• Triptorelin pamoate, a synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin), is an antineoplastic agent.

Uses

• Prostate Cancer

Triptorelin pamoate is used for the palliative treatment of advanced prostate cancer. The drug currently is considered alternative therapy when orchiectomy or estrogen therapy is not appropriate or is unacceptable to the patient.

In a randomized, active-control trial in men with advanced prostate cancer who received triptorelin pamoate as a 1-month formulation or another GnRH agonist monthly for 9 months, castration levels of serum testosterone were achieved in 91.2% of triptorelin pamoate patients at day 29 and 97.7% of patients at day 57. Maintenance of castration levels of serum testosterone from day 57 through day 253 was found in 96.% of triptorelin-treated patients. In addition, on day 85 of the study, serum LH concentrations were less than 1 IU/L in 98.% of evaluable patients when measured 2 hours after triptorelin pamoate administration on day 85, indicating desensitization of the pituitary gonadotroph receptors.

In a randomized, active-control trial in men with advanced prostate cancer who received triptorelin pamoate every 84 days as a 3-month formulation for up to 3 doses or every 28 days as a 1-month formulation for up to 9 doses, castration levels of serum testosterone were achieved at day 29 in 97.7% of patients receiving the 3-month formulation. Maintenance of castration levels of serum testosterone from day 57 through day 253 was found in 94.4% of patients treated with the 3-month formulation of triptorelin.

Dosage and Administration

• General

• Reconstitution and Administration

Triptorelin pamoate is administered by IM injection once monthly (every 28 days) as a depot 1-month formulation or every 84 days (12 weeks) as a long-acting 3-month formulation. As with other drugs administered by IM injection, the injection site for triptorelin should be altered, or rotated, periodically. Triptorelin should be injected IM into either buttock. The manufacturer states that the drug should be administered under the supervision of a clinician.

The powders for injection must be reconstituted just prior to administration. The manufacturer states that only sterile water for injection should be used to reconstitute the powders. Reconstitute the powders (1-month or 3-month formulation) by adding 2 mL sterile water for injection (using a syringe with a 20-gauge needle) and shaking well to disperse the particles thoroughly and obtain a uniform suspension (which will appear milky). If using the single-dose delivery system, the contents of the prefilled syringe (2 mL sterile water for injection) should be added to the vial containing the powder according to the manufacturer’s instructions. The entire contents of the vial should then be withdrawn and injected IM immediately. The suspension should be discarded if not used immediately after reconstitution.

• Dosage

Dosage of triptorelin pamoate is expressed in terms of the base. The usual adult dosage of triptorelin is 3.75 mg IM every 28 days as the 1-month formulation or 11. mg IM every 84 days (12 weeks) as the 3-month formulation.

• Special Populations

No special population recommendations at this time. AUCs in males with hepatic impairment or moderate or severe renal impairment were increased 2- to 4-fold compared with those in healthy males. Clinical importance of these findings and potential need for dosage adjustment have not been determined.

Cautions

• Contraindications

Known hypersensitivity to triptorelin or any other ingredient in the formulation, other GnRH agonists, or GnRH. Known or suspected pregnancy.

• Warnings/Precautions

Warnings

Endocrine Effects As with other GnRH agonists, worsening (flare) of signs and/or symptoms of prostate cancer and/or development of new manifestations occasionally have occurred during the initial weeks of therapy with triptorelin. This apparently results from triptorelin-induced increases in serum testosterone concentrations during the initial weeks of therapy. Bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction have been reported.

Cases of spinal cord compression contributing to paralysis, with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered.

The likelihood of neurologic and/or genitourinary complications is increased during initial triptorelin therapy in patients with prostatic carcinoma and metastatic vertebral lesions and/or urinary tract obstruction, and such patients should be observed closely during the initial weeks of triptorelin therapy.

Sensitivity Reactions

Hypersensitivity Reactions Anaphylactic shock and angioedema have been reported. Discontinue immediately and provide appropriate supportive and symptomatic care.

General Precautions

Concomitant Diseases Patients with metastatic vertebral lesions and/or upper or lower urinary tract obstruction should be observed closely during the first few weeks of therapy.

Other Precautions Serum testosterone and prostate-specific antigen concentrations should be determined periodically during triptorelin therapy to monitor therapeutic response in patients with prostate cancer.

Specific Populations

Pregnancy Category X. (See Users Guide.)

Nursing Women It is not known if triptorelin is distributed in breast milk; the manufacturer does not recommend use in nursing women.

Gender Not labeled for use in women.

Pediatric Use Safety and efficacy not established in children.

Geriatric Use Clinical studies have been conducted principally in patients 65 years of age and older since prostate cancer occurs mainly in an older patient population.

• Common Adverse Effects

Initial (usually during the first week of therapy with either the 1-month or the 3-month formulation) transient increases in serum testosterone concentrations occur in most patients receiving triptorelin and may be associated with temporary worsening of disease manifestations. 1, 2, 3, 5 (See Warnings/Precautions: Warnings, in Cautions.) At least 10% of patients receiving the 3-month formulation of triptorelin experienced abnormalities in laboratory values including decreased hemoglobin and red blood cell count and increased serum concentrations of glucose, BUN, AST (SGOT), ALT (SGPT), and alkaline phosphatase. Adverse effects occurring in 1% or more of patients receiving either formulation (1-month or 3-month) include hot flushes (flashes), skeletal pain, headache, impotence, pain at injection site, hypertension, leg pain, generalized pain, insomnia, fatigue, dizziness, diarrhea, and urinary retention. Additional adverse effects occurring in 1% or more of patients include vomiting, anemia, pruritus, urinary tract infection, and emotional lability in those receiving the 1-month formulation; and leg edema, dysuria, back pain, nausea, dependent edema, breast pain, arthralgia, decreased libido, chest pain, leg cramps, gynecomastia, constipation, dyspepsia, increased alkaline phosphatase, anorexia, coughing, rash, asthenia, peripheral edema, abdominal pain, abnormal hepatic function, myalgia, dyspnea, pharyngitis, eye pain, and conjunctivitis in those receiving the 3-month formulation.

Drug Interactions

• Drugs that Induce Hyperprolactinemia

Drugs that induce hyperprolactinemia (e.g., antipsychotic agents [chlorpromazine, haloperidol, molindone, olanzapine, prochlorperazine, risperidone], methyldopa, metoclopramide, reserpine): potential pharmacologic interaction (decreased triptorelin efficacy because the number of GnRH receptors is decreased in patients with hyperprolactinemia).

• Description

Triptorelin

Triptorelin pamoate is a synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin) that is structurally related to leuprolide acetate and goserelin.

Triptorelin is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses and has greater activity than naturally-occurring GnRH. After initial administration of triptorelin there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. Following chronic and continuous administration (generally 2-4 weeks after initiation of therapy), a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis are observed. Triptorelin is commercially available as a lyophilized powder for injection containing biodegradable microgranules of triptorelin pamoate.

Following IM injection of triptorelin pamoate suspension to males (Trelstar® Depot or Trelstar® LA), therapeutic plasma concentrations of triptorelin persist for 1 or 3 months, respectively. Reductions in serum testosterone concentrations in males receiving usual doses of triptorelin are comparable to those achieved after surgical castration (i.e., less than 50 ng/dL). Consequently, physiologic functions and tissues dependent on testosterone for maintenance become quiescent. These effects usually are reversible after cessation of therapy.

• Advice to Patients

Risk of worsening manifestations of prostate cancer during initial weeks of therapy.

Risk of anaphylactoid and other sensitivity reactions. Risk of other adverse effects.

Importance of reporting promptly weakness or paresthesia of the lower limbs and/or worsening of urinary signs and symptoms to clinicians.

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

If used in women, importance of informing clinicians if they are or plan to become pregnant or breastfeed.

Overview. For additional information until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Triptorelin Pamoate

Parenteral

For injection, for 3.75 mg (of triptorelin) Trelstar® Depot,IM use only Pfizer

Trelstar® Depot Debioclip®,Pfizer

11. mg (of triptorelin) Trelstar® LA,Pfizer

Trelstar® LA Debioclip®, Pfizer

• Nilutamide is a nonsteroidal antiandrogen.

Uses

• Prostate Cancer

Nilutamide is used in combination with orchiectomy in the treatment of metastatic prostate cancer that involves distant lymph nodes, bone, or visceral organs (stage D2). Results of controlled clinical studies in patients with metastatic prostate cancer indicate that nilutamide in combination with orchiectomy slows progression of the disease, relieve bone pain associated with metastatic disease, and improve overall survival rate after long-term therapy (8.5 years).

Prostate specific antigen (PSA) concentrations should be determined periodically during nilutamide therapy to monitor therapeutic response, including successful remission or possible progression of cancer. If PSA concentrations increase substantially and consistently during nilutamide therapy, the possibility of clinical progression should be evaluated. Progression noted after gonadal ablation (e.g., orchiectomy) and antiandrogen therapy may represent growth that is not androgen dependent. For patients receiving orchiectomy and nilutamide who have an objective progression of disease together with an elevated PSA, discontinuance of nilutamide may be considered. Withdrawal of nilutamide in such patients may be associated with a decrease in PSA. The mechanism of this response to nilutamide withdrawal has not been determined, but may involve the development of mutations at the androgen receptor.

Dosage and Administration

Patients should be advised to report immediately any dyspnea or worsening of preexisting dyspnea and to consult with their clinician if they experience symptoms of nausea, vomiting, abdominal pain, or jaundice.

Patients should be advised of the possibility of alcohol intolerance (e.g., facial flushing, malaise, hypotension) during nilutamide therapy. Such intolerance occurs in about 5% of patients treated with the drug. Patients who experience such intolerance during nilutamide therapy should avoid alcohol consumption.

During clinical trials, 13-57% of patients treated with nilutamide reported delays, ranging from seconds to a few minutes, in adapting to changes in light to dark. Such difficulty in visual adaptation to changes in light level may not diminish during continued therapy with the drug. Patients should be advised about the possibility of this effect and cautioned about driving at night or through tunnels should it occur. This effect can be minimized by wearing tinted glasses during exposure to bright light.

• Administration

Nilutamide is administered orally without regard to meals.

• Dosage

Because of the intended labeled use of nilutamide, safety and efficacy of the drug have not been established in women or children. Nilutamide is not intended for use in women and should not be used in women, particularly for nonserious or nonlife-threatening conditions.

Prostate Cancer

For use in combination with orchiectomy in the management of metastatic (stage D2) prostate cancer, the usual dosage of nilutamide is 300 mg once daily for 30 days, followed by 150 mg given once daily thereafter. Treatment with nilutamide should be initiated on the day of or the day after orchiectomy. The duration of nilutamide therapy depends on the duration of clinical response of the patient.

Prostate specific antigen (PSA) concentrations should be determined periodically during nilutamide therapy to monitor therapeutic response, including successful remission or possible progression of cancer. If PSA concentrations increase substantially and consistently during nilutamide therapy, the possibility of clinical progression should be evaluated.

Discontinuance of Therapy for Hepatic Toxicity

Severe liver injury, in some cases leading to hospitalization and/or death, has been reported rarely in association with nilutamide therapy. Hepatotoxicity generally occurred within the first 3-4 months of nilutamide therapy. Hepatitis or marked increases in serum concentrations of hepatic transaminases leading to discontinuance of nilutamide therapy were reported in 1% of patients receiving the drug in controlled clinical trials.

Serum transaminase concentrations should be measured prior to initiation of nilutamide therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter. If clinical signs or symptoms suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness) occur, serum transaminase concentrations should be measured immediately. Nilutamide should be discontinued immediately in any patient who develops jaundice or an increase in serum ALT concentration to greater than 2 times the upper limit of normal, and liver function should be monitored closely.

Discontinuance of Therapy for Interstitial Pneumonitis

Interstitial pneumonitis, in rare cases leading to hospitalization and death, has been reported in association with nilutamide therapy. Symptoms of interstitial pneumonitis included progressive exertional dyspnea, cough, chest pain, and fever; chest radiographs showed interstitial or alveolo-interstitial changes, and pulmonary function tests showed a restrictive pattern with decreased carbon monoxide diffusing capacity. In most patients, interstitial pneumonitis occurred within the first 3 months of nilutamide therapy and resolved following discontinuance of the drug. Interstitial pneumonitis was reported in 2% of patients receiving the drug in controlled clinical trials and in 17% (8/47) of patients in a small Japanese study.

A chest radiograph should be performed prior to the initiation of nilutamide therapy. Baseline pulmonary function tests also may be considered. Nilutamide therapy should be discontinued immediately at the onset of dyspnea or worsening of preexisting dyspnea and tests performed to determine if respiratory symptoms are drug related.

• Description

Nilutamide is a nonsteroidal antiandrogen that is structurally and pharmacologically related to bicalutamide and flutamide.

Nilutamide is a pure antiandrogen, possessing no intrinsic hormonal activity; the antiandrogenic mechanism of action of the drug is via androgen-receptor antagonism. Nilutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis. Nilutamide is a selective antiandrogen with no estrogenic, antiestrogenic, progestational, antiprogestational, or adrenocortical activity in various animal models. The relative binding affinity of nilutamide at the androgen receptor is less than that of bicalutamide, but similar to that of hydroxyflutamide, the active metabolite of flutamide.

Common pharmacologic therapies for prostate cancer (i.e., gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effects of the drugs. Androgen receptors in the hypothalamus are blocked by nilutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone. As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy. However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade. Concomitant administration of antiandrogens such as nilutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy.

SumMon®. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Nilutamide

Oral

Tablets 50 mg Nilandron®, (with povidone)

Aventis

150 mg Nilandron®, (with povidone)

Aventis

DHAD

• Mitoxantrone hydrochloride, a synthetic anthracenedione, is an antineoplastic agent.

Uses

Mitoxantrone is used as a component of combination chemotherapeutic regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) in adults. The drug also is used in combination with a corticosteroid in the palliative treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer.

Mitoxantrone should be used under the supervision of a qualified physician experienced in therapy with antineoplastic agents. Laboratory and supportive services must be available for hematologic and chemistry monitoring and adjunctive therapies, including anti-infectives; blood and blood products must be available to support patients during the expected period of medullary hypoplasia and severe myelosuppression. Particular care should be given to ensure full hematologic recovery before initiating consolidation therapy (if this treatment is used), and patients should be monitored closely during this phase.

According to the manufacturer, mitoxantrone should not be administered to patients with preexisting medullary suppression secondary to prior drug therapy unless it is believed that the possible benefit from such treatment warrants the risk of further myelosuppression. In addition, the manufacturer recommends that, except when used in the treatment of AML, mitoxantrone generally should not be given to patients with baseline neutrophil counts less than 1500/mm3.

Because of the possible risk of cardiac toxicity in patients previously treated with anthracyclines (e.g., daunorubicin or doxorubicin), the benefit-to-risk ratio of mitoxantrone in such patients should be determined before initiating therapy. (See Cautions: Cardiac Effects, in Doxorubicin 10:00.) Functional cardiac changes, including decreases in left-ventricular ejection fraction (LVEF) and irreversible congestive heart failure, can occur in patients receiving mitoxantrone. The risk of cardiotoxic effects may be increased in patients previously treated with an anthracycline or mediastinal radiotherapy and in those with preexisting cardiovascular disease. Such patients should undergo regular cardiac monitoring of LVEF. The risk of mitoxantrone-induced cardiotoxicity also may be increased with increasing cumulative doses. In clinical trials involving patients with tumor types other than prostate cancer or AML who received intermittent single doses of mitoxantrone, the cumulative probability of developing clinical evidence of congestive heart failure was 2.6% for patients who had received cumulative doses up to 140 mg/m2, and the overall cumulative probability of moderate or serious decreases in LVEF at a cumulative dose of 140 mg/m2 was 13% in comparative trials. For additional information, consult the manufacturer’s labeling.

• Acute Myeloid Leukemia

Mitoxantrone is used as a component of various chemotherapeutic regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL) in adults. AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias. Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow and normalization of peripheral blood counts (including hemoglobin concentration, hematocrit, granulocyte count, and platelet count). Mitoxantrone and other antineoplastic agents (e.g., cytarabine) have been used alone for remission induction, but combination therapy for induction of remissions is superior to single-agent therapy and is preferred. Although maintenance regimens (with lower doses) previously were administered for prolonged periods (e.g., years) in the treatment of AML, most current treatment regimens in the US no longer employ maintenance therapy but instead use intensive consolidation therapy that is administered for a shorter period of time at higher doses and then discontinued since there is no evidence of superior disease-free survival with prolonged maintenance.

