Suprefact (Buserelin Acetate Luteinizing Hormone-Releasing Hormone)

SUPREFACT® SUPREFACT® DEPOT

Hoechst Marion Roussel

Buserelin Acetate Luteinizing Hormone-Releasing Hormone (LH-RH)

Analog

Action and Clinical

Buserelin is a synthetic peptide analog of the natural gonadotropin releasing hormone (GnRH/LHRH). The substitution of glycine in position 6 by D-serine, and that of glycinamide in position 10 by ethylamide, leads to a nonapeptide with a greatly enhanced LHRH effect. The effects of buserelin on follicle stimulating hormone (FSH) and luteinizing hormone (LH) release are 20 to 170 times greater than those of LHRH. Buserelin also has a longer duration of action than natural LHRH.

Investigations in healthy adult males and females have demonstrated that the increase in plasma LH and FSH levels persist for at least 7 hours and that a return to basal values requires about 24 hours.

Clinical inhibition of gonadotropin release, and subsequent reduction of serum testosterone or estradiol to castration level, was found when large pharmacologic doses (50 to 500 g s.c./day or 300 to 1 200 g intranasal/day) were administered for periods greater than 1 to 3 months. Chronic administration of such doses of buserelin results in sustained inhibition of gonadotropin production, suppression of ovarian and testicular steroidogenesis and, ultimately, reduced circulating levels of gonadotropin and gonadal steroids. These effects form the basis for buserelin use in patients with hormone-dependent metastatic carcinoma of the prostate gland as well as in patients with endometriosis.

In the clinical pharmacology studies with the buserelin implant, the time-concentration curves of buserelin release from implants were reproducible and similar to those observed in preclinical studies. Maximum release on day 1 was followed by an extended plateau phase which lasted for 8 weeks. After this period, an accelerated biodegradation of the implant material was observed with a terminal half-life of release of 20 to 30 days. The single dose studies performed in healthy male subjects and in patients with benign prostatic hypertrophy showed a therapeutic release rate for 8 weeks (dosage interval); a minimum therapeutic release rate of 4.95 g/day after 8 weeks was fully effective in maintaining testosterone levels in the surgical castration range by controlled release of buserelin. At the end of the dosage interval, the average fraction of the buserelin dose released from the implants based on urinary excretion data was 84% (in healthy subjects) and 92% (in patients with benign prostatic hypertrophy). Chronic administration of the implant every 8 weeks ensures continuous suppression of testosterone secretion with no cumulation of buserelin release after repeated dosing.

Indications And Clinical Uses:

For the palliative treatment of patients with hormone-dependent advanced carcinoma of the prostate gland (Stage D).

Buserelin is also indicated for the treatement of endometriosis in patients who do not require surgery as primary therapy. The duration of treatment is usually 6 months and should not exceed 9 months. Experience with buserelin for the management of endometriosis has been limited to women 18 years of age and older.

Contra-Indications:

Patients with known hypersensitivity to buserelin or any other formulation component (see Supplied). In patients with prostatic cancer, buserelin is also contraindicated in patients who do not present with hormone-dependent carcinoma; and in patients who have undergone orchiectomy (in these patients, no further reduction of testosterone level is to be expected with buserelin therapy).:

Pregnancy: Buserelin is contraindicated in women who are pregnant. As with other LHRH agonists, it is not known whether buserelin caused fetal abnormalities in humans. Women of childbearing potential should be carefully examined before treatment to exclude pregnancy.

Lactation: The use of buserelin in patients who are breast-feeding is not recommended. Buserelin should not be administered to females having undiagnosed abnormal vaginal bleeding.

Warnings in Clinical States:

General: Initially, buserelin transiently increases serum testosterone in males, serum estradiol in females and other gonadal hormones.

Cases of early, transient exacerbation of disease signs and symptoms have been reported during treatment with LHRH agonists (see Precautions).

