leuprolide acetate 3.75 MG per 1 ML Prefilled Syringe
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically.
Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops menstruation.
Contraception is not insured, however, by taking LUPRON DEPOT.
Therefore, patients should use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant.
If a patient becomes pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic effect of the drug.
Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate: Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine.
If examination reveals papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking progestogens, the physician should be alert to the earliest manifestations of the disease in women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of add-back therapy with norethindrone acetate.
Norethindrone acetate should be used with caution in women with risk factors, including lipid abnormalities or cigarette smoking.
DRUG INTERACTIONS
Drug Interactions See CLINICAL PHARMACOLOGY, Pharmacokinetics.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site.
There is no evidence that there is a clinical counterpart of this phenomenon.
In early clinical trials using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose.
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LH-RH).
The analog possesses greater potency than the natural hormone.
The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural formula: LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6 mg).
The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
Lupron Structure
CLINICAL STUDIES
Endometriosis In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced by laparoscopy.
The clinical significance of a decrease in endometriotic lesions is not known at this time, and in addition laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first and second treatment months respectively.
Most of the remaining patients reported episodes of only light bleeding or spotting.
In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during two controlled clinical studies.
This included all patients at end of treatment and those who elected to participate in the follow-up period.
This might provide a slight bias in the results at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months.
Figure 1 Hormonal replacement therapy Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral density associated with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis.
(All patients in these studies received calcium supplementation with 1000 mg elemental calcium).
One controlled, randomized and double-blind study included 51 women treated with LUPRON DEPOT alone and 55 women treated with LUPRON plus norethindrone acetate 5 mg daily.
The second study was an open label study in which 136 women were treated with LUPRON plus norethindrone acetate 5 mg daily.
This study confirmed the reduction in loss of bone mineral density that was observed in the controlled study.
Suppression of menses was maintained throughout treatment in 84% and 73% of patients receiving LD/N in the controlled study and open label study, respectively.
The median time for menses resumption after treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study.
Figure 2 Uterine Leiomyomata (Fibroids) In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal bloating, pelvic pain, and pressure).
Excessive vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters.
In three clinical trials, enrollment was not based on hematologic status.
Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI.
These patients also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort.
Benefit occurred by three months of therapy, but additional gain was observed with an additional three months of LUPRON DEPOT 3.75 mg.
Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg patients among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy.
Menses usually returned within two months of cessation of therapy.
Mean time to return to pretreatment uterine size was 8.3 months.
Regrowth did not appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2 g/dL.
Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three months of therapy.
The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL.
Clinical response was judged to be a hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to surgery.
At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia.
As with the previous studies, episodes of spotting and menstrual-like bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and 54% of patients respectively.
LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT 3.75 mg.
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains: one prefilled dual-chamber syringe one plunger two alcohol swabs a complete prescribing information enclosure Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a biodegradable copolymer of lactic and glycolic acids.
When mixed with diluent, LUPRON DEPOT 3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]
GERIATRIC USE
Geriatric Use This product has not been studied in women over 65 years of age and is not indicated in this population.
INDICATIONS AND USAGE
Endometriosis LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions.
LUPRON DEPOT monthly with norethindrone acetate 5 mg daily is also indicated for initial management of endometriosis and for management of recurrence of symptoms.
(Refer also to norethindrone acetate prescribing information for WARNINGS, PRECAUTIONS, CONTRAINDICATIONS and ADVERSE REACTIONS associated with norethindrone acetate).
Duration of initial treatment or retreatment should be limited to 6 months.
Uterine Leiomyomata (Fibroids) LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata.
The clinician may wish to consider a one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone.
(See Table 1.) LUPRON may be added if the response to iron alone is considered inadequate.
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to three months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older.
Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL Treatment Group Week 4 Week 8 Week 12 LUPRON DEPOT 3.75 mg with Iron 41* 71† 79* Iron Alone 17 40 56 * P-Value < 0.01 † P-Value < 0.001
PEDIATRIC USE
Pediatric Use Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to women 18 years of age and older.
