Leuprolide acetate - TAP Pharmaceuticals Inc.

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WARNINGS
During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed. (See CLINICAL PHARMACOLOGY section.)
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process. The consequences of poor control include the return of pubertal signs such as menses, breast development, and testicular growth. The long-term consequences of inadequate control of gonadal steroid secretion are unknown, but may include a further compromise of adult stature.
PRECAUTIONS
Laboratory Tests Response to LUPRON DEPOT-PED should be monitored 1-2 months after the start of therapy with a GnRH stimulation test and sex steroid levels. Measurement of bone age for advancement should be done every 6-12 months.
Sex steroids may increase or rise above prepubertal levels if the dose is inadequate. (See WARNINGS section.) Once a therapeutic dose has been established, gonadotropin and sex steroid levels will decline to prepubertal levels.
Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been conducted. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
Drug/Laboratory Test Interactions Administration of LUPRON DEPOT 3.75 mg in women 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 LUPRON DEPOT may be misleading.
Information for Parents Prior to starting therapy with LUPRON DEPOT-PED, the parent or guardian must be aware of the importance of continuous therapy. Adherence to 4 week drug administration schedules must be accepted if therapy is to be successful.
During the first 2 months of therapy, a female may experience menses or spotting. If bleeding continues beyond the second month, notify the physician.
Any irritation at the injection site should be reported to the physician immediately.
Report any unusual signs or symptoms to the physician.
Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Adult patients have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
Although no clinical studies have been completed in children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery. However, following a study with leuprolide acetate, immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown.
Pregnancy, Teratogenic Effects Pregnancy Category X. (See CONTRAINDICATIONS section.)
Nursing Mothers It is not known whether leuprolide acetate is excreted in human milk. LUPRON should not be used by nursing mothers.
Geriatric Use See also the labeling for LUPRON DEPOT 7.5 mg which is indicated for the palliative treatment of advanced prostate cancer. For LUPRON DEPOT-PED 11.25 mg and LUPRON DEPOT-PED 15 mg, no clinical information has been established for persons aged 65 and over.
ADVERSE REACTIONS
Clinical Trials
Potential exacerbation of signs and symptoms during the first few weeks of treatment (See PRECAUTIONS section.) is a concern in patients with rapidly advancing central precocious puberty.
In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions which are not considered drug-related are excluded.
Number of Patients
N=395 (%)
Body as a Whole
General Pain 7 (2)
Integumentary System
Acne/Seborrhea 7 (2)
Injection Site Reactions
Including Abscess 21 (5)
Rash Including
Erythema Multiforme 8 (2)
Urogenital System
Vaginitis/Bleeding/ Discharge 7 (2)
In those same studies, the following adverse reactions were reported in less than 2% of the patients.
Body as a Whole - Body Odor, Fever, Headache, Infection; Cardiovascular System - Syncope, Vasodilation; Digestive System - Dysphagia, Gingivitis, Nausea/Vomiting; Endocrine System - Accelerated Sexual Maturity; Metabolic and Nutritional Disorders - Peripheral Edema, Weight Gain; Nervous System - Emotional Lability, Nervousness, Personality Disorder, Somnolence; Respiratory System - Epistaxis; Integumentary System - Alopecia, Skin Striae; Urogenital System - Cervix Disorder, Gynecomastia/Breast Disorders, Urinary Incontinence.
Postmarketing
During postmarketing surveillance, which includes other dosage forms, the following adverse events were reported.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Cardiovascular System - Hypotension; Hemic and Lymphatic System - Decreased WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal fracture/paralysis; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate pain.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different patient populations.
OVERDOSAGE
In rats, subcutaneous administration of 125 to 250 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 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.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT-PED must be administered under the supervision of a physician.
The dose of LUPRON DEPOT-PED must be individualized for each child. The dose is based on a mg/kg ratio of drug to body weight. Younger children require higher doses on a mg/kg ratio.
For each dosage form, after 1-2 months of initiating therapy or changing doses, the child must be monitored with a GnRH stimulation test, sex steroids, and Tanner staging to confirm downregulation. Measurements of bone age for advancement should be monitored every 6-12 months. The dose should be titrated upward until no progression of the condition is noted either clinically and/or by laboratory parameters.
The first dose found to result in adequate downregulation can probably be maintained for the duration of therapy in most children. However, there are insufficient data to guide dosage adjustment as patients move into higher weight categories after beginning therapy at very young ages and low dosages. It is recommended that adequate downregulation be verified in such patients whose weight has increased significantly while on therapy.
Discontinuation of LUPRON DEPOT-PED should be considered before age 11 for females and age 12 for males.
The recommended starting dose is 0.3 mg/kg/4 weeks (minimum 7.5 mg) administered as a single intramuscular injection. The starting dose will be dictated by the child's weight.
</= 25 kg 7.5 mg
> 25-37.5 kg 11.25 mg
> 37.5 kg 15 mg
If total downregulation is not achieved, the dose should be titrated upward in increments of 3.75 mg every 4 weeks. This dose will be considered the maintenance dose.
The lyophilized microspheres are to be reconstituted and administered as a single intramuscular injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following instructions:
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. Gently mix the microspheres (particles) thoroughly to form a uniform suspension. The suspension will appear milky.
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.
Inject the entire contents of the syringe intramuscularly at the ti