosage, Precautions, Adverse Effects
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Lupaneta Pack 3.75 mg - Product Information

Manufacture: AbbVie
Country: United States
Condition: Endometriosis
Class: Sex hormone combinations
Form: Intramuscular (IM), Tablets, Powder
Ingredients: leuprolide acetate, gelatin, DL-lactic and glycolic acids copolymer, D-mannitol, carboxymethylcellulose sodium, polysorbate 80, water for injection, USP, glacial acetic acid, norethindrone acetate USP, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc.

Indications and Usage

LUPANETA PACK (leuprolide acetate for depot suspension and norethindrone acetate tablets) is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms.

Limitation of Use: Duration of use is limited due to concerns about adverse impact on bone mineral density [see Warnings and Precautions]. The initial treatment course of LUPANETA PACK is limited to six months. A single retreatment course of not more than six months may be administered after the initial course of treatment if symptoms recur. Use of LUPANETA PACK for longer than a total of 12 months is not recommended.

Dosage and Administration

Dosing Information

LUPANETA PACK is a co-packaging of leuprolide acetate for depot suspension for intramuscular use and norethindrone acetate tablets for oral use. Administer as follows:

  • 3.75 mg of leuprolide acetate by intramuscular injection once a month for up to six injections (6 months of therapy); to be administered by a healthcare provider
  • 5 mg of norethindrone acetate orally once daily for up to 6 months of therapy

The initial course of treatment with leuprolide acetate for depot suspension 3.75 mg in combination with norethindrone acetate 5 mg daily is not to exceed six months.

If the symptoms of endometriosis recur after the initial course of therapy, consider retreatment with LUPANETA PACK for up to another six months. It is recommended that bone density be assessed before retreatment begins [see Warnings and Precautions].

Treatment beyond two six-month courses has not been studied and is not recommended due to concerns about adverse impact on bone mineral density.

Different Formulations of Leuprolide Acetate

Due to the specific release characteristics of the 1-month depot formulation, HCPs should not administer 3 doses of the 3.75 mg 1-month formulation simultaneously to mimic the pharmacological profile of the 11.25 mg 3-month formulation.

Reconstitution and Administration for Injection of Leuprolide Acetate

  • Reconstitute and administer the lyophilized microspheres as a single intramuscular injection.
  • Inject the suspension immediately or discard if not used within two hours, because leuprolide acetate for depot suspension does not contain a preservative.
  1. Visually inspect the leuprolide acetate for depot suspension powder. DO NOT USE the syringe if clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal prior to mixing with the diluent. The diluent should appear clear.
  2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn (see Figure 1 and Figure 2).

    Figure 1:

    Figure 2:

    white plunger

  3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first middle stopper is at the blue line in the middle of the barrel (see Figure 3).

    Figure 3:

    blue line

  4. Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking the syringe until the powder forms a uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into suspension (see Figure 4).

    Figure 4:

    syringe upright

  5. Keep the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting.
  6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the syringe is ready for injection.
  7. After cleaning the injection site with an alcohol swab, administer the intramuscular injection by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid (see Figure 5). Alternate injection sites.

    Figure 5:

    injection to the body

    NOTE: If a blood vessel is accidentally penetrated, aspirated blood will be visible just below the luer lock (see Figure 6) and can be seen through the transparent LuproLoc safety device. If blood is present, remove the needle immediately. Do not inject the medication.

    Figure 6:

    blood in syringe with text

  8. Inject the entire contents of the syringe intramuscularly.
  9. Withdraw the needle. Once the syringe has been withdrawn, immediately activate the LuproLoc safety device by pushing the arrow on the lock upward towards the needle tip with the thumb or finger, as illustrated, until the needle cover of the safety device over the needle is fully extended and a CLICK is heard or felt (see Figure 7).