Remission rates in adult AML are inversely related to age, with expected rates exceeding 65% in those younger than 60 years of age. In addition, some evidence suggests that, once attained, duration of remission may be shorter in older patients, and increased morbidity and mortality during induction also appear to be directly related to age. Other adverse prognostic factors include leukemic CNS involvement, systemic infection at diagnosis, elevated leukocyte count (exceeding 100,000/mm3) treatment-induced AML, and a history of myelodysplastic syndrome. In addition, leukemias that express the progenitor cell antigen CD34 and/or P-glycoprotein (MDR-1 gene product) have an inferior outcome. Cytogenetic analysis, although not readily available, provides the strongest prognostic information for newly diagnosed AML, with abnormalities that indicate a good prognosis including t(8;), inv(16), and t(15;); normal cytogenetics generally indicate average-risk AML. Patients with AML that is characterized by deletions of the long arms or monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome 3, t(6;), t(9;); or by abnormalities of 11q exhibit particularly poor prognoses with chemotherapy.

Although cytarabine and an anthracycline (usually daunorubicin) have been principal components of induction regimens, various regimens (e.g., cytarabine combined with mitoxantrone, daunorubicin, or idarubicin) have been used in combination therapy and comparative efficacy is continually being evaluated. The results of randomized trials comparing combined mitoxantrone and cytarabine therapy with combined daunorubicin and cytarabine therapy have shown the 2 regimens to have similar efficacy and toxicity as induction therapy in patients with previously untreated AML. Mitoxantrone also has been used in combination with etoposide or etoposide plus cytarabine for initial induction therapy in patients with AML. In addition, mitoxantrone has been used alone or in combination with etoposide and/or cytarabine in patients with refractory or relapsed AML, and incomplete cross-resistance between mitoxantrone and daunorubicin has been demonstrated in some trials.

In 2 large randomized multicenter trials, remission induction therapy for AML with mitoxantrone 12 mg/m2 daily for 3 days (administered IV over 10 minutes) and cytarabine 100 mg/m2 for 7 days (administered as a continuous 24-hour IV infusion) was compared with daunorubicin 45 mg/m2 daily (administered by IV infusion) for 3 days plus the same dose and schedule of cytarabine used with mitoxantrone. Patients who had an incomplete antileukemic response received a second induction course in which mitoxantrone or daunorubicin was given for 2 days and cytarabine for 5 days using the same daily dosage schedule. In patients receiving the mitoxantrone regimen, the complete response rate was 50-63%, with a median survival of 103-312 days. A complete response rate of 43-53% and a median survival duration of 160-237 days were observed in patients who received the daunorubicin regimen. In one of these studies, more patients achieved a complete response after one treatment cycle of mitoxantrone plus cytarabine than after one cycle of daunorubicin plus cytarabine.

In these studies, two consolidation courses were administered to complete responders in both groups. Consolidation therapy consisted of the same drug and daily dosage used for remission induction, but with only 5 days of cytarabine and 2 days of mitoxantrone or daunorubicin. The first consolidation course was administered 6 weeks after the start of the final induction course if the patient achieved a complete remission, and the second consolidation course generally was administered 4 weeks later. The benefit of consolidation therapy in patients with AML who achieve a complete remission is not firmly established; however, in the only well-controlled prospective, randomized multicenter trials with mitoxantrone in AML, consolidation therapy was given to all patients who achieved a complete remission.

• Prostate Cancer

Mitoxantrone is used in combination with a corticosteroid as initial chemotherapy for the treatment of advanced, symptomatic (i.e., painful) hormone-refractory prostate cancer. Use of antineoplastic agents in the treatment of advanced, hormone-resistant prostate cancer is palliative, with patients having median survival durations of less than 1 year; no therapy has been shown to improve survival to date, and therefore the principal goal of therapy in such cancer currently is improvement in quality-of-life, particularly pain. Randomized studies have shown that the addition of mitoxantrone to corticosteroid therapy results in a greater proportion of patients achieving a palliative response (i.e., pain reduction) and a longer duration of such response compared with corticosteroid treatment alone. Although statistically significant differences between the regimens were not demonstrated, improvement in some quality-of-life measures, including indicators related to pain, physical activity or function, constipation, and mood, favored combination therapy.

Combination therapy with mitoxantrone and low-dose prednisone was compared with low-dose prednisone alone in a randomized, multicenter trial. Patients included in the trial had metastatic or locally advanced prostate cancer that had progressed on standard hormonal therapy, serum testosterone concentrations consistent with castration, and at least mild pain at study entry. Patients were randomized to receive low-dose prednisone (5 mg orally twice daily) alone or combination therapy with low-dose prednisone and mitoxantrone (12 mg/m2 by short IV infusion every 3 weeks). Patients randomized to receive prednisone alone were crossed over to the combination therapy arm if their disease progressed or if no improvement was seen after at least 6 weeks of prednisone treatment.

In this trial, a primary palliative response was defined as a 2-point decrease in pain intensity in a 6-point pain scale associated with stable analgesic use and lasting a minimum of 6 weeks, and a secondary palliative response was defined as a 50% or greater decrease in analgesic use associated with stable pain intensity and lasting a minimum of 6 weeks. Higher primary and overall (primary and secondary) palliative response rates were achieved in patients who received combination therapy compared with those who received prednisone alone (29 and 38% versus 12 and 21%, respectively). In addition, median duration of primary and overall palliative responses were longer in patients who received combination therapy (7.5 and 5.6 months versus 2.1 and 1.9 months, respectively). Time to progression, defined as a 1-point increase in pain intensity, a greater than 25% increase in analgesic use, radiographic evidence of disease progression, or requirement for radiotherapy, was shorter in patients who received prednisone alone (2.3 months) than in those who received combination therapy (4.4 months). Median survival time did not differ significantly in the 2 groups. Among patients randomized to receive prednisone alone and subsequently crossed over to receive combination therapy, 19% achieved a palliative response with combined mitoxantrone and prednisone treatment.

A phase III trial comparing mitoxantrone and hydrocortisone to hydrocortisone alone in patients with hormone-refractory prostate cancer also was conducted (CALGB 9182). Patients in this trial received hydrocortisone orally at a dosage of 40 mg daily with or without mitoxantrone 14 mg/m2 IV every 21 days. Using National Prostate Cancer Project (NCPC) criteria for response, 8.4% of patients in the combination therapy group and 1.6% of patients in the hydrocortisone group achieved partial responses (by intent-to-treat analysis). A trend toward longer median time to progression was observed for the combination therapy group compared with the hydrocortisone monotherapy group (7.3 versus 4.1 months). Beneficial effects also were observed with the addition of mitoxantrone to hydrocortisone treatment in the best percent change from baseline in mean analgesic use (-17% versus +17%) and the best percent change from baseline in mean pain intensity (-14% versus +8%).

Dosage and Administration

• Reconstitution and Administration

Mitoxantrone hydrochloride is administered by IV infusion. The manufacturer states that safety of administration of mitoxantrone hydrochloride by routes other than IV has not been established. According to the manufacturer, mitoxantrone should not be administered by intra-arterial or intrathecal injection. Local or regional neuropathy, in some cases irreversible, has been reported following intra-arterial injection of mitoxantrone. In addition, manifestations of neurotoxicity, including paralysis and bowel and bladder dysfunction, have been observed following intrathecal injection of the drug.

Mitoxantrone hydrochloride for injection concentrate must be diluted prior to IV infusion. The dose of mitoxantrone hydrochloride should be diluted to at least 50 mL with either 0.9% sodium chloride injection or 5% dextrose injection. These solutions may then be further diluted with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose and 0.9% sodium chloride injection and used immediately. The manufacturer states that mitoxantrone hydrochloride for injection concentrate and diluted solutions of the drug should not be frozen.

Diluted mitoxantrone hydrochloride solutions should be introduced slowly into a freely running IV infusion solution of 0.9% sodium chloride or 5% dextrose over a period of at least 3 minutes, with infusions typically being administered over 15-30 minutes.

According to the manufacturer, after penetration of the container, undiluted mitoxantrone hydrochloride for injection concentrate may be stored no longer than 7 days at a room temperature of 15-25°C or 14 days under refrigeration, but should not be frozen.

If extravasation occurs, mitoxantrone hydrochloride administration should be stopped immediately and restarted in another vein. Although the nonvesicant properties of mitoxantrone hydrochloride minimize the possibility of severe local reactions following extravasation, care should be taken to avoid extravasation at the infusion site and to avoid contact of the drug with skin, mucous membranes, and the eyes.

Caution should be exercised in handling and preparing solutions of mitoxantrone hydrochloride. Because skin reactions may occur with accidental exposure to the drug, the manufacturer recommends the use of goggles, gloves, and protective gowns during preparation and administration of mitoxantrone hydrochloride. Skin accidentally exposed to the drug should be rinsed thoroughly with copious amounts of warm water, and standard irrigation techniques should be used immediately in the event of eye involvement.

Mitoxantrone hydrochloride solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Mitoxantrone hydrochloride should not be mixed in the same infusion as heparin because of the possibility of precipitate formation. Because specific compatibility data are not available, the manufacturer also recommends that mitoxantrone hydrochloride not be mixed in the same infusion with any other drugs.

According to the manufacturer, mitoxantrone hydrochloride solutions are compatible with filters; during the manufacturing process, a solution of the drug is passed through a 0.22-µm filter without loss of potency.

• Dosage

Dosage of mitoxantrone hydrochloride is expressed in terms of the base. Safety and efficacy of mitoxantrone in children younger than 12 years of age have not been established.

Acute Myeloid Leukemia

For remission induction therapy in patients with acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL), the recommended dosage of mitoxantrone is 12 mg/m2 daily given on days 1-3 (administered by IV infusion) in combination with cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) given on days 1-7. A second induction course, consisting of 2 days of mitoxantrone and 5 days of cytarabine in the same daily dosage levels, may be given in the event of an incomplete antileukemic response.

If severe or life-threatening nonhematologic toxicity is observed during the initial induction course, the second induction course should be withheld until toxicity resolves.

Consolidation therapy, which was used in 2 large randomized multicenter trials, consisted of mitoxantrone 12 mg/m2 daily (by IV infusion) given on days 1 and 2 and cytarabine 100 mg/m2 daily (as a continuous IV infusion over 24 hours) given on days 1-5. The initial consolidation course was given approximately 6 weeks after the final induction course, and the second consolidation course generally was administered 4 weeks after the initial course.

BR>Prostate Cancer

For the treatment of advanced hormone-refractory prostate cancer, the recommended mitoxantrone dosage is 12-14 mg/m2 given as a short IV infusion once every 21 days; mitoxantrone is given as an adjunct to corticosteroid therapy (e.g., oral prednisone 5 mg twice daily, oral hydrocortisone 40 mg daily). Because of the risk of cardiac toxicity, some clinicians have recommended discontinuance of mitoxantrone (and continuation of corticosteroid therapy alone) in patients who are still responding after a cumulative mitoxantrone dose of 140 mg/m2 has been administered.

• Dosage in Renal and Hepatic Impairment

The effect of renal and/or hepatic impairment on the disposition of mitoxantrone has not been fully determined.

Renal excretion of mitoxantrone is limited, accounting for only up to approximately 10% of the total clearance of the drug. Therefore, reduction of mitoxantrone dosage in patients with impaired renal function does not appear to be necessary.

Mitoxantrone appears to be eliminated principally by the hepatobiliary system, and the manufacturer states that the safety of the drug in patients with hepatic insufficiency is not established. The clearance of mitoxantrone has been reported to be reduced in patients with severe hepatic impairment (i.e., serum total bilirubin concentration exceeding 3.4 mg/dL). Decreased clearance of mitoxantrone also may occur in patients with abnormalities of the third space (e.g., edema, ascites, pleural effusion) because of the extensive tissue penetration and protein-binding of the drug. According to the manufacturer, specific dose adjustment recommendations for patients with hepatic impairment cannot be made at this time.

• Description

Mitoxantrone hydrochloride, a synthetic anthracenedione, is an antineoplastic agent. Mitoxantrone is derived from the anthraquinone dye ametantrone and is structurally similar to the anthracyclines doxorubicin and daunorubicin. Anthracenediones share the planar polycyclic aromatic ring structure (which enables interaction with DNA) of anthracyclines but lack the amino sugar moiety and tetracyclic A ring normally present in anthracyclines. In place of the amino sugar moiety, mitoxantrone contains two identical aminoalkyl side chains.

Although the exact mechanism(s) of action has not been fully elucidated, mitoxantrone is a DNA-reactive agent. Despite the presence of the planar polycyclic aromatic ring structure, DNA intercalation has been shown not to correlate with the in vivo cytotoxic activity of mitoxantrone. Instead, mitoxantrone is believed to exert its cytotoxic effect by interfering with the function of topoisomerase II, thereby preventing religation of DNA strand breaks. Topoisomerase enzymes catalyze the formation of single- or double-strand DNA breaks, facilitate passage of DNA strands through these breaks, and promote religation of the DNA strands via a covalently linked enzyme-DNA intermediate (the cleavable complex). This cleavable complex is involved in a reaction that alters the topology of DNA by introducing a temporary double-strand break in the sequence through which an intact helix can pass. Mitoxantrone is believed to stabilize the cleavable complex, preventing the rejoining of DNA strands. Other effects of mitoxantrone that may contribute to its cytotoxic activity include the aggregation and compaction of DNA via electrostatic cross-linking, generation of free radicals (which may cause breaks in DNA strands), inhibition of protein kinase C activity, and induction of apoptosis in leukemic cells.

Mitoxantrone exerts a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting a lack of cell-cycle phase specificity. Mitoxantrone produces concentration- and time-proportional delays in cell-cycle progression and, although not considered cell-cycle specific, the drug is most cytotoxic to cells in late S phase.

Tumor resistance to mitoxantrone may occur as a result of increased P-glycoprotein expression, alteration of the levels or activity of topoisomerase II, enhanced DNA repair mechanisms, or a combination of these and other mechanisms. Incomplete cross-resistance with anthracyclines has been demonstrated in vitro, and although partial cross-resistance to mitoxantrone and various anthracyclines is common in resistant cell lines in vitro, patients who fail to respond to anthracycline therapy have been reported to respond to mitoxantrone in some cases.

Additive or synergistic effects in inducing cellular DNA damage have been demonstrated in vitro with combined exposure of cells to mitoxantrone and other antineoplastic agents, including cytarabine, amsacrine, cisplatin, doxorubicin, and etoposide. In addition, sequential exposure of cells to mitoxantrone and cytarabine has been shown to result in enhanced cytotoxic effects.

SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Mitoxantrone Hydrochloride

Parenteral

For injection 2 mg (of mitoxantrone) per Novantrone®, OSI

concentrate, for mL (20, 25, and 30 mg) Pharmaceuticals (comarketed by

IV infusion Serono)

• Leuprolide acetate, a synthetic nonapeptide analog of naturally occurring porcine or ovine gonadotropin releasing hormone (GnRH, luteinizing hormone releasing hormone, gonadorelin), may be used as an antineoplastic agent and for its endocrine effects.

Drug Interactions

The manufacturer states there are no reports to date of drug interactions with leuprolide. The manufacturer also states that because leuprolide is a peptide that is mainly degraded by peptidase and not by cytochrome P-450 microsomal enzymes and because of the drug’s low degree of protein binding, drug interactions would not be expected to occur with leuprolide.

There is some evidence from studies in mice to suggest that the inhibitory effect of leuprolide on spermatogenesis may be used to therapeutic advantage in the prevention of azoospermia or severe oligospermia that frequently results from therapy with cytotoxic agents. In mice receiving combined therapy with leuprolide and cyclophosphamide, testicular damage was less than that observed in animals receiving cyclophosphamide alone. It has been suggested that leuprolide-induced interruption of the hypothalamic-pituitary-gonadal axis and resultant inhibition of spermatogenesis may decrease the sensitivity of testicular cells to cytotoxic effects, since resting cells are more resistant to cytotoxic therapy than dividing cells. To date, several preliminary studies in humans receiving combined therapy with cytotoxic agents and GnRH analogs have failed to show a protective effect of the analogs on testicular function. However, additional study is necessary to more fully determine the clinical importance, if any, of leuprolide‘s potential gonad-sparing effect in humans receiving cytotoxic agents.

