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-Dleucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt).
INDICATIONS AND USAGE
LUPRON DEPOT-PED is indicated in the treatment of children with central precocious puberty (CPP).
CPP is defined as early onset of secondary sexual characteristics (generally earlier than 8 years of age in girls and 9 years of age in boys) associated with pubertal pituitary gonadotropin activation. It may show a significantly advanced bone age that can result in diminished adult height.
Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentrations of luteinizing hormone (LH) (basal or stimulated with a GnRH analog), sex steroids, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumor), and adrenal steroid measurements to exclude congenital adrenal hyperplasia.
Mechanism of Action
Leuprolide acetate, a GnRH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Human studies indicate that following an initial stimulation of gonadotropins, chronic stimulation with leuprolide acetate results in suppression or “downregulation” of these hormones and consequent suppression of ovarian and testicular steroidogenesis. These effects are reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally.
DOSAGE AND ADMINISTRATION
Dose and Principles of Dosing 7.5 mg, 11.25 mg, or 15 mg for 1-month administration
LUPRON DEPOT-PED must be administered under the supervision of a physician.
LUPRON DEPOT-PED is administered as a single intramuscular injection once a month. The starting dose will be dictated by the child’s weight, as indicated in the table below.
|Table 1. Dosing Recommendations Based on Body Weight for LUPRON DEPOT-PED 1month Formulations|
|Body Weight||Recommended Dose|
|≤ 25 kg||7.5 mg|
|> 25-37.5 kg||11.25 mg|
|> 37.5 kg||15 mg|
The dose of LUPRON DEPOT-PED must be individualized for each child. If adequate hormonal and clinical suppression is not achieved with the starting dose, it should be increased to the next available higher dose (e.g., 11.25 mg or 15 mg at the next monthly injection). Similarly, the dose may be adjusted with changes in body weight. The injection site should be varied periodically.
The goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored after 1–2 months of initiating therapy and with each dose change to ensure adequate pituitary gonadotropin suppression. Once a dose that results in adequate hormonal suppression is found, it can often be maintained for the duration of therapy in most children. It is recommended, however, that adequate hormonal suppression be verified in such patients as weight can increase significantly while on therapy.
Each LUPRON DEPOT-PED strength and formulation has different release characteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.
LUPRON DEPOT-PED should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.
Dose and Principles of Dosing 11.25 mg or 30 mg for 3-month administration
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration must be administered under the supervision of a physician.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be administered once every three months (12 weeks) as a single intramuscular injection. Regardless of the dose chosen, the goal of therapy is to suppress pituitary gonadotropins and peripheral sex steroids, and to arrest progression of secondary sexual characteristics. Hormonal and clinical parameters should be monitored during treatment, for instance at month 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. In case of inadequate suppression, other available GnRH agonists indicated for the treatment of CPP should be considered.
Each LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration strength and formulation has different release ch aracteristics. Do not use partial syringes or a combination of syringes to achieve a particular dose.
LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.
Reconstitution and Administration Instructions
- The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection.
- Since LUPRON DEPOT-PED 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-PED 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.
5. Hold 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.
- 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 shoulder; 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-PED should be mixed and used immediately.
9. 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 is fully extended over the needle and a CLICK is heard or felt.
- Hypersensitivity to GnRH, GnRH agonists or any of the excipients in LUPRON DEPOTPED. Reports of anaphylactic reactions to GnRH agonists have been reported in the medical literature.
- All formulations of LUPRON DEPOT may cause fetal harm if administered to a pregnant woman. When LUPRON DEPOT was administered subcutaneously to rabbits it produced a dose related increase in major fetal abnormalities, and fetal mortality. The possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. LUPRON DEPOT-PED is contraindicated in women who are or may become pregnant. If this drug is inadvertently used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
WARNINGS AND PRECAUTIONS
Initial Rise of Gonadotropins and Sex Steroid Levels: During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms of puberty may be observed.
