Lupron Depot

1.1 Endometriosis

Monotherapy

LUPRON DEPOT 11.25 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions.

In Combination with Norethindrone Acetate

LUPRON DEPOT 11.25 mg in combination with norethindrone acetate is indicated for initial management of the painful symptoms of endometriosis and for management of recurrence of symptoms.

Use of norethindrone acetate in combination with LUPRON DEPOT 11.25 mg is referred to as add-back therapy, and is intended to reduce the loss of bone mineral density (BMD) and reduce vasomotor symptoms associated with use of LUPRON DEPOT 11.25 mg.

Limitations of Use:

The total duration of therapy with LUPRON DEPOT 11.25 mg plus add-back therapy should not exceed 12 months due to concerns about adverse impact on bone mineral density [see Dosage and Administration ( 2.1) and Warnings and Precautions ( 5.1)].

1.2 Uterine Leiomyomata (Fibroids)

LUPRON DEPOT 11.25 mg, used concomitantly with iron therapy, is indicated for the preoperative hematologic improvement of women with anemia caused by fibroids for whom three months of hormonal suppression is deemed necessary.

Consider a one-month trial period on iron alone, as some women will respond to iron alone [see Clinical Studies ( 14.2)]. LUPRON DEPOT 11.25 mg may be added if the response to iron alone is considered inadequate.

Limitations of Use:

LUPRON DEPOT 11.25 mg is not indicated for combination use with norethindrone acetate add-back therapy for the preoperative hematologic improvement of women with anemia caused by heavy menstrual bleeding due to fibroids [see Dosage and Administration ( 2.1)]. 

2.1 Important Use Information

LUPRON DEPOT 11.25 mg must be administered by a healthcare professional.

LUPRON DEPOT 11.25 mg for 3-month administration has different release characteristics than LUPRON 3.75 mg for 1-month administration and is dosed differently.

• Do not substitute LUPRON DEPOT 11.25 mg for LUPRON DEPOT 3.75 mg.
  
• Do not administer LUPRON DEPOT 11.25 mg more frequently than every 3 months.
  
• Do not give a fractional dose of the LUPRON DEPOT 11.25 mg, as it is not equivalent to the same dose of the LUPRON DEPOT 3.75 mg monthly formulation.

Endometriosis

The initial and retreatment dosage regimens for LUPRON DEPOT 11.25 mg for the management of women with endometriosis are outlined in Table 1.

1May use LUPRON DEPOT 11.25 mg with or without norethindrone acetate 5 mg tablet taken daily.

2Use LUPRON DEPOT 11.25 mg with norethindrone acetate for retreatment 5 mg tablet taken daily [see Warnings and Precautions ( 5.1)] and assess bone mineral density (BMD) prior to retreatment.

3Treatment should not exceed 12 months due to concerns about adverse impact on bone mineral density.

Fibroids

The recommended dosage of LUPRON DEPOT 11.25 mg is one IM injection of 11.25 mg which provides a three-month treatment course.

2.2 Reconstitution and Administration for Injection of LUPRON DEPOT

• Reconstitute and administer the lyophilized microsphere as a single IM injection as directed below. Visually inspect the drug product for particulate matter and discoloration prior to administration, whenever solution and container permit.
  
• Inject the LUPRON DEPOT 11.25 mg suspension immediately or discard if not used within two hours as the suspension does not contain a preservative.

1. Visually inspect the LUPRON DEPOT 11.25 mg 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 A and Figure B).

Figure A:

Figure B:

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

Figure C:

4. Keep the syringe upright. Mix the microsphere 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 D).

Figure D:

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. The syringe is now ready for injection.

7. After cleaning the injection site with an alcohol swab, administer the IM injection by inserting the needle at a 90-degree angle into the gluteal area, anterior thigh, or deltoid. Injection sites should be alternated (see Figure E).

Figure E:

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

Figure F:

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 G).

Figure G:

10. Dispose of the syringe according to local regulations/procedures.

8.1 Pregnancy

Risk Summary

LUPRON DEPOT 11.25 mg is contraindicated in pregnancy [see Contraindications ( 4)].

LUPRON DEPOT 11.25 mg may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology ( 12.1)]. There are limited human data on the use of LUPRON DEPOT in pregnant women. Based on animal reproduction studies, LUPRON DEPOT 11.25 mg may be associated with an increased risk of pregnancy complications, including early pregnancy loss and fetal harm. In animal reproduction studies, subcutaneous administration of leuprolide acetate to rabbits during the period of organogenesis caused embryo-fetal toxicity, decreased fetal weights and a dose-dependent increase in major fetal abnormalities in animals at doses less than the recommended human dose based on body surface area using an estimated daily dose. A similar rat study also showed increased fetal mortality and decreased fetal weights but no major fetal abnormalities at doses less than the recommended human dose based on body surface area using an estimated daily dose [see Data].

Data

Animal Data

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

8.2 Lactation

Risk Summary

There are no data on the presence of leuprolide acetate in either animal or human milk, the effects on the breastfed infants, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LUPRON DEPOT 11.25 mg and any potential adverse effects on the breastfed infant from LUPRON DEPOT 11.25 mg or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Exclude pregnancy in women of reproductive potential prior to initiating LUPRON DEPOT 11.25 mg if clinically indicated [see Warnings and Precautions ( 5.2)].