Combined therapy with a GnRH analog (e.g., leuprolide) and an antiandrogen (e.g., megestrol, flutamide) in patients with prostate cancer may produce additive antineoplastic effects by producing complete androgen withdrawal.

Acute Toxcicity

Limited information is available on the acute toxicity of leuprolide. Following subcutaneous administration of leuprolide acetate injection in rats at dosages 250-500 times the usual human dosage or 125-250 times the usual pediatric dosage, dyspnea, decreased activity, and local irritation at the injection site were observed; however, there is no evidence to date that overdosage in humans produces similar adverse effects. Following intraperitoneal, IM, or subcutaneous administration of leuprolide acetate suspension in mice and rats at dosages of 2-5 g/kg, no toxicity was observed during a 2-week period. Leuprolide dosages up to 20 mg daily for up to 2 years have not produced unusual adverse effects in humans with prostate cancer.

Pharmacology

Leuprolide acetate is a gonadotropin releasing hormone (GnRH) analog that shares the action of the naturally occurring hormone. The pharmacology of leuprolide is complex and several mechanisms of action may be involved.

• Endocrine Effects

Leuprolide has 20-60 times the luteinizing hormone (LH) releasing hormone, 10-30 times the follicle-stimulating hormone (FSH) releasing hormone, and 50-80 times the ovulation-inducing activity of GnRH. Administration of single doses of leuprolide stimulates pituitary release of gonadotropins (i.e., LH and FSH), resulting in increased serum LH and FSH concentrations and stimulation of ovarian and testicular steroidogenesis. Transient increases in serum testosterone and dihydrotestosterone (DHT) in males and in serum estrone and estradiol concentrations in premenopausal females have been observed during initial therapy with single daily doses of the drug.

• Mechanism of Action

Although leuprolide has potent GnRH agonist properties during short-term and/or intermittent therapy, the principal effect of the drug in animals and humans during long-term administration is inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis. The exact mechanism(s) of action has not been fully elucidated, but continuous therapy with leuprolide apparently produces a decrease in the number of pituitary GnRH6, and/or testicular LH receptors, resulting in pituitary and/or testicular desensitization, respectively. The drug does not appear to affect receptor affinity for gonadotropins.Leuprolide’s mechanism of action may also involve inhibition and/or induction of enzymes that control steroidogenesis. Studies with GnRH analogs in rats have shown that the drugs inhibit testicular steroid 17a-monooxygenase (17a-hydroxylase) and 17a-hydroxyprogesterone aldolase (17,20-desmolase) and induce 5a-reductase and testosterone A-ring reductase (aromatase). Other mechanisms of action may include secretion of an LH molecule with altered biologic activity or impairment of normal pulsatile patterns of LH and FSH secretion. Although depletion of pituitary LH has also been suggested as a possible mechanism of action, there is some evidence that leuprolide does not affect pituitary content of LH or FSH.

Species variation with regard to the mechanism of action of the drug has been observed. In rats, leuprolide appears to exert a direct testicular effect with little or no pituitary effect. Continuous administration of leuprolide in rats has resulted in a loss of testicular LH receptors and is associated with reduced testicular weight and decreased plasma testosterone concentrations. Following administration of leuprolide to hypophysectomized rats in one study, substantial inhibition of testicular steroidogenesis was observed. In vitro receptor-binding studies have shown that leuprolide decreases LH receptor binding in the testes of rats but has no effect on pituitary GnRH receptor binding in these animals. The presence of LH receptors in the testes of humans or primates has not been clearly established, and there is no evidence to date that leuprolide has a direct testicular effect in humans. It is believed that the drug acts principally on the pituitary gland in humans to suppress gonadotropin release.

• Effects in Males

Following continuous leuprolide administration (daily subcutaneous administration of the injection or monthly IM administration of the suspension) in males, decreases in serum LH, FSH, testosterone, and DHT concentrations have been observed. Reductions in gonadotropin release and in androgen synthesis are characterized by prostatic and testicular atrophy, resulting in decreased testicular and seminal vesicle weight. Reductions in serum testosterone concentrations in males receiving usual dosages of leuprolide are comparable with levels achieved after surgical castration (i.e., less than 50 ng/dL). Serum testosterone concentrations reportedly reach castration levels after 2-4 weeks of leuprolide therapy, and these decreases have been maintained for up to 5 years during continued therapy in patients with prostate cancer. In one study in patients with prostate cancer receiving leuprolide for at least one year, reductions in serum LH and testosterone concentrations were maintained throughout the course of therapy; however, serum DHT concentrations continued to decrease over time and serum FSH concentrations reached a nadir at 10-11 weeks of therapy but then gradually increased to a level that remained below pretreatment concentrations. Decreases followed by gradual increases in FSH concentrations reportedly did not occur in another study in patients with prostate cancer receiving leuprolide for more than 1 year. The mechanism of action for the potential increase in FSH concentration has not been established; however, it has been suggested that there may be a gradual reduction in a testicular factor (e.g., inhibin) that usually exerts a selective negative feedback effect on FSH and/or that a propensity exists for the pituitary to release a greater amount of FSH than LH while GnRH is suppressed. The long-term effect of the gradual rise of FSH concentrations following initial reduction in spermatogenesis has not been determined to date.

Changes in testicular histology have been observed in males receiving therapy with GnRH analogs. In rats following 2 weeks of GnRH analog administration in one study, some tubular degenerative changes were observed. After 8 weeks of therapy in these animals, testicular changes were characterized by generalized degenerative changes in tubules and the relative absence of spermatogenic cells compared with Sertoli cells. Structural modifications and/or changes in the number of Leydig cells generally have not been observed in rat testes following chronic administration of a GnRH analog. In one study in patients with prostate cancer who received leuprolide for 8-24 months prior to bilateral orchiectomy, a marked decrease in tubular membrane thickness, impaired maturation of spermatogenic cells, and decrease in the number of Leydig cells have been observed. Although several reports suggest that these testicular changes are at least partially reversible in animals receiving the drug short-term, some clinicians believe that the degree of tubular thickening and fibrosis and the decrease in the number of Leydig cells observed in humans receiving long-term therapy with leuprolide are suggestive of at least some irreversible effects; however, results from several clinical studies suggest that total reversibility of fertility impairment in males can be achieved following discontinuance of continuous therapy with leuprolide and other GnRH analogs for up to 24 weeks. Further study of the long-term testicular effects of leuprolide and the reversibility of these effects is necessary.

• Effects in Females

In females, leuprolide suppresses ovarian estrogen and androgen production principally by inhibiting pituitary gonadotropin release. It is not known whether leuprolide has any direct ovarian effect. In premenopausal women receiving continuous GnRH analog therapy, including leuprolide, decreases in serum LH, FSH, progesterone, and estrogen (estrone, estradiol) concentrations have been observed; serum estrogen concentrations may be reduced to menopausal levels. Inhibitory effects of GnRH analogs, including leuprolide, on androgen and estrogen production appear to be reversible following discontinuance of the drug. Limited evidence indicates that leuprolide-induced reductions in myometrial and leiomyomal volumes may result in part from decreased secretion of somatotropin (growth hormone) and estrogen-dependent growth factors (e.g., insulin-like growth factor I, IGF-I), but additional study is necessary to confirm these findings.

• Effects in Children with Central Precocious Puberty

In children with central precocious puberty, hormonal changes (e.g., increased pulsatile release of LH, increased LH response to GnRH, elevations of circulating gonadal [sex]steroid concentrations) are observed before onset of normal puberty; normal puberty usually occurs at 8-13 or 9-14 years of age in girls or boys, respectively. Secondary sexual characteristics of girls with central precocious puberty may include enlargement of the breasts and labia minora, estrogenic changes in the vaginal mucosa, growth of pubic hair, and onset of cyclic menses; in boys with central precocious puberty, these characteristics may include enlargement of the penis and testes, growth of pubic hair, increased muscle development, deepening of the voice, and aggressive behavior. An accelerated growth rate and skeletal maturation also are observed in these children.

Although GnRH analogs, including leuprolide, initially stimulate gonadotropin secretion, continued administration of the drugs results in inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis; the drugs do not affect the secretion of adrenal androgens. In addition, continuous therapy with leuprolide apparently produces an initial decrease in the number of pituitary GnRH6,and/or testicular LH receptors (“down-regulation”), resulting in pituitary and/or testicular desensitization, respectively. Although receptor levels subsequently may return to normal during continued therapy, desensitization persists, apparently secondary to uncoupling of receptors from the intracellular signaling effector pathway. With continuous administration (daily subcutaneous administration of the injection or monthly IM or subcutaneous administration of the suspension) of adequate doses in children with central precocious puberty, the mean LH response to GnRH generally may return to prepubertal levels within several weeks, followed several weeks thereafter by the return of testosterone and estradiol concentrations to prepubertal levels. Reduction of gonadotropins may allow for normal physical and psychological growth and development, including regression within 6-12 months of secondary sexual characteristics (e.g., reduction in breast size, decreased growth of pubic hair, decreased uterine and ovarian sizes, cessation of menstruation in girls and decreased testicular size, regression of acne, less frequent penile erections, diminished aggressive behavior in boys), and slowing of bone age and decreased rate of skeletal maturation; however, such regression depends on maintained suppression of gonadal steroids.

The decrease in skeletal maturation rate favors attainment of an increased (more normal) adult height, particularly if therapy is initiated soon after commencement of precocious puberty and/or bone age has not advanced substantially, since closure of the epiphyses will be delayed. While reductions in skeletal maturation rate may result directly from drug-induced reductions in gonadal steroids, some but not other evidence suggests such skeletal effects also may result indirectly from reductions in somatotropin (growth hormone) and insulin-like growth factor I associated with GnRH-analog therapy.

Leuprolide therapy in children with central precocious puberty should be continued until appropriate chronologic age of puberty or fusion of epiphyses occur. Inhibitory effects of GnRH analogs, including leuprolide, appear to be reversible and pubertal development resumes following discontinuance of the drug. Normal function of the hypothalamic-pituitary-gonadal system usually occurs 4-12 weeks after discontinuance of leuprolide therapy, and serum gonadal steroid concentrations may increase to pubertal levels within 2-12 months. Thus, the selective effect of GnRH analogs on gonadotropin secretion and absent direct effect on the release of other pituitary hormones result in a reversible pharmacologic gonadectomy.

• Contraceptive Effects

Continuous therapy with a GnRH analog, including leuprolide, produces contraceptive effects as a result of disruption of hypothalamic-pituitary-gonadal function, suppression of ovarian or testicular steroidogenesis, and subsequent inhibition of ovulation or spermatogenesis. Following subcutaneous administration of leuprolide in male rats, substantial reductions in intratesticular sperm counts have occurred after 20 days of therapy. Reductions in sperm motility and in sperm density of at least 70% have occurred in healthy males receiving therapy with a GnRH analog. Although reductions in serum testosterone concentrations occurred within 2 weeks of initiating GnRH analog therapy in these males, decreases in sperm density did not occur until after 4-6 weeks of therapy, suggesting that inhibitory effects of GnRH analogs on spermatogenesis are delayed compared with those on steroidogenesis. Continuous administration of GnRH analogs, including leuprolide, in females produces changes in menstrual bleeding patterns, including amenorrhea, and inhibition of ovulation and corpus luteum formation. There is also limited evidence from animal studies to suggest hat GnRH analogs produce a postcoital, preimplantational contraceptive effect through interference with hypophyseal-luteotropic mechanisms. Because inhibition of FSH and LH secretion appears to be the principal mechanism of action for the contraceptive effects of GnRH analogs, the lack of long-term suppression of FSH observed in some patients receiving the drug and subsequent contraceptive efficacy remain to be evaluated.

• Antineoplastic Effect

Because of its inhibitory effect on gonadotropin secretion and androgen or estrogen synthesis, leuprolide may inhibit the growth of hormone-dependent tumors. Leuprolide has reduced the size of the prostate gland and has inhibited prostatic tumor growth. Reductions in serum prostatic acid phosphatase (PAP) concentration from pretreatment values have been observed in patients with prostate cancer who were receiving leuprolide. In one study, decreases of greater than 25% in serum PAP concentration occurred in 70% of patients after 12 weeks of leuprolide therapy. Following 1-2 weeks of leuprolide therapy, serum PAP concentration may be slightly decreased or increased as a result of leuprolide-induced androgen stimulation.

Following intravaginal or subcutaneous administration, leuprolide inhibits 7,-dimethylbenz[a]-anthracene (DMBA)-induced mammary tumors in female rats. There is evidence to suggest that leuprolide inhibits the growth of estrogen-dependent mammary tumors mainly by inhibiting ovarian function and estrogen synthesis. Alternatively, leuprolide may also have a direct antitumor effect on certain types of breast cancer in humans. The presence of specific binding sites for GnRH in breast tumor tissue and suppression of breast tumor cell growth by GnRH analogs have been shown in a limited number of in vitro studies.

Pharmacokinetics

The pharmacokinetics of leuprolide has not been fully determined in children to date.

• Absorption

Because of its polypeptide nature, leuprolide acetate is destroyed in the GI tract and, therefore, usually is administered parenterally. The drug also may undergo pharmacologically and clinically important systemic absorption following intranasal or transdermal administration.

Following subcutaneous administration, leuprolide acetate is rapidly and almost completely absorbed. In adults, bioavailability of leuprolide acetate following subcutaneous administration is comparable to that following IV administration. Bioavailability of the drug reportedly is about 94% in rats following subcutaneous administration.

Following IM or subcutaneous administration of leuprolide acetate suspension, the drug is released slowly and gradually from its biodegradable copolymer-containing vehicle (after an initial, rapid absorption of immediately available drug), thus providing a prolonged duration of action. Following a single 7.5-mg IM dose in orchiectomized prostate cancer patients, initial plasma leuprolide concentrations averaged 19. ng/mL after 4 hours; plasma concentrations declined to about 0.8 ng/mL within 4 days, remained relatively stable for about 2.5 weeks, and then declined over the next several weeks. Within the first 4 weeks after IM administration of the suspension, 85-100% of the active drug is absorbed. Plasma concentrations of the drug are undetectable in most patients 8 weeks after IM administration of a single 7.5-mg dose. Following a single 22.5-mg IM dose of the suspension, initial peak plasma leuprolide concentrations averaged 48.9 ng/mL after 4 hours; at 12 weeks, mean plasma concentrations declined to 0.67 ng/mL. Leuprolide appeared to be released at a constant rate following the onset of steady-state levels during the third week after dosing, providing steady plasma concentrations through the 12-week dosing interval; however, intact leuprolide and an inactive major metabolite could not be distinguished by the assay employed in the study. In orchiectomized prostate cancer patients receiving a single 30-mg IM dose of leuprolide suspension, a mean plasma concentration of 59.3 ng/mL was observed at 4 hours, with a decline in mean plasma concentration to 0.3 ng/mL at 16 weeks. From weeks 3.5 to 16, the mean plasma concentration of leuprolide was 0.44 ng/mL (range: 0.2-1.06 ng/mL). Following the onset of steady-state levels during the fourth week after dosing, drug release appeared to occur at a constant rate, resulting in steady plasma concentrations throughout the 16-week dosing interval; however, the assay used in the study was not able to differentiate between the parent drug and an inactive major metabolite. Even though undetectable plasma concentrations of the drug have been observed during chronic IM administration of the suspension, serum testosterone concentrations appear to be maintained at castration levels. Following a single 3.75-mg IM dose in healthy women, mean plasma leuprolide concentrations of approximately 0.23-0.34 ng/mL were maintained for a period of 4-5 weeks. Plasma concentrations of the drug declined slowly and became undetectable 8 weeks after IM administration of a single 3.75-mg dose. Absolute bioavailability of the drug is about 80% following IM administration of a single 3.75-mg dose in adult females. Following IM administration of single 7.5-, 11.25-, or 15-mg doses of leuprolide acetate suspension in children with central precocious puberty, weighing an average of 22.7,32.5, or 44.2 kg, respectively, mean trough plasma leuprolide concentrations were approximately 0.77, 1.25, or 1.59 ng/mL, respectively, 4 weeks after administration of the drug. Following subcutaneous injection of 3.75, 7.5, or 15 mg of the suspension in patients with prostate cancer, peak plasma concentrations were dose-proportional (range: 13.1-54.5 ng/mL) and occurred within 3 hours after injection; mean plasma concentrations declined in a dose-proportional fashion and reached a plateau at 5 weeks.