Prostatic Cancer: General: The majority of clinical studies demonstrating the efficacy of buserelin were completed without concomitant therapy with antiandrogens during the first weeks of treatment. For the clinical studies with the buserelin implant, however, an antiandrogen was administered as initial concurrent treatment for a duration of 5 weeks, starting 7 days before the start of buserelin implant therapy. At the start of treatment, there is a temporary rise in male sex hormones. In a few patients, this rise may be associated with isolated cases of short-term worsening of signs and symptoms such as bone pain, urinary signs and symptoms (usually occurring in patients with a previous history of obstructive uropathy) or muscular weakness in the legs.

Patients with Vertebral Metastases: Due to the possibility of early, transient, lesion exacerbation, and consequent possible spinal cord compression, these patients should be closely monitored when LHRH agonist treatment is initiated.

Patients with Genitourinary Tract Symptoms: Patients with genitourinary symptoms may experience a transient increase in such symptoms early in LHRH agonist treatment. These patients should be particularly closely observed for events indicative of obstruction.

Reversibility of LHRH Agonist-Induced Hypogonadism: While hypogonadism is a pharmacologic consequence of long-term LHRH agonist treatment, its reversibility has not been established in patients suffering with prostatic carcinoma.

Endometriosis: Oral contraceptives must be discontinued before starting LHRH treatment; and nonhormonal methods of contraception should be employed during therapy (see Precautions).

Worsening of clinical conditions may occasionally require discontinuation of therapy and/or surgical intervention.

Precautions:

Transient Exacerbation of Disease Signs and Symptoms: The administration of LHRH agonists is occasionally related with early, transient (less than 10 days duration usually) exacerbation of the signs and symptoms of metastatic prostatic cancer or endometriosis which are sometimes but not necessarily, associated with a transient rise in serum testosterone or estradiol. Special precautions are recommended in the following patients with prostatic cancer since symptoms may progress to warrant, in rare cases, additional or alternate interventions: patients with metastatic vertebral lesions or patients with history of obstructive uropathy (see Warnings).

From clinical trials with the buserelin implant, administration of an antiandrogen before and concurrently at the start of buserelin implant therapy may avoid the occurrence of such signs and symptoms of the disease (in clinical trials, the antiandrogen was primarily given for the first 5 weeks, beginning 7 days prior to the first buserelin implant injection).

Monitoring of Patients: Prostatic Cancer: Regular clinical assessment of patients is recommended and should include clinical laboratory determinations of serum testosterone, prostatic acid phosphatase or acid phosphatase and prostate-specific antigen (PSA). If cancer is responsive to buserelin therapy, the prostate cancer tumor markers (PAP and PSA), if elevated prior to the commencement of treatment, are usually reduced by the end of the first month.

The status of bone lesions may be monitored by bone scans and that of the prostate lesions may be followed by ultrasonography and/or CT scan in addition to digital rectal examination.

Evaluation for obstructive uropathy may be undertaken by ultrasonography, i.v. pyelogram or CT scan in addition to clinical examination. In addition, it is recommended that serum testosterone levels be determined after 4 to 6 weeks of treatment with LHRH agonists and then at 3 monthly intervals. Inadequate serum testosterone suppression should lead to evaluation of patient compliance.

Patients with a history of depression or depressed moods should be observed closely for evidence of mood changes and treated accordingly.

In treated hypertensive patients, hypertensive crisis may occur. It is recommended that blood pressure be monitored regularly in these patients.

Isolated cases of loss of diabetic control have been observed. Blood glucose levels should be checked regularly in diabetic patients.

Effect on Clinical Laboratory Tests: LHRH agonist treatment will affect selected hormonal and other serum/urine parameters in the first week of treatment: elevation of testosterone and dihydrotestosterone, as well as acid phosphatase can be expected. With chronic drug administration, these elevated values of these variables will fall below baseline.

Renal function tests, blood urea nitrogen and creatinine may rarely be elevated during the first few days of LHRH agonist therapy in prostate cancer patients before returning to normal.