    Figure 7:

    three syringe photo

  10. Dispose of the syringe according to local regulations/procedures [see References].

Dosage Forms and Strengths

LUPANETA PACK 1-month copackaged kit contains two separate components:

  • Leuprolide acetate for depot suspension 3.75 mg for 1-month administration: Leuprolide acetate lyophilized powder for reconstitution with supplied diluent in a prefilled dual chamber syringe
  • Norethindrone acetate 5 mg tablets: White to off-white oval, flat-faced beveled edged, uncoated debossed with ‘G with breakline’ on one side and 304 on other side

Contraindications

LUPANETA PACK is contraindicated in women with the following:

  • Hypersensitivity to gonadotropin-releasing hormone (GnRH), GnRH agonist analogs, any of the excipients in leuprolide acetate for depot suspension, or norethindrone acetate
  • Undiagnosed abnormal uterine bleeding
  • Known, suspected or planned pregnancy during the course of therapy [see Use in Specific Populations]
  • Lactating women [see Use in Specific Populations]
  • Known, suspected or history of breast cancer or other hormone-sensitive cancer
  • Current or history of thrombotic or thromboembolic disorder
  • Liver tumors or liver disease

Warnings and Precautions

Loss of Bone Mineral Density

Leuprolide acetate for depot suspension induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible. Concurrent use of norethindrone acetate is effective in reducing the loss of BMD that occurs with leuprolide acetate [see Clinical Studies]. Nonetheless, duration of use of LUPANETA PACK is limited to two six-month courses of treatment due to concerns about the adverse impact on BMD. It is recommended that BMD be assessed before retreatment. Retreatment with leuprolide acetate for depot suspension alone is not recommended.

In women with major risk factors for decreased BMD such as chronic alcohol (> 3 units per day) or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD, such as anticonvulsants or corticosteroids, use of LUPANETA PACK may pose an additional risk, and the risks and benefits should be weighed carefully.

Pregnancy Risk

Leuprolide acetate for depot suspension may cause fetal harm if administered to a pregnant woman. Exclude pregnancy before initiating treatment with LUPANETA PACK. When used at the recommended dose and dosing interval, leuprolide acetate for depot suspension usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking leuprolide acetate for depot suspension. Therefore, patients should use nonhormonal methods of contraception. Advise patients to notify their healthcare provider if they believe they may be pregnant. Discontinue LUPANETA PACK if a patient becomes pregnant during treatment and inform the patient of potential risk to the fetus [see Contraindications (4) and Use in Specific Populations (8.1)].

Visual Abnormalities

Discontinue norethindrone acetate tablets in the LUPANETA PACK pending examination if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. Discontinue LUPANETA PACK if examination reveals papilledema or retinal vascular lesions.

Clinical Depression

Depression may occur or worsen during treatment with LUPANETA PACK. Carefully observe patients with a history of clinical depression and discontinue LUPANETA PACK if the depression recurs to a serious degree.

Serious Allergic Reactions

In clinical trials of LUPANETA PACK, 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.

Cardiovascular and Metabolic Disorders

Assess and manage risk factors for cardiovascular disease before starting LUPANETA PACK. Closely monitor women on norethindrone acetate who have risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., family history of VTE, obesity, and smoking) when using LUPANETA PACK. [see Contraindications].

Initial Flare of Symptoms

Following the first dose of leuprolide acetate, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in symptoms associated with endometriosis may be observed during the initial days of therapy, but these should dissipate with continued therapy.

Fluid Retention

Because norethindrone acetate may cause some degree of fluid retention, carefully observe women with conditions that might be influenced by this effect, such as epilepsy, migraine, cardiac or renal dysfunctions.

Convulsions

There have been postmarketing reports of convulsions in patients on leuprolide acetate therapy. These included patients with and without concurrent medications and comorbid conditions.

Adverse Reactions

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
 Controlled StudyOpen Label Study
LA-Only*LA/NLA/N
N=51N=55N=136
Adverse ReactionsN%N%N%
Any Adverse Reaction5098539612693
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
Metabolic and Nutritional Disorders
 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

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 VisitTreatment GroupNumber of Patients Reporting Hot FlashesNumber of Days with Hot FlashesMaximum Number of Hot Flashes in 24 Hours
 N(%)N2MeanN2Mean
Week 24LA-Only*32/37863719365.8
 LA/N22/385813871381.91

* LA-Only = leuprolide acetate 3.75 mg

LA/N = leuprolide acetate 3.75 mg plus norethindrone acetate 5 mg

1 Statistically significantly less than the LA-Only group (p<0.01)

2 Number of patients assessed.

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 mgleuprolide 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)
Baseline
Value*
Wk 24%
Change
Baseline
Value*
Wk 24%
Change
Baseline
Value*
Wk 24%
Change
Total Cholesterol170.59.2%179.30.2%181.22.8%
HDL Cholesterol52.47.4%51.8-18.8%51.0-14.6%
LDL Cholesterol96.610.9%101.514.1%109.113.1%
LDL/HDL Ratio2.05.0%2.143.4%2.339.4%
Triglycerides107.817.5%130.29.5%105.413.8%

* mg/dL

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.