Following application to the skin of an electrically stimulated (to alter cutaneous permeability) transdermal delivery system containing 5 mg of leuprolide, the drug was absorbed percutaneously in pharmacologically important amounts, producing effects on serum luteinizing hormone (LH) that were comparable to those produced by a 5-mg subcutaneous dose; however, onset of response was slower (147 versus 73 minutes) and the magnitude of early (during the initial 1.5 hours after administration) response was lower with transdermal versus subcutaneous administration. Although the drug also has produced pharmacologically and/or clinically important systemic effects following intranasal administration, systemic absorption of the drug appears to be substantially lower following this route of administration compared with subcutaneous injection.

• Distribution

Distribution of leuprolide acetate into human body tissues and fluids has not been determined. Since endogenous GnRH is distributed in high concentrations into kidney, liver, pineal, and pituitary tissue in animals, with lower concentrations in hypothalamus, cerebral cortex, and muscle, it is likely that distribution of leuprolide into these tissues may also occur. In one study, leuprolide was distributed into anterior pituitary tissue in animals. In healthy men receiving leuprolide by IV bolus, a mean steady-state volume of distribution of 27 L was reported, and in vitro binding to human plasma proteins ranged from 43-49%. At therapeutic serum concentrations, leuprolide acetate has been reported to be about 7-15% bound to serum proteins (mainly albumin) in vitro. It is not known whether leuprolide crosses the placenta or is distributed into milk.

• Elimination

The metabolic fate and elimination characteristics of leuprolide acetate in humans have not been fully elucidated to date. The drug reportedly has an elimination half-life of about 3 hours following IV administration. Following administration of 1 mg leuprolide by IV bolus in healthy male volunteers, a mean systemic clearance of 7.6 L per hour and a terminal elimination half-life of approximately 3 hours (based on a 2-compartment model) were reported. Several enzymes in the hypothalamus and anterior pituitary may be responsible in part for the metabolism of endogenous GnRH, and leuprolide may also be metabolized to some extent by similar mechanisms; leuprolide‘s increased biologic potency compared with naturally occurring GnRH may be related to resistance of leuprolide to enzymatic inactivation in vivo. In vitro studies suggest that GnRH analogs with d-amino acid substitutions at position 6 (e.g., leuprolide) are resistant to the hypothalamic peptidase responsible for cleavage of naturally occurring GnRH between positions 6 and 7.90, 91 Radioisotope studies in rats and dogs have shown that leuprolide is metabolized to smaller inactive peptides, a pentapeptide (metabolite I), tripeptides (metabolites II and III), and a dipeptide (metabolite IV). Following administration of leuprolide to several patients with prostate cancer, peak plasma concentrations of the major metabolite (M-I) were reached 2-6 hours after dosing and were approximately 6% of the maximum parent drug concentration; 1 week after drug administration, mean plasma M-I concentrations were about 20% of mean leuprolide concentrations. In several patients receiving 3.75 mg leuprolide acetate for depot suspension, less than 5% of the dose was recovered as parent drug and M-I metabolite in urine.

The pharmacokinetics of leuprolide in patients with impaired renal or hepatic function has not been determined to date.

Chemistry and Stability

• Chemistry

Leuprolide acetate, a synthetic nonapeptide analog of naturally occurring porcine or ovine gonadotropin releasing hormone (GnRH, luteinizing hormone releasing hormone, gonadorelin), may be used as an antineoplastic agent. Leuprolide differs structurally from GnRH by the presence of the d-isomer of leucine at position 6 and an ethylamide group replacing glycine at position 10. These structural modifications result in increased potency of leuprolide (in terms of luteinizing hormone release) compared with GnRH.

Leuprolide acetate occurs as a white to off-white powder. The drug has solubilities of greater than 250 mg/mL in water and greater than 1 g/mL in alcohol at 25°C.

Leuprolide acetate is commercially available as a sterile solution of the drug in water for injection for subcutaneous administration and as a sterile, lyophilized powder for injectable suspension for IM administration. Leuprolide acetate injection also contains benzyl alcohol as a preservative; sodium hydroxide and/or acetic acid may be added during manufacture of the injection to adjust pH to 4.5-7, and sodium chloride is added to provide an isotonic solution. The commercially available injection occurs as a clear, colorless solution. The powder for injectable suspension contains microspheres of leuprolide acetate in a biodegradable copolymer of lactic and glycolic acids; the powder for injectable suspension also may contain gelatin and mannitol. During manufacture of the powder for injectable suspension, acetic acid is lost, leaving the peptide. Following reconstitution with the diluent provided by the manufacturer, leuprolide acetate suspension is milky in appearance and provides a vehicle from which the drug is slowly and gradually released following IM administration. The diluent provided by the manufacturer provides the appropriate vehicle for reconstitution and delivery of the drug and contains carboxymethylcellulose sodium, mannitol, acetic acid, and polysorbate 80 in sterile water for injection. Leuprolide acetate powder for injectable suspension also is available in a dual-chamber, disposable, single-use syringe; chamber 1 of the system contains leuprolide acetate lyophilized powder and mannitol, while chamber 2 contains the same sterile diluent that is supplied by the manufacturer with the single-use vials.

• Stability

Unopened vials of leuprolide acetate injection should be refrigerated at 2-8°C; freezing should be avoided. The vial in use may be stored at room temperature for several months without substantial loss of potency. Leuprolide acetate injection should be protected from light.

Leuprolide acetate powder for injectable suspension (provided in single-use vials or dual-chamber, disposable, single-use syringe) and its diluent may be stored at room temperature. It is not necessary to store the drug or its diluent under refrigeration; freezing should be avoided. Although the suspension is stable for 24 hours following reconstitution, it should be discarded if not used immediately since it does not contain a preservative. An excess of diluent is provided (in the ampuls supplied with the single-dose vials), and any unused diluent should be discarded.

For further information on the pharmacology of antineoplastic agents, resistance, and general principles in cancer chemotherapy, see the Antineoplastic Agents General Statement 10:00. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Leuprolide Acetate

Parenteral

For injectable 3.75 mg Lupron Depot®, (with gelatin, suspension, dl-lactic and glycolic acids, extended-release, copolymer, and mannitol and for IM use with diluent containing carboxymethylcellulose, sodium mannitol, polysorbate 80, and water for injection; available as prefilled dual-chambered syringes and single-dose vials) TAP Pharmaceuticals 7.5 mg Lupron Depot®, (with gelatin, dl-lactic and glycolic acids, copolymer, and mannitol and with diluent containing carboxymethylcellulose, sodium mannitol, polysorbate 80, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals Lupron Depot-Ped®, (with gelatin, dl-lactic and glycolic acids, copolymer, and mannitol and with diluent containing carboxymethylcellulose, sodium mannitol, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals 11. mg Lupron Depot-Ped®, (with gelatin, dl-lactic and glycolic acids, copolymer, and mannitol and with diluent containing carboxymethylcellulose, sodium mannitol, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals Lupron Depot®-3 Month, (with mannitol and polylactic acid and with diluent containing carboxymethylcellulose, sodium mannitol, polysorbate 80, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals 15 mg Lupron Depot-Ped®, (with gelatin, dl-lactic and glycolic acids, copolymer, and mannitol and with diluent containing carboxymethylcellulose, sodium mannitol, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals 22. mg Lupron Depot®-3 Month, (with polylactic acid and mannitol and with diluent containing carboxymethylcellulose, sodium mannitol, polysorbate 80, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals 30 mg Lupron Depot®-4 Month, (with polylactic acid and mannitol  and with diluent containing  carboxymethylcellulose, sodium mannitol, polysorbate 80, and water for injection; available as prefilled dual-chambered syringes and single-dose vials)

TAP Pharmaceuticals Injection, for 5 mg/mL Leuprolide Acetate Injection, subcutaneous use Eon Lupron®, (with benzyl alcohol 9 mg/mL)

TAP Pharmaceuticals Lupron® for Pediatric Use, (with benzyl alcohol 9 mg/mL; with disposable syringes)

TAP Pharmaceuticals

A worsening (flare) of signs and/or symptoms of hormone-dependent disease (e.g., endometriosis, prostatic carcinoma) has occasionally occurred during the initial 1-2 weeks of leuprolide therapy (secondary to the initial leuprolide-induced stimulation of pituitary release of gonadotropins and resultant ovarian and testicular steroidogenesis) and then subsided during continued therapy. In males with prostate cancer, this transient exacerbation of signs and/or symptoms apparently results from initial leuprolide-induced increases in serum testosterone concentrations. During the first week of leuprolide therapy, serum testosterone concentrations increase in most patients with prostatic carcinoma. Serum testosterone concentrations may be 1.5-2 times higher than baseline values during initial therapy. Increased bone pain is the most frequent manifestation of disease flare in leuprolide-treated patients with metastatic prostate cancer; increased signs and/or symptoms of urinary tract obstruction (e.g., dysuria, hematuria) and/or vertebral metastases (e.g., weakness or paresthesia of the lower extremities) occur less frequently. The likelihood of neurologic and/or genitourinary complications is increased during initial leuprolide therapy in patients with prostatic carcinoma and metastatic vertebral lesions and/or urinary tract obstruction. Several patients with prostate cancer who developed disease flare died during the flare. Concomitant therapy with an antiandrogen (e.g., flutamide, nilutamide) has been used in an effort to minimize the development of disease flare and improve overall response rates in patients with advanced prostate cancer. Disease flare manifested as increased bone pain reportedly has also occurred in patients with endometriosis and metastatic breast cancer who were receiving leuprolide therapy.

• Endocrine Effects

The most frequent adverse effect of leuprolide is hot flushes (flashes), reportedly occurring in 40-77% of patients receiving the drug. Leuprolide-induced hot flushes have ranged in severity from occasional mild flushing to frequent sweating. Although leuprolide-induced hot flushes appear to be more severe than those associated with estrogen therapy or following orchiectomy, this adverse effect usually does not require discontinuance of therapy.

Although not generally considered an adverse effect in women with endometriosis or certain other gynecologic conditions, amenorrhea occurs frequently in women receiving leuprolide and is dose dependent, occurring more frequently with larger doses and continued therapy. In women receiving monthly injections (3.75 mg) of long-acting leuprolide acetate for endometriosis, amenorrhea reportedly develops in 64-74 and 98% of women after the first and second dose, respectively. In most of these women, spotting occurs at least once after suppression of menses. In women receiving such therapy for endometriosis, normal menstrual cycles resumed in 7, 71, and 95% of those who did not become pregnant within the first, second, and third posttreatment months, respectively. Most women not developing amenorrhea during leuprolide therapy for endometriosis exhibit only light vaginal bleeding (hypomenorrhea) or spotting. Amenorrhea and vaginal bleeding also occurs in other women receiving the drug (e.g., those being treated for breast cancer or leiomyoma uteri [fibroids]). Although most women receiving leuprolide for leiomyoma uteri develop amenorrhea, excessive vaginal bleeding (menorrhagia), which may result in anemia, has been reported in a few women with submucosal fibroids. It was suggested that such bleeding in these women may result from underlying degenerative changes that become evident during leuprolide-induced involution of submucosal fibroids.

Other effects attributed to leuprolide-induced hypoestrogenism in women include headache, vaginitis, vaginal dryness, mental depression/emotional lability, decreased bone density, decreased libido, GI disorders, breast changes (e.g., tenderness, pain, reduction in size), joint disorder, neuromuscular disorders, myalgia, sleep disorders (e.g., insomnia), acne, and increased plasma concentrations of certain lipids and lipoproteins (e.g., triglycerides, total cholesterol). Reductions in serum estrogen concentrations induced by leuprolide are reversible following discontinuance of the drug. Androgenic-like effects also have been reported in women receiving leuprolide, but less frequently than in those receiving danazol.

In clinical studies in women receiving six monthly 3.75-mg doses of the long-acting IM formulation of leuprolide acetate for endometriosis, serum total cholesterol concentrations were elevated at the completion of therapy in 7% of women whose concentrations were in the normal range prior to initiation of therapy with the drug. Increases during therapy averaged 14.-16. mg/dL. Serum triglyceride concentrations were elevated in 12% of women receiving such leuprolide therapy, and such elevations appear to occur less frequently with danazol therapy. Serum concentrations of high-density lipoprotein (HDL) cholesterol decreased by 2% at the completion of leuprolide therapy in such women, and such reductions appear to occur substantially more frequently in women receiving danazol for endometriosis. Low-density lipoprotein (LDL) cholesterol concentrations are elevated in 6% of women receiving this regimen of leuprolide, which appears to be less frequent than that associated with danazol therapy. In addition, while the LDL/HDL ratio was increased twofold in women receiving danazol therapy, the ratio was unchanged in those receiving leuprolide. In women receiving the drug for anemia associated with uterine leiomyomata, mean increases in cholesterol ranged from 11-29 mg/dL, mean increases in LDL cholesterol ranged from 8-22 mg/dL, mean increases in HDL cholesterol ranged from 0-6 mg/dL, and mean change in LDL/HDL ratio ranged from -0.1 to +0.5. In one study where triglyceride concentrations were determined, the mean increase from baseline was 32 mg/dL.

The potential for hypoestrogenic-induced decreases in bone density is a principal concern about long-term therapy with GnRH analogs, including leuprolide, in women. These changes in bone density appear to result from increased bone resorption and turnover and changes in calcium homeostasis secondary to the hypoestrogenic state that results from suppression of ovarian steroidogenesis; biochemical changes (e.g., serum and urinary measures of bone resorption) supportive of this mechanism have been observed in women receiving the drugs. However, the extent of changes in bone density induced by GnRH analogs may depend on the degree and duration of ovarian suppression induced by the drugs. The manufacturer reports that vertebral bone density (as determined by dual-photon absorptiometry) decreased on average by 3.9% following 6 months of leuprolide therapy in a controlled study in women with endometriosis; in women with uterine leiomyomata receiving leuprolide therapy for 3 months, vertebral trabecular bone mineral density (as determined by quantitative digital radiography) decreased on average by 2.7%. Although lumbar bone mineral density (as determined by dual-photon absorptiometry) decreased slightly but not statistically significantly in one study in women receiving intranasal leuprolide therapy (1.6 mg daily for 6 months) for endometriosis with concomitant calcium supplementation, vertebral trabecular bone density (as determined by quantitative computed tomography) decreased on average by 11.% following 6 months of therapy with 3.75 mg of IM leuprolide acetate given at monthly intervals as the long-acting formulation in another study in women with endometriosis. The reason for these reported differences in effects is not known but may be related to differences in study design, the degree and duration of ovarian suppression, and/or calcium intake. Of the limited number of patients who were followed up in the latter study, bone density improved (complete to partial recovery) in most patients following discontinuance of the drug, with an average density loss of 2.4% one year after completion of leuprolide therapy; however, some of the bone loss may be slowly reversible or irreversible. Use of leuprolide for endometriosis for periods exceeding 6 months, for uterine leiomyomata for periods exceeding 3 months, or in patients with other risk factors for decreased bone mineral content may result in additional bone loss; therefore, the potential benefits versus possible risks of such use must be weighed carefully. (See Cautions: Precautions and Contraindications.) Consideration of measures (e.g., dietary and hormonal manipulation) to minimize bone mineral depletion during prolonged therapy with GnRH analogs has been suggested. GnRH analogs do not appear to affect substantially cortical bone mineral density.

Impotence and decreased libido have been reported frequently during leuprolide therapy for prostate cancer. Increased libido also has been reported. Gynecomastia and/or breast tenderness occur rarely in patients receiving leuprolide for the treatment of prostate cancer, and this adverse effect occurs less frequently than with DES therapy. Testicular atrophy has been reported in about 5-20% of patients receiving the drug. Thyroid enlargement/hard nodule in throat, hypoglycemia, and diabetes also have been reported.

Accelerated sexual maturity, breast disorders (including gynecomastia), peripheral edema, and weight gain have been reported in less than 2% of children with central precocious puberty receiving leuprolide therapy.

• Musculoskeletal Effects

Increased bone pain reportedly occurs in 10% or less of leuprolide-treated patients who have metastatic prostate cancer, apparently resulting from drug-induced disease flare during initial therapy. Patients with increased bone pain may require supplemental therapy with analgesics. Decreases in bone density have been reported in women receiving the drug. Myalgia and flu-like syndrome reportedly have occurred in less than 5% of patients receiving the drug. Neuromuscular disorders, joint disorders, ankylosing spondylosis, joint pain, pelvic fibrosis, and spinal fractures/paralysis also have been reported.

