Leuprolide and norethindrone

This medication is a combined treatment that includes a leuprolide injection and norethindrone tablets taken by mouth.

Leuprolide is usually given as a single injection into a muscle every 3 months for up to 6 months. Norethindrone tablets are taken every day for 3 months after your leuprolide injection.

A healthcare provider will give you the leuprolide injection. You will take the norethindrone tablets at home.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Store norethindrone tablets at room temperature away from moisture and heat.

You may need frequent medical tests to help your doctor determine how long to treat you with leuprolide and norethindrone.

Leuprolide can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using leuprolide and norethindrone.

Call your doctor at once if your endometriosis symptoms get worse when you start using this medication.

Based on your response to leuprolide and norethindrone treatment, your doctor may want you to have a second 6-month treatment.

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.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

Leuprolide:

• It is given as a shot into a muscle.

Norethindrone:

• Take with or without food. Take with food if it causes an upset stomach.

What do I do if I miss a dose?

Leuprolide:

• Call your doctor to find out what to do.

Norethindrone:

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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.

Endometriosis: Females: 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.

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)

Pregnancy test (prior to therapy); bone mineral density (prior to re-treatment); endometrial-related pain; serum lipids

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 leuprolide / norethindrone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Leuprolide: Data not available

Norethindrone: Mild to moderate liver dysfunction: Data not available.
Norethindrone: Contraindicated in markedly impaired liver function or disease.

Consult WARNINGS section for dosing related precautions.

Leuprolide administered to animals at 1/300 to 1/3 of the human dose on day 6 of pregnancy produced a dose-related increase in major fetal abnormalities. Increased fetal mortality and decreased fetal weights with higher doses of leuprolide (highest dose being 0.024 mg/kg) were also seen in animals. There are no controlled data in human pregnancy. FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

FDA pregnancy category: X Use of Leuprolide-norethindrone is contraindicated. Comments: Since contraception is not ensured by taking leuprolide-norethindrone, patients should use a nonhormonal method of contraception during treatment.