See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the safety and effectiveness in children with central precocious puberty.
PREGNANCY
Pregnancy Teratogenic Effects Pregnancy Category X (see CONTRAINDICATIONS section).
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, LUPRON DEPOT 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.
NUSRING MOTHERS
Nursing Mothers It is not known whether LUPRON DEPOT is excreted in human milk.
Because many drugs are excreted in human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-fed child have not been determined, LUPRON DEPOT should not be used by nursing mothers.
INFORMATION FOR PATIENTS
Information for Patients Patients should be aware of the following information: Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient should notify her physician if regular menstruation persists.
Patients missing successive doses of LUPRON DEPOT may experience breakthrough bleeding.
Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON DEPOT.
Safe use of the drug in pregnancy has not been established clinically.
Therefore, a non-hormonal method of contraception should be used during treatment.
Patients should be advised that if they miss successive doses of LUPRON DEPOT, breakthrough bleeding or ovulation may occur with the potential for conception.
If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.
Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, reduction in breast size, and vaginal dryness.
Estrogen levels returned to normal after treatment was discontinued.
Patients should be counseled on the possibility of the development or worsening of depression and the occurrence of memory disorders.
The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, some of which may not be reversible.
Clinical studies show that concurrent hormonal therapy with norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with LUPRON.
(All patients received calcium supplementation with 1000 mg elemental calcium.) (See Changes in Bone Density section).
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered.
Retreatment beyond this one six month course cannot be recommended.
It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
Retreatment with LUPRON DEPOT alone is not recommended.
In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may pose an additional risk.
In these patients, the risks and benefits must be weighed carefully before therapy with LUPRON DEPOT alone is instituted, and concomitant treatment with norethindrone acetate 5 mg daily should be considered.
Retreatment with gonadotropin-releasing hormone analogs, including LUPRON is not advisable in patients with major risk factors for loss of bone mineral content.
Because norethindrone acetate may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunctions require careful observation during norethindrone acetate add-back therapy.
Patients who have a history of depression should be carefully observed during treatment with norethindrone acetate and norethindrone acetate should be discontinued if severe depression occurs.
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.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with norethindrone acetate is six months.
The choice of LUPRON DEPOT alone or LUPRON DEPOT plus norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be made by the health care professional in consultation with the patient and should take into consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of LUPRON DEPOT administered monthly and norethindrone acetate 5 mg daily may be considered.
Retreatment beyond this one six-month course cannot be recommended.
It is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.
LUPRON DEPOT alone is not recommended for retreatment.
If norethindrone acetate is contraindicated for the individual patient, then retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.
Uterine Leiomyomata (Fibroids) Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months.
The symptoms associated with uterine leiomyomata will recur following discontinuation of therapy.
If additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions: Reconstitution and Administration Instructions The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection.
Since LUPRON DEPOT does not contain a preservative, the suspension should be injected immediately or discarded if not used within two hours.
As with other drugs administered by injection, the injection site should be varied periodically.
The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED 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.
To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.
Hold the syringe UPRIGHT.
Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger until the first stopper is at the blue line in the middle of the barrel.
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.
Hold the syringe UPRIGHT.
With the opposite hand pull the needle cap upward without twisting.
Keep the syringe UPRIGHT.
Advance the plunger to expel the air from the syringe.
Now the syringe is ready for injection.
After cleaning the injection site with an alcohol swab, the intramuscular injection should be performed by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is accidentally penetrated.
If present, blood can be seen through the transparent LuproLoc® safety device.
If blood is present remove the needle immediately.
Do not inject the medication.
Inject the entire contents of the syringe intramuscularly at the time of reconstitution.
The suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used immediately.
AFTER INJECTION Withdraw the needle.
Once the syringe has been withdrawn, activate immediately 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.
ADDITIONAL INFORMATION Dispose of the syringe according to local regulations/procedures.
white plunger syringe upright keep syringe upright injection to skin aspirated blood three syringe images