• Genitourinary Effects

Adverse genitourinary effects of leuprolide are usually transient and may result from drug-induced disease flare during initial therapy. Increased hematuria, dysuria, bladder spasms, frequency/urgency, incontinence, testicular pain, urinary tract infection, urinary disorders, penile swelling, penile disorders, testicular disorders, prostate pain, and flank pain have been reported occasionally in patients with prostate cancer receiving the drug. Dysuria, vaginitis, vaginal dryness pyelonephritis, and urinary disorders have been reported in women receiving the drug. Increased BUN and serum creatinine concentrations and polyuria have occurred rarely in patients with prostate cancer receiving the drug. Leuprolide-induced genitourinary complications have been associated with increased urinary tract obstruction in patients with prostate cancer. The possibility that drug-induced disease flare during initial therapy could result in genitourinary and renal complications in women with endometriotic ureteral obstruction should be considered.

Vaginal disorders, including vaginitis, discharge, and/or bleeding, have been reported in 2% or more of children with central precocious puberty receiving leuprolide therapy; disorders of the cervix and urinary incontinence occurred in less than 2% of these children.

• Nervous System Effects

Adverse nervous system effects reportedly occurring in 5% or more of patients receiving leuprolide include dizziness, vertigo, insomnia/sleep disorders, pain, mental depression/emotional lability, general pain, and headache.Lethargy, asthenia, fatigue, insomnia, irritability, anxiety, personality disorder, delusions, mood swings, depression, nervousness, memory disorder, hypoesthesia, paresthesia, peripheral neuropathy, numbness, syncope/blackouts, and tinnitus have been reported in less than 5% of patients receiving the drug. Confusion also has been reported.

Headache, nervousness, personality disorder, emotional lability, and somnolence have been reported in less than 2% of children with central precocious puberty receiving leuprolide therapy.

• Cardiovascular Effects

Leuprolide dosages of 1 mg daily produce fewer adverse cardiovascular effects and thromboembolic complications than DES dosages of 3 mg daily. Peripheral edema has been reported in about 12% or less of leuprolide-treated patients. Thrombophlebitis, phlebitis, and/or pulmonary embolus, and congestive heart failure have occurred rarely in patients receiving leuprolide, but a causal relationship to the drug has not been established. Angina, cardiac arrhythmias, bradycardia, heart failure, myocardial infarction, anemia, edema, and lymphedema have occurred in less than 5% of patients receiving the drug. Palpitation,tachycardia, syncope, ECG changes/ischemia, hypertension, hypotension, heart murmurs, and transient ischemic attacks/stroke also have been reported.

Syncope and vasodilation have been reported in less than 2% of children with central precocious puberty receiving leuprolide therapy.

• GI Effects

Leuprolide dosages of 1 mg daily produce less nausea and vomiting than DES dosages of 3 mg daily. Adverse GI effects occurring in 5% or more of patients receiving leuprolide include nausea and/or vomiting, constipation, weight gain or loss, GI disorders, and anorexia. Appetite changes, GI bleeding, diarrhea, GI disturbance, duodenal ulcer, peptic ulcer, rectal polyps, dysphagia, increased appetite, appetite changes, dry mouth, glossitis, thirst, enlarged abdomen, taste perversion, and sour or unusual taste in the mouth have been reported in less than 5% of patients receiving the drug.

Nausea and/or vomiting, dysphagia, and gingivitis have been reported in less than 2% of children with central precocious puberty receiving leuprolide therapy.

• Other Adverse Effects

Adverse local effects occurring occasionally with leuprolide include erythema, ecchymosis, injection site reaction, and irritation at the injection site. Irritation at the injection site, including abscess, has been reported in 2% or more of children with central precocious puberty receiving leuprolide therapy. Adverse respiratory effects, including pneumonia, pulmonary infiltrates, respiratory disorders, cough, pharyngitis, sinus congestion, dyspnea, epistaxis, hemoptysis,rhinitis, pleural rub, pleural effusion, and pulmonary fibrosis, have occurred occasionally. Epistaxis has been reported in less than 2% of children with central precocious puberty receiving leuprolide therapy. Other adverse effects of leuprolide occurring infrequently include fever, rash,hives,alopecia, hair disorder, ecchymosis, pruritus, dry skin, local skin reactions, pigmentation, dermatitis, skin lesions, nail disorder, lymphadenopathy,lactation,carcinoma of the skin/ear, ophthalmologic disorders (e.g., blurred vision, amblyopia, abnormal vision, dry eyes, conjunctivitis), hypoproteinemia, increased serum calcium concentration, increased serum uric acid concentration, and infection/inflammation. General pain, acne and/or seborrhea, rash (including erythema multiforme) have been reported in more than 2% of children with central precocious puberty receiving leuprolide therapy; body odor, alopecia, skin striae, fever, and infection occurred in less than 2% of these children.

Abnormal liver function test results, including serum concentrations of AST (SGOT) and LDH greater than twice normal and alkaline phosphatase greater than 1.5 times normal, occur frequently in patients receiving leuprolide. However, the significance of these abnormalities is difficult to assess in patients with prostate cancer. Increased serum alkaline phosphatase and transaminase concentrations also have been reported in women receiving the drug. Slight to moderate increases in hematocrit and serum concentrations of hemoglobin, total protein, albumin, and calcium have been reported in women with endometriosis receiving leuprolide. Increased serum LDH and phosphorus concentrations also have been reported in 5-8% of such women in comparative (danazol) studies. Decreases in platelet count, leukocyte count, and neutrophils and slight to moderate increases in glucose, uric acid, BUN, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorous concentrations have been observed in women receiving the drug for anemia associated with uterine leiomyomata. Decreased leukocyte counts also were observed in women receiving leuprolide.

• Precautions and Contraindications

Leuprolide occasionally may produce a worsening (flare) of signs and/or symptoms of disease (e.g., increased bone pain) in patients with prostate cancer during the initial 1-2 weeks of therapy. Worsening of symptoms may contribute to paralysis with or without fatal complications. For patients at risk, clinicians may consider initiating leuprolide therapy with daily administration of the injection (rather than monthly administration of the suspension) for the first two weeks to facilitate withdrawal of treatment if it is considered necessary. Patients with prostate cancer and metastatic vertebral lesions and/or urinary tract obstruction should be closely observed during initial leuprolide therapy, since temporary weakness or paresthesia of the lower limbs and/or worsening of urinary signs and symptoms may occur. Leuprolide should be used with extreme caution in patients with life-threatening disease in whom rapid symptomatic relief is necessary, since exacerbation of signs and/or symptoms of the disease potentially may result in a rapid fatal outcome in some of these patients. The possibility of disease flare during initiation of leuprolide therapy in women also should be considered. An anaphylactic reaction to synthetic GnRH has been reported.

Because safety in women has not been established beyond 6 months and because of concerns about potential long-term effects on bone density, leuprolide therapy extending beyond this period or additional courses of therapy with this or another GnRH analog currently are not recommended in women.If retreatment with the drug is considered, bone density should be assessed and be within normal limits before initiating another course of leuprolide therapy. Leuprolide should be used with caution, carefully weighing the risks and benefits, in women with known major risk factors for decreased bone mineral content. Such factors include chronic alcohol and/tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., corticosteroids, certain anticonvulsants [e.g., phenytoin]).

Patients should be advised that they may experience hot flushes during leuprolide therapy. Patients should also be advised that a temporary exacerbation of the signs and/or symptoms of prostate cancer (e.g., increased bone pain, difficulty in urinating, and, less commonly but most importantly, onset or aggravation of neurologic symptoms) may occur during the first few weeks of therapy with the drug and that they should discuss these effects with their physician if such effects occur. Women receiving the drug also should be advised of the possibility of temporary exacerbation of manifestations of their disease during initiation of therapy. In addition, women should be advised that leuprolide usually inhibits ovulation; however, contraception is not ensured during therapy with the drug, and an effective nonhormonal method of contraception should be employed. (See Cautions: Pregnancy, Fertility, and Lactation.) Since menstruation should stop with effective leuprolide therapy, women should contact their physician if regular menstruation persists during therapy or abnormal vaginal bleeding develops. Women also should be advised that breakthrough bleeding and ovulation (with the potential for conception) may occur if a successive dose of the drug is missed; if pregnancy occurs, leuprolide should be discontinued and their physician consulted.

Serum testosterone, prostate-specific antigen, and prostatic acid phosphatase (PAP) concentrations should be determined periodically during leuprolide therapy in patients with prostate cancer to monitor therapeutic response, including successful remission or possible progression of the disease. Serum testosterone concentrations may increase during the first week of leuprolide therapy but should decrease to less than or equal to baseline values within 2 weeks. After 2-4 weeks of leuprolide therapy, serum testosterone concentrations should reach castrate levels and be maintained at this level for the duration of therapy. Transient elevations in testosterone concentrations following suppression to castration levels have been reported in a small number of patients receiving the 3- and 4-month leuprolide depot suspensions in clinical trials. Serum PAP concentrations may also increase initially in patients receiving leuprolide; however, increases in serum PAP concentrations should decrease to at or near baseline values by the fourth week of therapy. Some clinicians suggest that periodic determination of serum testosterone concentration is not necessary in all patients with prostate cancer during leuprolide therapy but may be useful in determining noncompliance in patients who appear to respond poorly to therapy with the drug.

Leuprolide acetate injection should be used with caution in patients with known hypersensitivity to benzyl alcohol, since local hypersensitivity reactions, including erythema or induration at the injection site, may develop. Leuprolide is contraindicated in patients with known hypersensitivity to GnRH, GnRH analogs, or any ingredient in the respective leuprolide formulation. The drug also is contraindicated during pregnancy (see Cautions: Pregnancy, Fertility, and Lactation) and in women with abnormal vaginal bleeding of unknown etiology.

• Pediatric Precautions

Safety and efficacy of leuprolide in children for uses other than the treatment of central precocious puberty have not been established.

Prior to initiation of therapy with leuprolide in children with precocious puberty, height and weight evaluations should be performed; serum testosterone or estrogen concentrations should be determined in boys or girls, respectively. In addition, adrenal steroid and ?-human chorionic gonadotropin concentrations should be determined to rule out congenital adrenal hyperplasia and chorionic gonadotropin secreting tumors, respectively. The manufacturer also states that a pelvic, adrenal, or testicular ultrasound examination should be performed to rule out steroid secreting tumors; computerized tomography of the head may rule out intracranial tumors. Parents or guardians of female patients should be advised that menstruation or spotting may occur during the first 2 months of leuprolide therapy and they should notify the physician if vaginal bleeding continues after 2 months of drug therapy. Parents or guardians should be instructed to notify the physician if any irritation at the injection site or any unusual sign or symptom occurs. Gonadotropin and sex steroid concentrations may increase during the early phase of leuprolide therapy secondary to the naturally stimulating effect of the drug which may result in increased clinical signs and symptoms of the disease. Serum sex steroid concentrations should be determined and a GnRH stimulation test should be performed 1-2 months after initiation of leuprolide therapy and periodically (e.g., every 6 months thereafter) to evaluate response to the drug; bone age should be determined every 6-12 months. Parents or guardians also should be advised about the importance of continuous therapy; successful therapy with leuprolide requires adherence to the suggested 4-week (with IM administration of leuprolide suspension) or daily (with subcutaneous administration of the injection) dosage schedule.

Noncompliance with leuprolide therapy in children with central precocious puberty may result in inadequate control of the disease including onset of menses and enlargement of breasts in girls and testicular enlargement in boys. The long-term effects of inadequate control of gonadal (sex) steroid secretion are not known; however, they may result in compromised adult stature.

Leuprolide may produce worsening of signs and symptoms of central precocious puberty in children with rapidly progressive disease during the first few weeks of therapy.

• Mutagenicity and Carcinogenicity

It is not known if leuprolide is mutagenic or carcinogenic in humans. Leuprolide has not exhibited mutagenic activity to date in microbial or mammalian test systems. Dose-related increases in the incidence of benign pituitary hyperplasia and adenomas have been observed in rats following subcutaneous administration of 0.6-4 mg/kg of leuprolide daily for 24 months; there was an increase (but not dose related) in pancreatic islet-cell adenomas in females and in testicular interstitial cell adenomas in males (highest incidence in the low-dose group). Pituitary abnormalities were not observed in mice receiving leuprolide dosages up to 60 mg/kg for 2 years. Pituitary abnormalities also have not been observed in adults following subcutaneous administration of leuprolide at dosages of up to 10 mg daily for up to 3 years or up to 20 mg daily for 2 years.

• Pregnancy, Fertitlity and Lactation

Pregnancy

Leuprolide is contraindicated in women who are or may become pregnant while receiving the drug since fetal harm may occur. Women of childbearing potential should use an effective nonhormonal method of contraception during leuprolide therapy and be advised to discontinue therapy with the drug and contact their physician if they think that they may be pregnant. Women also should be advised to contact their physician if regular menstruation persists after initiation of leuprolide therapy. If the drug is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, leuprolide should be discontinued and the woman informed of the potential hazard to the fetus. The potential duration of effect of the long-acting formulation (leuprolide acetate injection) also should be considered. Since the effects on fetal mortality are logical consequences of the changes in hormonal levels induced by leuprolide, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy. Pregnancy should be ruled out prior to administration of leuprolide.

When administered to rabbits on day 6 of pregnancy at dosages of 0.24, 2.4, and 24 mcg/kg, leuprolide caused a dose-related increase in major fetal malformations. Similar studies in rats did not result in an increase in fetal malformations. Increased fetal mortality and decreased fetal weights occurred with the two higher doses in rabbits and with the highest dose in rats. Effects on fetal mortality are extensions of the drug’s pharmacologic effects (i.e., alterations in hormonal concentrations). The possibility exists that spontaneous abortions may occur if leuprolide is administered during pregnancy.

Fertility

Clinical and pharmacologic studies in adults indicate that GnRH analogs, including leuprolide, can reversibly suppress fertility in males and females receiving the drug. Complete reversibility has been shown following continuous therapy for up to 24 weeks. Whether suppression of fertility also is reversible in children has not been established since fertility studies in children have not been completed. However, results of animal fertility studies in prepubertal and adult rats and monkeys indicate that GnRH analogs (e.g., leuprolide) can reversibly suppress fertility. Tubular degeneration without histologic recovery in the testes occurred in immature male rats who received leuprolide therapy, but fertility in these rats was similar to that in rats not receiving the drug; however, no histologic changes were observed in female rats receiving leuprolide. Offspring of these female or male rats appeared to be normal, but the clinical relevance of these findings is not known. The effect on reproductive performance of first-generation offspring whose parents received leuprolide therapy has not been studied to date.

Continuous leuprolide therapy may impair fertility in males as a result of the drug’s pharmacologic effects. Decreased gonadotropin release with subsequent inhibition of testosterone production and spermatogenesis and changes in testicular histology have occurred. Results from animal studies suggest that leuprolide-induced testicular changes are at least partially reversible; however, some clinicians believe that the degree of change in testicular histology (i.e., tubular thickening and fibrosis, decreased number of Leydig cells) observed in humans receiving long-term therapy with the drug is suggestive of at least some irreversible effects on fertility. Continuous leuprolide therapy may also impair fertility in females as a result of decreased gonadotropin release and subsequent inhibition of estrogen production, ovulation, and corpus luteum formation. Amenorrhea and other menstrual changes have occurred during continuous therapy with GnRH analogs. (See Cautions: Endocrine Effect.) In one study after 3-12 months of continuous therapy with a GnRH analog, inhibitory effects on ovulation appeared to be reversible following discontinuance of the drug.

Lactation

Because the effects of leuprolide on lactation and nursing infants currently are not known, the drug should not be used in nursing women.

Leuprolide acetate suspension is administered IM, and leuprolide acetate injection is administered subcutaneously. The manufacturer states that the suspension is not intended for self-administration and therefore should be administered under the supervision of a physician. Various dosage forms of the drug have also been administered IV72, 77 and intranasally, but these routes of administration currently are not recommended. Injection sites should be rotated periodically. Leuprolide acetate injection should be inspected visually for particulate matter and discoloration prior to administration.