Drug Interactions:

During treatment with buserelin, the effect of antidiabetic agents may be attenuated (see also Adverse Effects).

Allergic Reactions: Allergic asthma with dyspnea as well as in isolated cases, anaphylactic/anaphylactoid shock have been observed in patients treated with buserelin, necessitating early treatment of such conditions. For patients experiencing anaphylactic/anaphylactoid reactions who were given the buserelin implant, it may be necessary to surgically remove it.

Endometriosis: Pregnancy: Safe use of the drug in pregnancy has not been established; therefore, a nonhormonal method of contraception should be used during treatment. Patients should be advised that if they miss or postpone a dose of buserelin, ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.

Diagnostic Interference: Administration of buserelin in therapeutic doses results in suppression of the pituitary-gonadal system. Normal function is usually restored after a few weeks of the last dose of buserelin. Diagnostic tests of pituitary-gonadal function conducted during the treatment and within a few weeks after discontinuation of buserelin therapy may therefore be misleading.

General: Changes in Bone Density: Bone loss can be expected as part of natural aging and of natural menopause and can also be anticipated during medically induced hypogonadic status caused by long-term use of LHRH agonists such as buserelin. In patients with significant risk factors for decreased bone mineral content and/or bone mass such as family history of osteoporosis, chronic use of corticosteroids or anticonvulsants or chronic abuse of alcohol or tobacco, LHRH agonists may pose additional risk. In these patients, risk and benefits must be weighed carefully before initiation of LHRH agonist therapy. In patients with endometriosis, use of buserelin for longer than the recommended 6 months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.

Adverse Reactions:

:The adverse effects observed in patients treated with buserelin and buserelin implant are, principally, directly related to its anticipated pharmacologic action, i.e., suppression of pituitary (gonadotropin) and gonadal (testosterone or estradiol) hormone production with resulting clinical signs and symptoms of hypogonadism.

Long-term treatment with LHRH agonists may, in isolated cases, lead to development of pituitary adenomas; in humans, however, this has not yet been observed with buserelin therapy.

Prostatic Cancer: Injection and Nasal Solution: An early in treatment transient increase in serum testosterone levels usually occurs. Occasionally, this may be associated with transient worsening of clinical status and secondary reactions such as: occurrence or exacerbation of bone pain in patients with bone metastases, signs of neurological deficit due to tumor compression, impaired micturition, hydronephrosis, lymphostasis or thrombosis with pulmonary embolism. This transient initial rise in serum androgen will be followed by a progressive decrease to castration levels (see Warnings and Precautions).

In patients treated with the buserelin implant, such reactions can be avoided when an antiandrogen is given concomitantly in the initial phase of buserelin treatment (see Precautions). Some of these patients may, nevertheless, develop a mild, transient increase in tumor pain and a deterioration in general well-being.

Injection and Nasal Solution: Serious clinical flare reactions were reported in approximately 1% of patients in buserelin efficacy trials.

In a large, North American multicenter study of buserelin, the following reactions were encountered: patients receiving daily s.c. buserelin: 71.6% reported hot flushes, 84.8% reported loss of libido, 79.4% reported impotence. However, more than 50% of all buserelin subjects reported loss of libido and impotence at admission.

For patients receiving intranasal buserelin: 66.1% reported hot flushes, 75% reported loss of libido, 75% reported impotence, 12.5% reported nasal irritation and 28.5% reported headache. Not all cases were considered to be buserelin related.

Other adverse reactions considered to be buserelin related and occurring in more than 1% of patients were: gynecomastia, pruritus and gastrointestinal disturbances.

Of patients who received maintenance buserelin therapy by daily s.c. injection, 11.9% reported one or more generally transient injection site reactions: pain (4.6%), irritation (3.3%), swelling (3.3%), urticaria (2%) and other (4.6%). None of the reactions were severe or required discontinuation of therapy.