Psychiatric Events: Psychiatric events have been reported in patients taking GnRH agonists, including LUPRON DEPOT-PED. Postmarking reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with LUPRON DEPOT-PED
Convulsions: Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including leuprolide acetate. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above.
Monitoring and Laboratory Tests: Response to LUPRON DEPOT-PED 7.5 mg, 11.25 mg, or 15 mg for 1-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels beginning 1-2 months following initiation of therapy, with changing doses, or potentially during therapy in order to confirm maintenance of efficacy. Measurement of bone age for advancement should be done every 6-12 months.
Response to LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration should be monitored with a GnRHa stimulation test, basal LH or serum concentration of sex steroid levels at months 2-3, month 6 and further as judged clinically appropriate, to ensure adequate suppression. Additionally, height (for calculation of growth rate) and bone age should be assessed every 6-12 months.
Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels. Gonadotropins and/or sex steroids may increase or rise above prepubertal levels if the dose is inadequate. Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels.
The following adverse events have been observed with this or other formulations of leuprolide acetate injection. As leuprolide has multiple indications, and therefore patient populations, some of these adverse events may not be applicable to every patient.
Allergic reactions (anaphylactic, rash, urticaria, and photosensitivity reactions) have also been reported.
Gastrointestinal Disorders: nausea, abdominal pain, vomiting;
General Disorders and Administration Site Conditions: chest pain, injection site reactions including induration and abscess have been reported;
Investigations: decreased WBC, weight increased;
Metabolism and Nutrition Disorders: diabetes mellitus;
Musculoskeletal and Connective Tissue Disorders: tenosynovitis-like symptoms;
Psychiatric Disorders: Emotional lability, such as crying, irritability, impatience, anger, and aggression has been observed with GnRH agonists, including LUPRON DEPOT-PED; Depression, including rare reports of suicidal ideation and attempt, has been reported for GnRH agonists, including LUPRON DEPOT-PED, in children treated for central precocious puberty. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.
Nervous System Disorders: neuropathy peripheral, convulsion, spinal fracture/paralysis;
Skin and Subcutaneous Tissue Disorders: hot flush, flushing, hyperhidrosis;
Reproductive System and Breast Disorders: prostate pain;
Vascular Disorders: hypertension, hypotension.
Pituitary apoplexy: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone 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.
No pharmacokinetic-based drug-drug interaction studies have been conducted; however, drug interactions are not expected to occur.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT-PED in therapeutic doses results in suppression of the pituitary-gonadal system. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and up to six months after discontinuation of LUPRON DEPOT-PED may be affected. Normal pituitary-gonadal function is usually restored within six months after treatment with LUPRON DEPOT-PED is discontinued.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category X
LUPRON DEPOT-PED is contraindicated in women who are or may become pregnant while receiving the drug.
Safe use of leuprolide acetate in pregnancy has not been established in clinical studies. Before starting and during treatment with leuprolide acetate, it is advisable to establish whether the patient is pregnant. Leuprolide acetate is not a contraceptive. If contraception is required, a non-hormonal method of contraception should be used.
Nursing Mothers: It is not known whether leuprolide acetate is excreted in human milk. LUPRON DEPOT-PED should not be used by nursing mothers.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of LUPRON DEPOT-PED in children under 2 years is not recommended.
Geriatric Use: LUPRON DEPOT 1-month 7.5 mg and 4-month 30 mg are indicated for the palliative treatment of advanced prostate cancer. For LUPRON DEPOT-PED 11.25 mg or 15 mg for 1-month administration and LUPRON DEPOT-PED 11.25 mg or 30 mg for 3-month administration, no clinical information is available for persons aged 65 and over.
In early clinical trials using leuprolide acetate in adult patients, 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.
In rats, subcutaneous administration of leuprolide acetate as a single dose 225 times the recommended human pediatric dose, expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no evidence at present that there is a clinical counterpart of this phenomenon.
In cases of overdosage, standard of care monitoring and management principles should be followed.