Leuprolide acetate powder for injectable suspension should be reconstituted using only the diluent provided by the manufacturer; other diluents should not be substituted. To reconstitute the suspensions containing 3.75, 7.5, 11.25, or 15 mg of drug per dose, 1 mL of the diluent should be withdrawn from the ampul (using a syringe with a 22-gauge needle) and added to the vial containing the powder for injectable suspension. To reconstitute the suspensions containing 22.5 or 30 mg of drug per dose, 1.5 mL of the diluent should be withdrawn from the ampul (using a syringe with a 23-gauge needle for the 22.5-mg suspension and with at least a 22-gauge needle for the 30-mg suspension) and added to the vial containing the powder for injectable suspension (extra diluent is provided, and any remaining should be discarded). The vial should be shaken well to thoroughly disperse the particles and obtain a uniform suspension (which will appear milky). The entire contents of the vial should then be withdrawn to provide a 3.75-, 7.5-, 11.25-, 15-, 22.5-, or 30-mg dose, depending on the labeled concentration of the vial used. Because the 22.5- and 30-mg suspensions settle very quickly following reconstitution, it is preferable that the suspension be mixed and used immediately; if settling occurs, the suspension should be reshaken. Alternatively, leuprolide acetate powder for injectable suspension, provided in the dual-chamber, disposable, single-use syringes should be reconstituted with the accompanying diluent in accordance with the instructions provided by the manufacturer.

Patients receiving leuprolide acetate injection for self-administration and parents or guardians who administer leuprolide acetate injection to children with central precocious puberty should be instructed carefully about proper administration techniques and precautions and should be given a copy of the patient instructions provided by the manufacturer. Patients should be advised to use the syringe(s) provided by the manufacturer and to contact their physician or pharmacist for advice if one of these syringes cannot be used. If it is absolutely necessary to substitute another syringe for the one provided by the manufacturer for use with leuprolide acetate injection, a 0.5-mL disposable, low-dose, U-100 insulin syringe is the only syringe that should be used. For administration of leuprolide acetate injection with this insulin syringe, the patient should be instructed to fill the syringe to the 20-unit mark. Patients should also be advised that, although the drug is refrigerated prior to dispensing, the vial of drug currently in use can be stored at a room temperature less than 30°C (86°F) and that storage in direct sunlight or near a source of heat (e.g., a radiator) or other very warm place should be avoided. Patients should be instructed to contact their physician if local adverse effects, other than mild, transient irritation (e.g., burning, itching, swelling), occur at the site of injection.

• Dosage

Prostate Cancer

For the palliative treatment of advanced prostate cancer, the usual dosage of leuprolide acetate suspension is 7.5 mg IM once monthly, 22.5 mg IM once every 3 months (84 days), or 30 mg IM once every 4 months (16 weeks). Because of different release characteristics, a fractional dose of the 22.5- or 30-mg suspension formulation is not equivalent to the same dose of the once-monthly formulation, and should not be used for monthly doses. If a monthly dose is missed, a delay of up to 12 days may or may not compromise the patient’s treatment; however, if a monthly dose is missed by 2 or more weeks, serum testosterone concentrations will increase substantially.

If leuprolide acetate injection is used for the palliative treatment of advanced prostate cancer, the usual dosage is 1 mg daily given by subcutaneous administration. Some clinicians have increased leuprolide dosages up to 20 mg daily, but dosages higher than 1 mg daily have not resulted in a greater incidence of remission. If leuprolide therapy is initiated with daily subcutaneous administration of the injection in patients at risk of worsening signs and symptoms of the disease, daily therapy should be used for about 2 weeks prior to administration of the once-monthly suspension.

If flutamide is used concomitantly with leuprolide for the palliative treatment of advanced prostate cancer, flutamide therapy is initiated concurrently with leuprolide therapy at an oral dosage of 750 mg daily, given in equally divided doses (i.e., 250 mg) every 8 hours.

Patients receiving leuprolide acetate injection should be advised that continuous, daily therapy with leuprolide is necessary in the treatment of prostate cancer with this dosage form. Patients receiving leuprolide therapy with the injection or suspension should also be advised that the drug should be continued even when signs and/or symptoms of the disease improve.

Endometriosis

For the palliative treatment of endometriosis, the usual dosage of leuprolide acetate suspension is a single course of 3.75-mg doses administered IM once monthly for 6 consecutive months. Retreatment with additional courses of therapy currently is not recommended because safety in women has only been established for a single 6-month course and because of concerns about potential long-term effects on bone density.If retreatment is considered following recurrence of endometriosis, the potential benefits and possible risks should be weighed carefully, and bone density should be assessed and be within normal limits before initiating another course of leuprolide.

Uterine Leiomyomata

For the correction of anemia associated with uterine leiomyomata (uterine fibroids) prior to surgery, the usual dosage of leuprolide acetate suspension is a single course of 3.75-mg doses administered IM once monthly for up to 3 consecutive months; iron therapy also is administered concomitantly. If additional therapy is considered, bone density should be assessed prior to initiation of therapy to ensure that values are within normal limits.

Central Precocious Puberty

Dosage of leuprolide must be individualized and should be based on actual body weight; younger children generally appear to require higher dosages on a mg/kg basis than older children. The manufacturer and some clinicians state that 1-2 months after initiation of leuprolide therapy or when dosage of the drug is being changed certain tests (e.g., a GnRH stimulation test, a Tanner staging test) and sex steroid concentrations should be determined to confirm inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis. Inadequate dosage of leuprolide may lead to increased sex steroid concentrations; once a therapeutic dosage of leuprolide has been achieved, gonadotropin and sex steroid concentrations will decline to prepubertal concentrations. In most children, the first dosage of leuprolide found to adequately inhibit gonadotropin secretion and suppress ovarian or testicular steroidogenesis may be maintained for the duration of therapy. However, data currently are insufficient for special dosage recommendations in children in whom leuprolide was initiated at a low dosage and a very young age and whose weight has changed such that the patient would be in a different weight range/dose category. The manufacturer recommends that inhibition of gonadotropin secretion and suppression of ovarian or testicular steroidogenesis be monitored closely in children whose weight has increased considerably while receiving leuprolide therapy. Discontinuance of leuprolide therapy should be considered in girls or boys before they reach the age of 11 or 12 years, respectively.

For the management of central precocious puberty in girls or boys younger than 8 or 9 years old, respectively, the usual dosage of leuprolide acetate suspension is a single dose of 0.3-mg/kg (minimum 7.5 mg) administered IM155, 158 or subcutaneously and repeated every 4 weeks.The manufacturer states that the initial dose of leuprolide acetate suspension should be 7.5 mg in children weighing 25 kg or less, 11. mg in those weighing 25-37.5 kg, and 15 mg in those weighing more than 37.5 kg. The dose of leuprolide acetate should be titrated upward in increments of 3.75 mg every 4 weeks until clinical or laboratory tests indicate no progression of the disease.

If leuprolide acetate injection is used in the management of central precocious puberty, the usual initial dosage is 50 mcg/kg, given by subcutaneous injection, once daily. If total suppression of ovarian or testicular steroidogenesis is not achieved, the dosage should be titrated upward by 10 mcg/kg daily.

Leuprolide acetate is used for the palliative treatment of advanced prostate cancer. The drug currently is considered alternative therapy for patients with inoperable prostatic tumors and/or who are intolerant to estrogen therapy (i.e., those at risk of estrogen-induced thromboembolic and thrombotic disorders, other cardiovascular effects, or other adverse effects) and for patients who refuse orchiectomy and/or estrogen therapy. Most clinical studies with the drug have been performed in patients with prostate cancer clinically diagnosed as stage D2 (i.e., tumor with metastases to distant lymph nodes, bone, and/or viscera). Responses to leuprolide therapy generally have been evaluated based on the criteria of the National Prostatic Cancer Project (NPCP). Leuprolide acetate injection and suspension have been shown to have comparable efficacy and safety in the treatment of advanced prostate cancer. Although direct comparison in clinical trials has not been performed, the safety and efficacy of the 4-month depot injection appear similar to the other leuprolide depot formulations. In most patients, use of the suspension may be preferred to use of the injection because of greater convenience of administration and patient compliance with therapy.

Leuprolide appears to be at least as effective as orchiectomy or estrogen therapy (specifically diethylstilbestrol [DES], no longer commercially available in the US) in previously untreated patients with advanced prostate cancer and is associated with fewer serious adverse effects than estrogen therapy (at least when DES is given in a dosage of 3 mg daily). In the treatment of advanced prostate cancer, leuprolide has produced an objective response in about 80% of previously untreated patients. Patients who respond to leuprolide therapy usually exhibit disease stabilization or, to a lesser extent, partial responses; complete responses occur rarely. The duration of clinical response with leuprolide appears to be comparable to that following orchiectomy or estrogen therapy; however, further long-term study is needed to clearly establish the duration of response to leuprolide. Patients whose disease responds to or is stabilized with hormonal manipulation (e.g., orchiectomy, estrogen therapy) appear to have increased survival compared with those whose disease progresses; however, there are insufficient data to date to determine the effect of leuprolide on long-term survival in patients with prostate cancer. Leuprolide is not recommended for use in patients with recurrent, advanced prostate cancer who previously underwent orchiectomy and/or previously received estrogen therapy. Patients most likely to respond to leuprolide probably are those whose tumors are relatively androgen dependent (approximately 80% of cases of newly diagnosed prostate cancer are androgen dependent).

In the treatment of advanced prostate cancer, it has not been clearly established whether immediate or delayed hormonal manipulation is optimal in asymptomatic patients. Many clinicians suggest that hormonal manipulation for newly diagnosed, advanced prostate cancer should be withheld until symptoms appear in patients who are asymptomatic and sexually potent; however, other clinicians suggest initiation of therapy at the time of diagnosis in asymptomatic patients to prevent further disease progression and delay of potentially effective treatment. A difference in survival between patients with stage D prostate tumors receiving immediate hormonal manipulation and those receiving delayed therapy has not been clearly demonstrated. Further study is needed to fully evaluate immediate-vs-delayed hormonal manipulation for the treatment of advanced prostate cancer and the effect on long-term survival.

Leuprolide therapy has been compared with conventional DES therapy in patients with stage D2 prostate tumors in a prospective, randomized, multicenter study (Leuprolide Study Group). Results from this study show that 1 mg of leuprolide and 3 mg of DES daily produce comparable objective and subjective responses and the median time to initial progression of disease was similar for both drugs. Because leuprolide causes initial increases in FSH and LH release and in serum testosterone concentrations, some clinicians suggest that the drug may induce an initial flare in the disease and worsen the prognosis in some patients. In the Leuprolide Study Group, leuprolide therapy was associated with a slight increase in bone pain during the first week of therapy, but similar numbers of leuprolide- or DES-treated patients had increased bone pain during the second and subsequent weeks of therapy. Transient increases in bone pain and symptoms of urinary obstruction in leuprolide-treated patients have also been reported in other studies.

The initial response to leuprolide therapy in patients with advanced prostate cancer, as determined by decreases in serum testosterone, dihydrotestosterone, and prostatic or total acid phosphatase concentrations, is delayed compared with DES therapy. In the Leuprolide Study Group, the delay was apparent for 1 and 12 weeks for serum testosterone and prostatic or total acid phosphatase concentrations, respectively. The duration of the initial clinical response following leuprolide therapy appears to be similar to that following orchiectomy or DES therapy. The median duration of clinical response in the Leuprolide Study Group was 60 or 61 weeks for leuprolide or DES, respectively. In several clinical studies, the duration of leuprolide-induced response ranged from 8-25 months, but follow-up of some of these patients is still ongoing and more prolonged responses (e.g., 4 years or longer) have been observed. Although survival rates during early evaluation of therapy were comparable in the Leuprolide Study Group, one-year survival rates were 87 or 78% in patients receiving leuprolide or DES, respectively. Long-term follow-up of these patients reportedly has shown a median survival of 146 or 136 weeks for those receiving leuprolide or DES, respectively.Additional long-term follow-up is necessary to determine the rate of disease progression and overall survival in leuprolide-treated patients. Comparative studies of leuprolide with DES dosages of less than 3 mg daily or with other GnRH analogs have not been performed to date.

Leuprolide appears to be of little value in patients with recurrent, advanced prostate cancer who previously underwent orchiectomy and/or previously received estrogen therapy compared with previously untreated patients. In a limited number of patients, about 80% of those who previously underwent orchiectomy or previously received DES had evidence of disease progression within 5 or 4 months, respectively, during leuprolide therapy; objective evidence of tumor regression was present in none or about 5% of these patients, respectively.

Administration of DES during the week before and the first week of leuprolide therapy has been used in a limited number of patients to inhibit the initial androgen stimulation and potential exacerbation of symptoms that may occur during leuprolide therapy. Pretreatment with DES did not completely inhibit the increases in testosterone and dihydrotestosterone concentrations, but the peak concentrations were substantially lower than those observed in patients not receiving pretreatment with DES and worsening of disease was not observed in any patient. Pretreatment with DES (no longer commercially available in the US) may be of benefit in selected patients prior to leuprolide therapy, but should probably not be used routinely since leuprolide-induced androgen stimulation is not clinically important in most patients.

Combined therapy with a GnRH analog (e.g., leuprolide) and an antiandrogen (e.g., megestrol, flutamide, nilutamide) appears to produce additive effects and may be more effective than GnRH analog therapy alone in the treatment of advanced prostate cancer. In a large prospective, randomized multicenter study in previously untreated patients with stage D2 prostatic tumors, combined therapy with leuprolide and flutamide was more effective than leuprolide alone in prolonging progression-free survival and overall survival. Symptomatic improvement was greatest during the first 3 months of combined therapy, when use of leuprolide alone may produce a painful flare in the disease. Combined therapy was particularly effective in patients with minimal disease and good performance status, but the number of patients in this subgroup was limited and further evaluation is needed. Concomitant therapy with a GnRH analog and an antiandrogen has been used in an effort to minimize the development of disease flare and improve overall response rates.

Although there occasionally may be dramatic and long-term disease-free survival with combined GnRH-analog and antiandrogen therapy in patients with advanced prostate cancer, median long-term survival with combination therapy generally has not exceeded 3 years in studies to date, and most such patients still will die from prostate cancer. In addition, pooled analysis of 22 randomized studies involving 5710 patients with advanced prostate cancer did not show any statistically significant improvement in long-term survival for combined GnRH-analog and antiandrogen therapy compared with surgical (orchiectomy) or medical (GnRH-agonist) castration. In this analysis, life-table estimates of 5-year survival rates were 26.2 versus 22.8% (representing a nonsignificant improvement of 3.5%) for combined therapy versus castration, which were not significantly different. Additional studies are under way and follow-up of existing studies is ongoing; once these data are available, the pooled analysis will be redone to determine whether additional accrual of patients and duration of follow-up alters the current conclusions.

• Other Neoplasms

Leuprolide has been used with some success for the treatment of breast cancer in a limited number of premenopausal and postmenopausal women. Clinical studies with leuprolide for the treatment of breast cancer generally have been performed in women who have received mastectomy, radiation, and/or previous antineoplastic and/or antiestrogenic therapy. In one study in premenopausal women with breast cancer, leuprolide produced an objective response rate of 64%; median duration of response was 39 or 19 weeks in patients having a partial response or disease stabilization, respectively. In postmenopausal women with breast cancer, leuprolide has produced an objective response in 35% of patients and remission was generally of short duration. Many patients with breast cancer who respond to leuprolide therapy have tumors that are estrogen-receptor positive; however, responses have occurred in some patients with estrogen-receptor-negative tumors, suggesting that the drug may have a direct antitumor effect in addition to its inhibitory effect on ovarian function. Pending further accumulation of data, many clinicians currently recommend that leuprolide be limited to use in premenopausal women with breast cancer. Further study is needed to determine the optimum sequence of therapy and the effect of combined therapy with GnRH analogs and other forms of hormonal manipulation (e.g., antiestrogenic agents) in the treatment of breast cancer.