Contraception

Females

LUPRON DEPOT 11.25 mg may cause embryo-fetal harm when administered during pregnancy. LUPRON DEPOT 11.25 mg is not a contraceptive. If contraception is indicated, advise females of reproductive potential to use a non-hormonal method of contraception during treatment with LUPRON DEPOT 11.25 mg [see Warnings and Precautions ( 5.2)].

Infertility

Based on its pharmacodynamic effects of decreasing secretion of gonadal steroids, fertility is expected to be decreased while on treatment with LUPRON DEPOT 11.25 mg. Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have shown reversibility of fertility suppression when the drug is discontinued after continuous administration for periods of up to 24 weeks [see Clinical Pharmacology ( 12.1)].

There is no evidence that pregnancy rates are affected following discontinuation of LUPRON DEPOT 11.25 mg.

Animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery of fertility suppression.

8.4 Pediatric Use

Safety and effectiveness of LUPRON DEPOT 11.25 mg for management of endometriosis and the preoperative hematologic improvement of women with anemia caused by fibroids have been established in females of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. The safety and effectiveness of LUPRON DEPOT 11.25 mg for these indications have not been established in premenarcheal pediatric patients.

8.5 Geriatric Use

LUPRON DEPOT 11.25 mg is not indicated in postmenopausal women and has not been studied in this population.

5.1 Loss of Bone Mineral Density

LUPRON DEPOT 11.25 mg induces a hypoestrogenic state that results in loss of bone mineral density (BMD), some of which may not be reversible after stopping treatment. In women with major risk factors for decreased BMD such as chronic alcohol use (> 3 units per day), tobacco use, strong family history of osteoporosis, or chronic use of drugs that can decrease BMD, such as anticonvulsants or corticosteroids, use of LUPRON DEPOT 11.25 mg may pose an additional risk. Carefully weigh the risks and benefits of LUPRON DEPOT 11.25 mg use in these populations.

The duration of LUPRON DEPOT 11.25 mg treatment is limited by the risk of loss of bone mineral density [see Dosage and Administration ( 2.1)].

When using LUPRON DEPOT 11.25 mg for the management of endometriosis, combination use of norethindrone acetate (add-back therapy) is effective in reducing the loss of BMD that occurs with leuprolide acetate [see Clinical Studies ( 14.2)]. Do not retreat with LUPRON DEPOT 11.25 mg without combination norethindrone acetate. Assess BMD before retreatment.

5.2 Embryo-Fetal Toxicity

Based on animal reproduction studies and the drug’s mechanism of action, LUPRON DEPOT 11.25 mg may cause fetal harm if administered to a pregnant woman and is contraindicated in pregnant women. Exclude pregnancy prior to initiating treatment with LUPRON DEPOT 11.25 mg if clinically indicated. Discontinue LUPRON DEPOT 11.25 mg if the woman becomes pregnant during treatment and inform the woman of potential risk to the fetus [see Contraindications ( 4) and Use in Specific Populations ( 8.1)]. Advise women to notify their healthcare provider if they believe they may be pregnant.

When used at the recommended dose and dosing interval, LUPRON DEPOT 11.25 mg usually inhibits ovulation and stops menstruation. Contraception, however, is not ensured by taking LUPRON DEPOT 11.25 mg. If contraception is indicated, advise women to use non-hormonal methods of contraception while on treatment with LUPRON DEPOT 11.25 mg.

5.3 Hypersensitivity Reactions

Acute Hypersensitivity

Acute hypersensitivity reactions, including anaphylaxis, have been reported with LUPRON DEPOT use. LUPRON DEPOT 11.25 mg is contraindicated in women with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH) or GnRH agonist analogs [see Adverse Reactions ( 6.2)].

In clinical trials of LUPRON DEPOT 11.25 mg, 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.

Delayed hypersensitivity

Delayed hypersensitivity reactions including the severe cutaneous adverse reactions (SCAR) of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been very rarely reported post-marketing in association with leuprolide-containing therapy [see Adverse Reactions ( 6.2)]. Discontinue future leuprolide therapy at first signs or symptoms of a delayed hypersensitivity reaction, and treat patients according to current treatment guidelines.

5.4 Initial Flare of Symptoms

Following the first dose of LUPRON DEPOT 11.25 mg, sex steroids temporarily rise above baseline because of the physiologic effect of the drug. Therefore, an increase in symptoms may be observed during the initial days of therapy, but these should dissipate with continued therapy.

5.5 Convulsions

There have been postmarketing reports of convulsions in women on GnRH agonists, including leuprolide acetate. These included women with and without concurrent medications and comorbid conditions.

5.6 Clinical Depression

Depression may occur or worsen during treatment with GnRH agonists including LUPRON DEPOT 11.25 mg [see Adverse Reactions ( 6.1)]. Carefully observe women for depression, especially those with a history of depression and consider whether the risks of continuing LUPRON DEPOT 11.25 mg outweigh the benefits. Women with new or worsening depression should be referred to a mental health professional, as appropriate.

5.7 Risks Associated with Norethindrone Combination Treatment

If LUPRON DEPOT 11.25 mg is administered with norethindrone acetate, the warnings and precautions for norethindrone acetate apply to this regimen. Refer to the norethindrone acetate prescribing information for a full list of the warnings and precautions for norethindrone acetate.