Other adverse effects arranged by body system possibly or probably related to the administration of buserelin (individual signs/symptoms not marked with an asterisk occurred at an incidence below 1%=incidence between 1 and 2%) included: Body as a Whole* (s.c. use only): clinical flare reaction*, fever, pain.

In an open-label, noncomparative, international multicenter study of the buserelin implant comprising a total of 241 patients, the following adverse reactions considered to be remotely, possibly or probably related to the buserelin implant were encountered during 1 year of treatment: 15.8% reported hot flushes, 2.5% reported libido decreased, 1.2% reported impotence, 1.2% reported injection site pain, hypertension [including hypertensive crises in treated hypertensive patients] (2.9%), depression (2.9%) and edema of the ankles and calves (2.1%).

Other adverse reactions, arranged by body system, and remotely, possibly or probably related to the administration of the buserelin implant (individual signs/symptoms occurred at an incidence of less than 1%) were: Body as a Whole: nonserious clinical flare reaction, fever, pain.

Miscellaneous: In the international database, other adverse events, including events which were observed only in females (excluding female gender-specific events) or for other unlabelled indications, have been observed in patients treated with buserelin, as itemized below (not all events were considered to be related to buserelin therapy):

Digestive: changes in appetite (e.g., anorexia), increased thirst, vomiting.

Hemic and Lymphatic: leukopenia, thrombopenia.

Laboratory Values: changes in blood lipids (e.g., hypercholesterolemia, hyperlipidemia), increase in bilirubin levels, increase in serum liver enzymes levels (e.g., transaminases).

Nervous: concentration and memory disturbances, dizziness, drowsiness, emotional instability, feelings of anxiety, mood changes, nervousness, tiredness.

Skin and Appendages: articular pains, irritation of the mucosa in the nasopharynx due to nasal solution administration (which may lead to nosebleeds, hoarseness, disturbances of smell or taste), rhinorrhea, skin reaction (wheal) allergy.

Special Senses: eye dryness and irritation, feeling of pressure behind the eyes, impaired vision (e.g., blurred vision), hearing disorders, tinnitus.

Endometriosis: During the first 2 weeks of treatment with intranasal buserelin, estradiol levels may increase but, thereafter decrease to basal or lower levels. This transient increase in estradiol may result in a temporary exacerbation of signs and symptoms (see Warnings and Precautions).

Symptoms And Treatment Of Overdose:

OverdoseThere have been no clinical reports of acute overdosage with buserelin or buserelin implant.

From acute studies of buserelin acetate in rodents, neither 0.5 mg/kg/IV (mouse) nor 1 mg/kg/IV (rat) produced evidence of toxic signs.

Two groups of 6 and 4 healthy volunteers, aged 26 to 40 years and 31 to 40 years respectively, were given 1 mg buserelin or 5 mg buserelin orally as a single dose. No LH or FSH release was observed. No clinical effects were observed.

Dosage And Administration:

Buserelin injection and nasal solution and buserelin implant should be administered at approximately equal time intervals to ensure that the desired therapeutic effect is maintained.

Prostatic Cancer: Injection and Nasal Solution: Initial Treatment: For the first 7 days of treatment give buserelin 500 g (0.5 mL) every 8 hours by s.c. injection. For patient comfort, vary the injection site (see Information for the Patient).

Maintenance Treatment: Depending upon patient preference, or physician recommendation, maintenance treatment may be by daily s.c. injection or by intranasal administration 3 times daily.

During maintenance dosing by the s.c. route, the buserelin dose is 200 g (0.2 mL) daily. For patient comfort, vary the site of injection (see Information for the Patient).

During maintenance dosing by the intranasal administration route, the buserelin dose is 400 g (200 g into each nostril) 3 times daily using the metered-dose pump (nebulizer) provided. Each pump action delivers 100 g buserelin acetate or 0.1 mL solution (see Information for the Patient).