• Endometriosis

Leuprolide is used for the palliative treatment of endometriosis. Experience with the long-acting parenteral formulation of leuprolide in the management of this condition has been limited to women 18 years of age and older for up to 6 months of consecutive monthly injections, and evidence of efficacy relative to placebo to date mainly has involved measures of symptomatic relief. Leuprolide, like other GnRH analogs, produces a reversible hypoestrogenic state, which is thought to be principally responsible for the beneficial effects observed in endometriosis. A 6-month course of leuprolide therapy can provide symptomatic (e.g., pain) relief and a reduction in endometriotic lesions, and some degree of improvement has persisted for at least 1 year following completion of a course of therapy in many patients. While there currently is no evidence that IM leuprolide therapy affects fertility in women with endometriosis, intranasal leuprolide therapy has resulted in 1-year posttreatment pregnancy rates comparable to those of oral danazol therapy, and therapy with other GnRH analogs also has resulted in posttreatment pregnancy rates comparable to those of danazol therapy. Overall efficacy of GnRH analogs in the palliative treatment of endometriosis generally appears to be similar to that achieved with danazol therapy. Although GnRH analogs generally appear to be better tolerated than danazol because of the androgenic and anabolic effects of the latter drug, concerns exist about the potential long-term effects of GnRH analogs on bone density.

In a controlled study comparing 3.75-mg doses of IM leuprolide acetate (as the long-acting formulation) and placebo administered every 4 weeks for 6 doses in women with varying stages of laparoscopy-confirmed endometriosis, leuprolide was more effective than placebo in relieving dysmenorrhea and pelvic pain, tenderness, and induration by the third month of therapy and at completion of therapy; the drug also appeared to ameliorate dyspareunia in most patients. Symptoms recurred within 3-12 months after completion of therapy in most patients who enrolled in a posttreatment follow-up. Dysmenorrhea recurred within 6 months in 57% of patients, although this symptom still had not returned to baseline severity in 33% of patients after 1 year. Pain returned to baseline severity within 3 months in 54% of patients with moderate to severe pretreatment pelvic pain; however, 37% of those with this pretreatment severity exhibited some degree of relief after 1 year. Pelvic tenderness was absent in 58% of patients throughout the follow-up period, and pelvic induration was absent in 67% of patients at 1 year. Because safety has only been established to date for a single 6-month course of leuprolide therapy and because of concerns about potential long-term effects on bone density, retreatment with leuprolide currently is not recommended. If retreatment with leuprolide is considered following recurrence of endometriosis, the potential benefits and possible risks should be weighed carefully, and bone density should be assessed and be within normal limits before initiating another course of leuprolide. (See Cautions: Precautions and Contraindications.)

Leuprolide therapy also has been used as a preoperative adjunct to surgery in a limited number of women with endometriosis. In several women with endometriotic ureteral obstruction, 6-9 months of leuprolide therapy prior to surgical therapy for endometriosis resulted in a reduction in pelvic masses with an associated reduction in ureteral obstruction in most of these women; however, in one woman whose obstruction resulted from endometriotic lesions within the ureter, a 6-month course of leuprolide did not effectively reduce the obstruction. The drug also provided symptomatic pulmonary relief in at least 1 patient with pulmonary endometriosis that failed to respond adequately to excision of pleural endometriotic tissue and partial pleurectomies.

• Uterine Leiomyomata

Leuprolide is used in combination with iron therapy to correct anemia associated with uterine leiomyomata (uterine fibroids) prior to surgery. Experience with the long-acting parenteral formulation of leuprolide in this condition has been limited to women 18 years of age and older. The manufacturer recommends up to 3 months of consecutive monthly injections as the duration of such leuprolide therapy. Prior to initiating therapy with leuprolide, the clinician may wish to consider a 1-month trial of iron therapy alone, since some patients may respond adequately to such therapy; if the patient does not respond adequately to iron alone, leuprolide may then be added.

In controlled clinical trials, monthly IM administration of 3.75 mg of leuprolide acetate suspension for a period of 3 or 6months was shown to decrease uterine and fibroid volume, allowing for relief of clinical symptoms (e.g., abdominal bloating, pelvic pain, and pressure). Excess vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic parameters. In one controlled clinical trial where enrollment was based on hematologic parameters (hematocrit of 30% or less and/or hemoglobin of 10. g/dL or less), administration of leuprolide 3.75 mg IM once monthly with concomitant iron therapy produced an increase in hematocrit of 6% or greater and an increase in hemoglobin concentration of 2 g/dL or greater in 77% of patients at 3 months. The mean change in hematocrit and hemoglobin concentration was 10.% and 4.2 g/dL, respectively. Clinical response to therapy was defined as a hematocrit of 36% or greater and a hemoglobin concentration of 12 g/dL or greater, which would allow patients to perform autologous blood donation prior to surgery; 75% of patients treated met these criteria at 3 months. At 3 months, 80% of patients experienced relief from menorrhagia or menometrorrhagia, although episodes of spotting or menstrual-like bleeding were noted in some patients. A decrease of 25% or greater was seen in uterine and myoma volumes in 60 and 54% of patients treated, respectively; treatment also was associated with relief of symptoms such as bloating, pelvic pain, and pressure.

In other controlled clinical trials where enrollment was not based on hematologic status, treatment with leuprolide resulted in a decrease of mean uterine or myoma volume of 41 or 37%, respectively, as evidenced by ultrasound or magnetic resonance imaging. Decrease in symptoms including excessive vaginal bleeding or pelvic discomfort also was observed. Although benefit was observed at 3 months, additional improvement was seen with another 3 months of therapy. Of the 95% of patients experiencing amenorrhea during leuprolide therapy, 61, 25, or 4% developed amenorrhea during the first, second, or third month of therapy, respectively. Posttreatment follow-up in a small number of the 77% of patients who experienced a 25% or greater decrease in uterine volume while on leuprolide therapy found that menses usually returned within 2 months of stopping therapy, and mean time to return to pretreatment uterine volume was 8.3 months if not corrected surgically. Regrowth did not appear to be related to pretreatment uterine volume. The symptoms associated with uterine leiomyomata that is not corrected surgically will recur following discontinuance of leuprolide therapy.

• Precocious Puberty

Leuprolide is used for the treatment of central (via activation of the hypothalamic-pituitary-gonadal axis) precocious puberty (true precocious puberty, GnRH-dependent sexual precocity, complete isosexual precocity) in children, and use of the drug or another GnRH analog currently is considered the therapy of choice for this condition and generally has supplanted medroxyprogesterone in this form of precocity.Leuprolide is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition. The principal goals of therapy with GnRH analogs in this condition are to prevent rapid sexual maturation, avoid early menarche in girls, and achieve or exceed a near-normal adult height. Leuprolide, like other GnRH analogs, is ineffective as primary therapy in the treatment of GnRH-independent(peripheral; gonadal steroid secretion is independent of gonadotropin secretion) precocious puberty, including familial male precocious puberty (testotoxicosis), congenital virilizing adrenal hyperplasia (e.g., secondary to steroid 21-hydroxylase, 11b-hydroxylase, or 3b-hydroxysteroid dehydrogenase deficiency), and McCune-Albright syndrome. However, the drugs occasionally may be useful as adjuncts to other therapy (e.g., testolactone, medroxyprogesterone) during later stages of such forms of precocity if secondary GnRH-dependent precocity develops or to counteract pubertal increases in gonadotropins. Premature thelarche (breast development) in the absence of an underlying pathologic cause usually is self-limited and does not require therapy, and premature adrenarche (appearance of pubic and axillary hair) or pubarche in the absence of other physical evidence of sexual precocity or underlying abnormality also generally does not require therapy.

GnRH-analog (e.g., leuprolide) therapy is indicated for children who have a clinical diagnosis (confirmed by pubertal response to a gonadotropin releasing hormone [GnRH] stimulation test) of central idiopathic or neurogenic precocious puberty with onset of secondary sexual characteristics in girls or boys younger than 8 or 9 years old, respectively, and subsequent rapid advancement. In addition, such children should have rapid advancement of height, height velocity, and/or bone age (e.g., at least 1 year more advanced than their chronologic age). Some clinicians also state that therapy with a GnRH analog is indicated in boys younger than 8 years of age with a serum testosterone concentration exceeding 100 ng/dL and in girls with onset of menarche and recurrent menses at younger than 9 years of age.

Efficacy of GnRH analogs, including leuprolide, in central (GnRH-dependent) precocious puberty depends on suppression of pituitary gonadotropin (i.e., luteinizing hormone [LH], follicle-stimulating hormone [FSH]) release and resultant decreases in serum LH and FSH concentrations and depression of ovarian and testicular steroidogenesis; continuous therapy is required to maintain such suppression and achieve “down-regulation.” Depression of gonadal steroid production in children with precocious puberty generally prevents further progression or leads to regression of secondary sexual characteristics and slows accelerated growth and skeletal maturation; the effects of GnRH therapy on skeletal maturation may be delayed (e.g., peaking during the second year of therapy) compared with laboratory (e.g., gonadotropin and gonadal sex steroid concentrations) and other physical (secondary sexual characteristics) responses. In addition, while GnRH therapy can increase predicted adult height, such therapy may not restore fully the patient’s genetic height potential, particularly if initiation of therapy is delayed (e.g., beyond a bone age of 12 years). Therapy with the drugs usually is continued until fusion of the epiphyses or attainment of appropriate chronologic pubertal age (e.g., consideration made at 11 and 12 years of age in girls and boys, respectively). Inhibitory effects of GnRH analogs, including leuprolide, on androgen and estrogen production appear to be reversible following discontinuance of the drug, with resultant normal progression of pubertal development. For additional information on the effects of leuprolide in this condition, see Endocrine Effects: Effects in Precocious Puberty, in Pharmacology.

• Other Uses

Experimental studies suggest that continuous administration of GnRH analogs, including leuprolide, may potentially be useful as male contraceptive agents. When GnRH analogs have been used experimentally as male contraceptive agents, the concomitant use of testosterone has produced additive inhibitory effects on spermatogenesis and prevented the development of decreased libido and impotence, which are frequently associated with GnRH analog therapy. However, the long-term safety and contraceptive efficacy of this therapy have not been determined, and concerns about the lack of long-term suppression of FSH by GnRH analogs have been expressed.

Leuprolide may be potentially useful for the treatment of endocrine disorders, including polycystic ovarian disease, but additional study is needed.

Leuprolide‘s stimulatory effect on reproductive function following intermittent pulsatile administration may potentially be useful in the treatment of hypogonadism, delayed puberty, oligospermia, anovulation, and amenorrhea, but additional study is necessary.

• Goserelin acetate, a synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin), may be used as an antineoplastic agent and for its endocrine effects.

Uses

• Prostate Cancer

Goserelin acetate is used for the palliative treatment of advanced prostate cancer. Therapy with a GnRH agonist (e.g., goserelin) currently is considered one of several first-line options for hormonal therapy in patients with prostate cancer; other options include orchiectomy, estrogens, and antiandrogens.

In controlled clinical studies in patients with advanced prostate cancer, goserelin (3.6 mg administered subcutaneously every 4 weeks) was as effective as orchiectomy as determined by the degree of testosterone suppression, duration of response and survival, and/or objective response rate. Results of several dose-response studies in patients with advanced prostate cancer indicate that pharmacodynamic effects (i.e., reductions in serum testosterone and prostate specific antigen [PSA] concentrations) associated with administration of a 10.8-mg goserelin implant every 12 weeks are similar to those associated with administration of a 3.6-mg implant every 4 weeks. Clinical outcome in patients receiving goserelin 10. mg every 12 weeks is expected to be similar to that of patients receiving goserelin 3.6 mg every 4 weeks.

Results of studies in patients with locally advanced prostate cancer (generally, stage III [C]) indicate that initiation of long-term goserelin therapy at the time of radiation therapy improves local control and 5-year disease-free survival compared with radiation alone. When radiation therapy is used for the treatment of stage III prostate cancer, some experts recommend that hormonal therapy (e.g., a GnRH analog) be considered in conjunction with radiation therapy.

Goserelin also is used in conjunction with flutamide and radiation therapy in the treatment of locally confined stage T2b-T4 (B2-C) prostate cancer. In a multicenter, randomized, controlled study in patients with bulky primary tumors confined to the prostate (stage B2) or extending beyond the capsule (stage C), therapy with goserelin (3.6 mg every 4 weeks) and flutamide (250 mg 3 times daily) administered before and during radiation therapy produced a substantially lower incidence of local progression compared with radiation therapy alone.

• Endometriosis

Goserelin is used for the palliative treatment of endometriosis.The manufacturer states that experience with goserelin in the management of this condition has been limited to women 18 years of age and older who received consecutive therapy (3.6 mg every 4 weeks) with the drug for 6 months. 1 Goserelin, like other GnRH analogs, produces a reversible hypoestrogenic state, which is thought to be principally responsible for the beneficial effects observed in endometriosis. A 6-month course of goserelin therapy can provide symptomatic (e.g., pain) relief and a reduction in endometriotic lesions; some degree of improvement has persisted in many patients for at least 6 months following completion of therapy. Substantial improvement of clinical symptoms usually occurs within 4 weeks of initiation of goserelin therapy.

In controlled comparative studies, goserelin (3. mg administered every 4 weeks for 6 months) was as effective as danazol (400 mg twice daily or 200 mg 3 times daily for 6 months) in relieving clinical symptoms (e.g., dysmenorrhea, dyspareunia, pelvic pain) and signs (e.g., pelvic tenderness, pelvic induration) of endometriosis and in reduction of the size of endometrial lesions as determined by laparoscopy. In 2 controlled comparative studies, substantial reduction (at least 50%) in the extent of endometrial lesions was reported in 62-63 or 42-51% of patients receiving goserelin or danazol, respectively. In these studies, amenorrhea developed in 80-92% of women receiving goserelin within 8 weeks of initiation of drug therapy; menses usually returned within 8 weeks after completion of therapy.

• Breast Cancer

Goserelin is used in the palliative treatment of advanced breast cancer in premenopausal and perimenopausal women.In a multicenter, randomized, controlled clinical trial in women with estrogen- or progesterone-receptor-positive breast cancer, goserelin therapy or oophorectomy was associated with objective response rates (complete or partial responses) of 22-31 or 12-27%, time to treatment failure of 6-6. or 4-5.5 months, and median survival time of 33.2 or 33.6 months, respectively. In addition, subjective response, characterized by relief of pain and improved performance status, was reported in 48 or 50% of women receiving goserelin or undergoing surgery, respectively.

• Dysfunctional Uterine Bleeding

Goserelin is used as an endometrial-thinning agent prior to endometrial ablation procedures for the treatment of dysfunctional uterine bleeding. In women with dysfunctional uterine bleeding, administration of goserelin (two doses of goserelin [3.6 mg each] given 4 weeks apart) prior to surgery suppressed endometrial growth, reduced uterine size and endometrial thickness, and facilitated surgical ablation.

Drug Interactions

No formal drug interaction studies have been performed.

• Description

Goserelin acetate is a synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin) that is structurally related to leuprolide, nafarelin, and triptorelin.

Goserelin is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses and has greater activity than naturally occurring GnRH. After initial administration of goserelin, there is a transient surge in circulating levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol. Following chronic and continuous administration of goserelin (generally, 2-4 weeks after initiation of therapy), a sustained decrease in LH and FSH secretion and a marked reduction of testicular and ovarian steroidogenesis are observed.

Reductions in serum testosterone concentrations in males receiving goserelin are comparable to those achieved after surgical castration (i.e., less than 50 ng/dL). Consequently, physiologic functions and tissues dependent on testosterone for maintenance become quiescent. In clinical trials, with follow-up of more than 2 years, such suppression of testosterone concentrations has been maintained for the duration of therapy. Serum testosterone concentrations usually return to baseline after cessation of therapy.

In most premenopausal women receiving goserelin, serum estradiol concentrations are reduced to levels comparable to those observed after menopause within 3 weeks of initiating therapy. 1 3 5 Consequently, physiologic functions and tissues dependent on gonadal steroids (estrogen) for maintenance become quiescent.Serum estradiol, FSH, and LH concentrations usually return to pretreatment levels within about 12 weeks after subcutaneous implantation of the last 3.6-mg dose of goserelin. In clinical trials, isolated elevations of estradiol have been observed in about 10% of women. In addition, sustained decreases in LH and FSH secretion may not occur in some women receiving goserelin.

In vitro and animal studies suggest that goserelin may produce regression or inhibition of growth of hormonally sensitive dimethylbenzanthracene (DMBA)-induced mammary tumors in female rats and Dunning R3327H prostate tumors in male rats.

The drug is commercially available as a biodegradable copolymer implant in which goserelin acetate is dispersed in a matrix of lactic and glycolic acids. Following subcutaneous implantation of an implant containing 3.6 or 10.8 mg of goserelin, therapeutic plasma concentrations of goserelin persist for 4 or 12 weeks, respectively.