Table 4. Percent of Patients with Serum Lipid Values Outside of the Normal Range
 leuprolide acetate for depot suspension 3.75 mg plus norethindrone acetate 5 mg daily
Controlled Study
(n=41)
Open Label Study
(n=117)
BaselineWk 24*BaselineWk 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.

Drug Interactions

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].

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.

Use in Specific Populations

Pregnancy

Pregnancy Category X – [See Contraindications]

Teratogenic Effects

LUPANETA PACK is contraindicated in women who are or may become pregnant while receiving the drug [see Contraindications]. Before starting and during treatment with leuprolide acetate for depot suspension, establish whether the patient is pregnant. Leuprolide acetate for depot suspension is not a contraceptive. In reproductively capable women, a non-hormonal method of contraception should be used [see Warnings and Precautions].

Leuprolide acetate for depot suspension may cause fetal harm when administered to a pregnant woman.

When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, leuprolide acetate for depot suspension 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 leuprolide acetate for depot suspension in rabbits and with the highest dose (0.024 mg/kg) in rats.

Nursing Mothers

Do not use LUPANETA PACK in nursing mothers because the effects of leuprolide acetate for depot suspension on lactation and/or the breast-fed child have not been determined.

It is not known whether leuprolide acetate for depot suspension is excreted in human milk.

Detectable amounts of progestins have been identified in the milk of mothers receiving them [see Contraindications].

Pediatric Use

LUPANETA PACK is not indicated in premenarcheal adolescents. Safety and effectiveness of LUPANETA PACK have not been established in pediatric patients. Experience with LUPANETA PACK for treatment of endometriosis has been limited to women 18 years of age and older.

Geriatric Use

LUPANETA PACK is not indicated in postmenopausal women and has not been studied in women over 65 years of age.

How Supplied/Storage and Handling

LUPANETA PACK for 1-month copackaged kit (NDC 0074-1052-05) is available in

cartons containing: leuprolide acetate for depot suspension 3.75 mg for 1-month

administration Kit (NDC 0074-3641-04)

norethindrone acetate 5 mg tablets; 30 count bottle (NDC 0074-1049-02)

  1. Leuprolide acetate for depot suspension 3.75 mg for 1-month administration kit contains:
    • one prefilled dual-chamber syringe
    • one plunger
    • two alcohol swab

    Each syringe contains sterile lyophilized microspheres of leuprolide acetate incorporated in a biodegradable copolymer of lactic and glycolic acids. When mixed with diluent, leuprolide acetate for depot suspension 3.75 mg for 1-month administration is administered as a single intramuscular injection.

  2. Norethindrone acetate 5 mg 30 count bottle

    White to off-white oval, flat faced beveled edged, uncoated tablets debossed with ‘G with breakline’ on one side and 304 on other side.

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature]

Patient Counseling Information

See FDA-approved patient labeling (Patient Information)

Counsel patients about the Warnings and Precautions for LUPANETA PACK, including:

  • Do not use this drug if they have experienced an allergic reaction to GnRH agonists or progestins
  • Do not use this drug if they are pregnant or planning a pregnancy, suspect they may be pregnant, or are breastfeeding
  • Risk of loss of bone mineral density and limitation of treatment to two six-month courses of treatment
  • Risk to an exposed fetus and need to use nonhormonal contraception
  • Discontinue norethindrone if they develop sudden loss of vision, double vision or sudden migraine
  • The possibility of development or worsening of depression during treatment with leuprolide acetate for depot suspension
  • Need for close monitoring if they have cardiovascular risk factors, or conditions like epilepsy, migraine or renal dysfunction
  • Notify their healthcare provider if they develop new or worsened symptoms after beginning treatment

Leuprolide Acetate for Depot Suspension 3.75 mg

Manufactured For

AbbVie Inc.

North Chicago, IL 60064

by Takeda Pharmaceutical Company Limited

Osaka, Japan 540–8645

Norethindrone Acetate

Manufactured For

AbbVie Inc.

North Chicago, IL 60064

Manufactured By

Glenmark Pharmaceuticals Ltd.

Colvale-Bardez, Goa

403 513, India

Lupaneta Pack

Packaged By

AbbVie Inc.

North Chicago, IL 60064

Revised 6/2015