Suprefact Depot: Implant Dosing: The contents of 1 applicator, consisting of 2 implant rods, equivalent to a total of 6.3 mg buserelin, is injected s.c. every 2 months into the lateral abdominal wall. Before injection, a local anesthetic may be used if desired. It is important to maintain a regular, 2-month rhythm for the dosage interval. In exceptional cases, the dosage interval may be shortened or extended by a few days.

The applicator containing the implant rods should be kept horizontal before injection (see Manufacturer’s Package Insert).

Suprefact Depot is intended for the long-term treatment of prostatic carcinoma.

Initial Antiandrogen Comedication: About 7 days before the first injection of the buserelin implant, an antiandrogen should be administered in accordance with the manufacturer’s directions. This comedication is to be continued for 4 weeks after the first buserelin implant injection, when testosterone levels can be expected to have entered the surgical castration range.

Instructions for Using the Applicator (see package insert for illustrations): Please note: To prevent the implant rods from falling out of the injection needle, hold the applicator in a vertical position until immediately prior to puncture, with the needle pointing upwards.

After removing the applicator from the foil wrapping, check that both implant rods are located in the window of the handle. If necessary, tap the protective cap of the needle lightly to reposition them in the window.

Disinfect the injection site of the lateral abdominal wall and administer a local anesthetic, if desired. After removing the protective case from the plunger, remove the cap from the injection needle.

Lift a fold of skin and insert the needle approximately 3 cm (somewhat more than 1 inch) into the s.c. tissue, with the tip of the needle pointed slightly upwards. Withdraw the applicator about 1 to 2 cm prior to injection of the implant rods.

While fully depressing the plunger, inject the implant rods into the s.c. tissue. Compress the puncture channel while withdrawing the needle so that the implant rods are retained in the tissue.

To ensure that both implant rods have been injected, check the tip of the plunger to see if it is visible at the tip of the needle.

Endometriosis: Nasal Solution: The dose of buserelin in patients with endometriosis is 400 g (200 g into each nostril) 3 times daily using the metered-dose pump (nebulizer) provided. Each pump action delivers 100 g or 0.1 mL solution (see Information for the Patient). The treatment duration is usually 6 months and should not exceed 9 months.

Availability And Storage:

Suprefact: Injection: Each mL of sterile aqueous injection solution contains: buserelin acetate 1.05 mg (equivalent to 1 mg pure anhydrous buserelin free base). Nonmedicinal ingredients: benzyl alcohol, monobasic sodium phosphate and sodium chloride. Clear glass, multidose vials of 5.5 mL. Cartons of 2. Store at 15 to 30°C. Do not freeze, do not expose to sources of heat.

Nasal Solution: Each mL of aqueous intranasal solution contains: buserelin acetate 1.05 mg (equivalent to 1 mg pure anhydrous buserelin free base). Nonmedicinal ingredients: benzalkonium chloride, sodium chloride, citric acid/sodium citrate. Amber glass bottles of 10 mL with metered-dose pumps (nebulizers) provided. Cartons of 4. Store at room temperature, below 25°C in the original container. Do not freeze and do not expose to sources of heat. The metered-dose pump (nebulizer) provided has a mechanical action and contains no propellants. Refer to Information for the Patient for details on pump operation.

There is no information available on possible incompatibilities between buserelin injection and nasal solution and other agents.

Suprefact Depot: A sterile, ready to use, disposable, for s.c. injection, applicator with an integrated needle. Each carton is supplied with 1 sterile foil bag containing 1 applicator prefilled with 1 implant dose consisting of 2 identical cream-colored, biodegradable and biocompatible rods, each of 3.3 mg buserelin acetate. Each implant dose contains a total of 6.6 mg buserelin acetate, equivalent to 6.3 mg buserelin base, 26.4 mg poly-(D,L-lactide co glycolide). Cartons of 1. Store intact package between 15 and 30°C. Do not freeze and protect from heat.

SUPREFACT® SUPREFACT® DEPOT Hoechst Marion Roussel Buserelin Acetate Luteinizing Hormone-Releasing Hormone (LH-RH) Analog

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