• Advice to Patients

Risk of worsening manifestations of prostate or breast cancer during initial weeks of therapy.

Risk of anaphylactoid and other sensitivity reactions. Risk of other adverse effects, including decreases in bone mineral density.

Necessity of advising women to avoid pregnancy during therapy and until the return of menses or 12 weeks after administration of the last 3.6-mg dose of goserelin. Necessity of advising women not to breast-feed. 1 Importance of women informing their clinician if regular menstruation persists. 1 Women also should be advised that breakthrough bleeding or ovulation (with potential for conception) may occur if one or more successive doses of the drug are missed.

Importance of informing clinicians of existing or contemplated therapy, including prescription or OTC drugs or herbal supplements.

Overview. For additional information until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Goserelin Acetate

Parenteral

Implants 3.6 mg (of goserelin) Zoladex ®, (available as prefilled disposable syringe)

AstraZeneca

10.8 mg (of goserelin) Zoladex ®, (available as prefilled disposable syringe)

Goserelin acetate is administered as a biodegradable implant subcutaneously into the upper abdominal wall, under the supervision of a clinician. Implants containing 3.6 mg of goserelin are administered every 4 weeks. When indicated, implants containing 10. mg of goserelin are administered every 12 weeks. 2 6 Although a delay of a few days is permitted, the manufacturer states that every effort should be made to adhere to the recommended schedule. A local anesthetic may be given prior to implantation of goserelin. In the event that the implant needs to be removed, it may be located by ultrasound. The manufacturer’s labeling should be consulted for proper methods of administration and associated precautions.

Dosage of goserelin acetate is expressed in terms of goserelin.

• Prostate Cancer

For the palliative treatment of advanced prostate cancer, the usual dosage of goserelin in men is 3.6 or 10.8 mg implanted subcutaneously every 4 or 12 weeks, respectively. For this indication, goserelin is intended for long-term administration unless it is clinically inappropriate.

When goserelin therapy is used as an adjunct to radiation therapy in patients with stage III (C) prostate cancer, treatment with the drug usually is initiated on the first day of radiation or during the last week of radiation.  In studies evaluating safety and efficacy of long-term administration of goserelin for this indication, a dosage of 3.6 mg was implanted subcutaneously every 4 weeks.

When goserelin is used in conjunction with flutamide in the management stage T2b-T4 (B2-C) prostate cancer, the manufacturer states that treatment with the drugs should be initiated 8 weeks prior to and continued during radiation therapy.  The manufacturer also states that a 3.6-mg dose of goserelin can be implanted subcutaneously 8 weeks prior to radiation therapy and be followed by subcutaneous implantation of a 10.8-mg dose of goserelin on day 28 (4 weeks after the initial 3.6-mg dose). Alternatively, goserelin 3.6 mg can be implanted subcutaneously at 4-week intervals (starting 8 weeks prior to radiation therapy) for a total of 4 doses.

• Endometriosis

For the palliative treatment of endometriosis, the usual dosage of goserelin in women 18 years of age or older is 3.6 mg implanted subcutaneously every 4 weeks for 6 consecutive months.Retreatment with additional courses of therapy currently is not recommended because safety in women only has been established for a 6-month course of therapy and because of concerns about potential long-term effects on bone density. 1 If retreatment is considered following recurrence of endometriosis, bone density should be assessed.

• Breast Cancer

For the palliative treatment of advanced breast cancer in premenopausal and perimenopausal women, the usual dosage of goserelin is 3.6 mg implanted subcutaneously every 4 weeks.In clinical trials in women whose serum estradiol concentrations were not reduced to postmenopausal levels after 8 weeks of goserelin therapy, dosage of the drug was increased to 7.2 mg (3.6 mg implanted to 2 different sites) every 4 weeks.For the management of advanced breast cancer, goserelin is intended for long-term administration unless clinically inappropriate.

• Dysfunctional Uterine Bleeding

When goserelin is used as an endometrial-thinning agent prior to endometrial ablation in women with dysfunctional uterine bleeding, a single 3.6-mg dose can be implanted subcutaneously 4 weeks before surgery. Alternatively, the initial 3.6-mg dose of goserelin can be followed by a second 3.6-mg dose implanted subcutaneously 4 weeks after the first dose; surgery should be performed 2-4 weeks after the second dose.

• Special Populations

No special population dosage recommendations at this time.

Cautions

• Contraindications

Known hypersensitivity to goserelin or any ingredient in the formulation, other GnRH agonists, or GnRH. The implant containing 10. mg of goserelin should not be used in women, since there are insufficient data available to date to determine whether this preparation is associated with reliable suppression of serum estradiol. 2 Known or suspected pregnancy or lactation. 1 Abnormal vaginal bleeding of unknown etiology.

• Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals. Before initiating goserelin therapy in women, pregnancy must be excluded. 1 Women of childbearing potential should be advised to avoid pregnancy while receiving the drug and use an effective nonhormonal method of contraception during goserelin therapy and continue contraception until the return of menses or for at least 12 weeks following subcutaneous implantation of the last 3.6-mg dose of goserelin. 1 21 No adequate and well-controlled studies to date in humans. 1 If a patient with endometriosis or undergoing endometrial thinning becomes pregnant during goserelin therapy, the drug should be discontinued and the patient should be advised about potential fetal hazard. 1 2 In addition, if used during pregnancy (i.e., in women with advanced breast cancer), apprise of potential fetal hazard. 1 Although continuous use of goserelin usually inhibits ovulation and stops menstruation, contraception is not ensured.

Endocrine Effects As with other GnRH agonists, worsening (flare) of signs and/or symptoms (e.g., increased bone pain) of prostate or breast cancer and/or development of new manifestations occasionally have occurred during the initial weeks of therapy with goserelin.Development of these effects apparently results from goserelin-induced transient increases in serum testosterone (in men) or estrogen (in women) concentrations during the initial weeks of therapy. 1 Concomitant therapy with an antiandrogen (e.g., bicalutamide, flutamide, nilutamide) 1 week before and during the first few weeks of goserelin therapy has been used to minimize the development of disease flare in men with prostate cancer.

Cases of spinal cord compression and/or ureteral obstruction have been reported in men with prostate cancer receiving GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases, an immediate orchiectomy should be considered.Goserelin should be administered with caution to patients at particular risk of developing spinal cord compression or ureteral obstruction and these patients should be observed closely during the first month of therapy. Patients with spinal cord compression or ureteral obstruction should receive appropriate treatment for these conditions prior to initiating therapy with goserelin.

Since goserelin exerts pharmacologic effects on the uterus and cervix and may cause an increase in cervical resistance, 1 cervical dilation should be performed carefully in patients undergoing endometrial ablation following use of goserelin as an endometrial thinning agent.

Musculoskeletal Effects As with other GnRH agonists or hormonal therapy (e.g., estrogens, antiestrogens), hypercalcemia has occurred following initiation of goserelin therapy in patients with prostate or breast cancer with bone metastases. If hypercalcemia develops, appropriate treatment should be instituted.

Sensitivity Reactions

Hypersensitivity Reactions Antibody formation, acute anaphylactic reactions, and urticaria have been reported with GnRH agonists.

General Precautions

Patient Monitoring Serum testosterone should be determined periodically in patients with prostate cancer in whom the anticipated clinical or biochemical response to goserelin has not been achieved.In men with prostate cancer, reduction in serum prostate specific antigen (PSA) concentrations may provide information about duration of progression-free status.However, in patients receiving hormonal therapy, decreases in PSA concentrations may occur independent of tumor response, and, therefore, clinicians cannot rely solely on PSA concentrations to monitor a patient’s response.

Specific Populations

Pregnancy Category D (in advanced breast cancer); Category X (in endometriosis and when used as an endometrial-thinning agent).

Lactation Goserelin is distributed into milk in animals.Discontinue nursing prior to initiating goserelin therapy.

Gender Goserelin 10.8-mg implant is not labeled for use in women.

Pediatric Use Safety and efficacy not established in children.

Geriatric Use Clinical studies for use in prostate cancer have been conducted principally in patients 65 years of age and older since prostate cancer occurs mainly in this patient population.

• Common Adverse Effects

Initial (usually during the first weeks of therapy) transient increases in serum testosterone occur in most men receiving goserelin and may be associated with temporary worsening in manifestation of prostate cancer. Similarly, initial increases in serum estrogen concentrations occur in most women receiving goserelin and may be associated with transient worsening in the manifestations of breast cancer. Transient changes in blood pressure (hypotension or hypertension) have occurred in patients receiving goserelin.

Adverse effects occurring in 5% or more of men include hot flushes (flashes), sexual dysfunction, decreased erections, lower urinary tract symptoms, lethargy, pain (worsened in the first month), edema, upper respiratory tract infection, rash, sweating, anorexia, chronic obstructive pulmonary disease, congestive heart failure, dizziness, insomnia, and nausea. Decreases in bone mineral density, osteoporosis, and bone fracture have been reported in men receiving goserelin for prostate cancer.

Adverse effects occurring in 5% or more of women include hot flushes (flashes), vaginitis, headache, emotional lability, decreased/increased libido, sweating, depression, acne, breast atrophy, seborrhea, edema (may be peripheral), breast enlargement, pelvic symptoms, pain (e.g., abdominal, breast, back), dyspareunia, infection, asthenia, nausea, hirsutism, insomnia, flu-like syndrome, dizziness, application site reaction, and pharyngitis. Decreases in bone mineral density have occurred in women receiving goserelin; 1 concurrent use of hormone replacement therapy or bisphosphonates (e.g., alendronate) may minimize bone mineral loss associated with GnRH agonist therapy without compromising efficacy of these drugs in the management of endometriosis.

• Flutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.

Uses

• Prostate Cancer

Flutamide is used in combination with a gonadotropin-releasing hormone (GnRH) analog (e.g., goserelin, leuprolide acetate) in the treatment of prostate cancer that is clinically localized, such as that confined to the prostate but with extensive involvement of one lobe or with involvement of both lobes (stage B2) and that localized to the periprostatic area but extending beyond the capsule and possibly affecting seminal vesicles (stage C). Flutamide also is used in combination with a GnRH analog in the treatment of metastatic prostate cancer that involves distant lymph nodes, bone, or visceral organs (stage D2). For additional information on combined antiandrogenic and GnRH analog therapy.

Prostate specific antigen (PSA) concentrations should be determined periodically during combined flutamide and GnRH analog therapy to monitor therapeutic response, including successful remission or possible progression of cancer. If PSA concentrations increase substantially and consistently during flutamide therapy, the possibility of clinical progression should be evaluated. Progression noted after gonadal ablation (i.e., pharmacologic treatment with a GnRH analog or orchiectomy) and antiandrogen therapy may represent growth that is not androgen dependent. For patients who have an objective progression of disease together with an elevated PSA, treatment with a GnRH analog without flutamide may be considered. Withdrawal of flutamide in such patients can be associated with a decrease in PSA. The mechanism of this response to flutamide withdrawal has not been determined, but may involve the development of mutations at the androgen receptor.

Flutamide is metabolized in part to 4-nitro-3-fluoro-methylaniline. Toxicities associated with aniline exposure and flutamide therapy include methemoglobinemia, hemolytic anemia, and cholestatic jaundice. Methemoglobin concentrations should be monitored periodically in susceptible patients (e. g., those with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, smokers).

Dosage and Administration

Patients should be advised of the possibility of facial flushing during flutamide therapy and that alcohol could exacerbate this effect. Patients who experience such intolerance during therapy with the drug should avoid alcohol consumption.

• Administration

Flutamide is administered orally without regard to meals.

• Dosage

Because of the intended labeled use of flutamide, safety and efficacy of the drug have not been established in women or children. Flutamide is not intended for use in women and should not be used in women, particularly for nonserious or nonlife-threatening conditions.

Prostate Cancer

For use in combination with a gonadotropin-releasing hormone (GnRH) analog in the management of clinically localized (stage B2 or C) or metastatic (stage D2) prostate cancer, the usual dosage of flutamide is 250 mg 3 times daily. In patients with clinically localized (stages B2 and C) prostatic cancer, treatment with flutamide and the GnRH analog should be initiated 8 weeks prior to and continued during radiation therapy. In patients with metastatic (stage D2) prostate cancer, treatment with flutamide and the GnRH analog should be initiated on the same day. The duration of combined therapy with flutamide and a GnRH analog depends on the clinical response of the patient and usually should continue until progression of the disease in patients with metastatic stage D2 prostate cancer.

Periodic monitoring of serum prostate specific antigen (PSA) may be useful for assessing the patient’s response to therapy. For patients with objective progression of disease and an elevated serum PSA, temporary withdrawal of flutamide therapy while continuing therapy with the GnRH analog may be considered.

Discontinuance of Therapy for Hepatic Toxicity

Hepatic injury, manifested by elevated serum transaminase concentrations, jaundice, hepatic encephalopathy, and death related to acute hepatic failure, has been reported in patients receiving flutamide. Liver failure associated with flutamide has required hospitalization in some cases and rarely has been fatal. Onset of hepatic injury occurred within the first 3 months of flutamide therapy in about half of the cases reported. Hepatic injury was reversible in some patients following discontinuance of the drug. Serum transaminase should be measured prior to starting flutamide therapy, and the drug is not recommended in patients with baseline serum ALT (SGPT) concentrations exceeding twice the upper limit of normal. Measurement of serum transaminase concentrations should be performed monthly for the first 4 months of flutamide therapy and periodically thereafter. Liver function tests also should be performed at the first sign or symptom of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, unexplained flu-like symptoms). If liver function test results are elevated (i.e., transaminases increase to 2-3 times the upper limit of normal) or if jaundice occurs, flutamide therapy should be discontinued immediately and liver function tests monitored closely until resolution.

• Dosage in Hepatic and Renal Impairment

Flutamide is extensively metabolized to at least 6 metabolites.

No information is available concerning use of flutamide in patients with hepatic impairment. The manufacturer states that flutamide should not be used in patients with severe hepatic impairment. Serum transaminase concentrations should be measured prior to initiation of flutamide therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter in all patients receiving flutamide.

In individuals with chronic renal insufficiency receiving a single 250-mg dose of flutamide, there was no correlation between creatinine clearance and plasma concentrations of the drug. Renal impairment did not affect peak concentrations or AUCs of the drug and principal active metabolite. In individuals with a creatinine clearance of less than 29 mL/minute, the half-life of the active metabolite is slightly prolonged. Adjustment of flutamide dosage in patients with renal impairment generally is unnecessary.

• Description

Flutamide, a toluidine derivative, is a nonsteroidal antiandrogen that is structurally and pharmacologically related to bicalutamide and nilutamide.

Flutamide is a pure antiandrogen, possessing no intrinsic hormonal activity; the antiandrogenic mechanism of action of the drug is via androgen-receptor antagonism. Flutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis. Flutamide is a selective antiandrogen with no estrogenic, antiestrogenic, progestational, antiprogestational, antigonadotropic, or adrenocortical activity in various animal models.

Flutamide is metabolized in vivo to 2-hydroxyflutamide, which appears to be principally responsible for the antiandrogenic activity; this metabolite is a potent competitive inhibitor of androgen-receptor binding, exhibiting 1.5 times the antiandrogenic potency of flutamide in animal models. The relative binding affinity of 2-hydroxyflutamide at the androgen receptor is less than that of bicalutamide but similar to that of nilutamide. In addition to blocking the binding of dihydrotestosterone (DHT) at androgen receptors, flutamide inhibits androgen uptake into target cells, and decreases the number of intraprostatic androgen receptors by secondarily (i.e., subsequent to DHT-binding blockade) preventing translocation of the androgen-receptor complex into cellular nuclei. Metabolism of adrenal androgen precursors of testosterone (e.g., dehydroepiandrosterone [DHEA]) to inactive metabolites increases in castrated patients with prostatic cancer receiving flutamide.

Common pharmacologic therapies for prostate cancer (i.e., gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effect of the drug. Androgen receptors in the hypothalamus are blocked by flutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone. As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy.However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade. Concomitant administration of antiandrogens such as nilutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy.

SumMon®. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications. For further information on the handling of antineoplastic agents, see the ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs at http://www.ahfsdruginformation.com.

Preparations

Flutamide

Oral

Capsules 125 mg Eulexin®, (with parabens and povidone;) Schering Flutamide Capsules, Barr Eon IVAX Teva