SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 16 DOSAGE AND ADMINISTRATION 16 OVERDOSAGE 19 ACTION AND CLINICAL PHARMACOLOGY 19 STORAGE AND STABILITY 21 DOSAGE FORMS, COMPOSITION AND PACKAGING 22
PHARMACEUTICAL INFORMATION 23 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 34 TOXICOLOGY 40 REFERENCES 45
PRSUPREFACT(r) Buserelin Acetate
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Subcutaneous Injection | Solution 1 mg/mL | For a complete listing see Dosage Forms, Composition and Packaging section. |
| Intranasal | Solution 1 mg/mL | For a complete listing see Dosage Forms, Composition and Packaging section. |
SUPREFACT(r) (buserelin acetate) is indicated for: Subcutaneous injection: The palliative treatment (initial and maintenance treatment) of patients with hormone- dependent advanced carcinoma of the prostate gland (Stage D).
Nasal solution:
The palliative treatment (maintenance treatment) of patients with hormone-dependent advanced carcinoma of the prostate gland (Stage D). The treatment of endometriosis in patients who do not require surgery as primary therapy. The duration of treatment is usually six months and should not exceed nine months. SUPREFACT(r) injection should be administered under the supervision of a health care professional.
Geriatrics:
No data is available
Pediatrics (< 18 years of age):
Experience with SUPREFACT(r) for the management of endometriosis has been limited to women 18 years of age and older.
SUPREFACT(r) is contraindicated in patients who are hypersensitive to this drug, to any ingredient in the formulation or component of the container. Isolated cases of anaphylaxis have been reported. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.
PATIENTS WITH PROSTATIC CANCER SUPREFACT(r) is contraindicated in patients who do not present with hormone-dependent carcinoma and in patients who have undergone orchiectomy.
PATIENTS WITH ENDOMETRIOSIS SUPREFACT(r) is contraindicated in women who are pregnant. As with other LHRH agonists, it is not known whether SUPREFACT(r) causes fetal abnormalities in humans. Women of childbearing potential should be carefully examined before treatment to exclude pregnancy. The use of SUPREFACT(r) in patients who are breast-feeding is not recommended. SUPREFACT(r) should not be administered to females having undiagnosed abnormal vaginal bleeding.
General
Certain adverse effects (e.g. dizziness) may impair the patient's ability to concentrate and react, and therefore, constitute a risk in situations where these abilities are of special importance (e.g. operating a vehicle or machinery). Initially, SUPREFACT(r) transiently increases serum testosterone in males, serum estradiol in females and other gonadal hormones. 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.
PATIENTS WITH PROSTATIC CANCER SUPREFACT(r) (buserelin acetate), like other LHRH agonists, causes a transient increase in serum concentration of testosterone during the first weeks of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without complications, have been reported with LHRH agonists. If spinal cord compression or renal impairment due to ureteral obstruction develops, standard treatment of these complications should be instituted. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should begin buserelin therapy under close supervision. It is strongly recommended that administration of an antiandrogen be started as adjunctive therapy before starting treatment with SUPREFACT(r). This adjunctive therapy must be continued in parallel with SUPREFACT(r) therapy for 4-5 weeks. After this time testosterone levels have usually fallen to the castrate level thus therapy with SUPREFACT(r) as a single agent can be continued. Co-administration of anti-androgens with SUPREFACT(r) should be initiated to block testosterone flare. The majority of clinical studies demonstrating the efficacy of SUPREFACT(r) were completed without concomitant therapy with antiandrogens during the first weeks of treatment.
PATIENTS WITH ENDOMETRIOSIS Oral contraceptives must be discontinued before starting LHRH treatment; and non-hormonal methods of contraception (e.g. condoms) should be employed during therapy (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnancy). Worsening of the clinical condition may occasionally require discontinuation of therapy and/or surgical intervention.
Cardiovascular
In treated hypertensive patients, hypertensive crisis may occur. It is recommended that blood pressure be monitored regularly in these patients.
Endocrine and Metabolism
Isolated cases of loss of diabetic control (reduction in glucose tolerance) have been observed. Blood glucose levels should be checked regularly in diabetic patients. The use of LHRH agonists may be associated with decreased bone density and may lead to osteoporosis and an increased risk of bone fracture. The risk of skeletal fracture increase with the duration of therapy.
PATIENTS WITH PROSTATIC CANCER While hypogonadism is a pharmacologic consequence of long-term LHRH agonist treatment, its reversibility has not been established in patients suffering with prostatic carcinoma.
PATIENTS WITH ENDOMETRIOSIS Changes in bone density: Since bone loss can be anticipated as part of natural menopause, it may also be expected to occur during a medically induced hypoestrogenic state caused by SUPREFACT(r). In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, SUPREFACT(r), like other LHRH analogues, may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with SUPREFACT(r) is instituted. Use of SUPREFACT(r) for longer than the recommended six months or in the presence of other known risk factors for decreased bone mineral content may cause additional bone loss.
Hepatic/Biliary/Pancreatic
Studies have not been conducted in patients with hepatic impairment.
Immune
The hypersensitivity reactions may become manifest as, e.g. reddening of the skin, itching, skin rash (including urticaria) and allergic asthma with dyspnea as well as in isolated cases, anaphylactic/ anaphylactoid shock have been observed in patients treated with SUPREFACT(r), necessitating early treatment of such conditions.
Psychiatric
Patients with a history of depression or depressed moods should be observed closely for evidence of mood changes and treated accordingly.
Renal
Studies have not been conducted in patients with renal impairment.
Special Populations
Safe use of the drug in pregnancy has not been established; therefore, a non-hormonal method of contraception (e.g. condoms) should be used during treatment. To exclude pre-existing pregnancy at the beginning of therapy, it is recommended that treatment be started on the first or second day of menstruation. If there is any doubt, a pregnancy test is recommended (see CONTRAINDICATIONS). Patients should be advised that if they miss or postpone a dose of SUPREFACT(r), ovulation may occur with the potential for conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult her physician.
SUPREFACT(r) passes into breast milk in small amounts. Although negative effects on the infant have not been observed, it is recommended that breast-feeding be avoided during treatment with SUPREFACT(r) in order to prevent the infant from ingesting small quantities of SUPREFACT(r) with breast milk.
Experience with SUPREFACT(r) for the management of endometriosis has been limited to women 18 years of age and older.
No data is available
Monitoring and 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 and estradiol can be expected. With chronic drug administration, these elevated values of these variables will fall below baseline.
PATIENTS WITH PROSTATIC CANCER Regular clinical assessment of patients is recommended and should include clinical laboratory determinations of serum testosterone, prostatic acid phosphatase (PAP) or acid phosphatase, and prostate-specific antigen (PSA). If cancer is responsive to SUPREFACT(r) 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, intravenous 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.
Adverse Drug Reaction Overview
The adverse effects observed in patients treated with SUPREFACT(r) 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. The most frequent adverse events reported in patients with prostatic cancer receiving SUPREFACT(r) are hot flushes, loss of libido, impotence, nasal irritation (nasal solution) and headache (nasal solution). The most frequent adverse events reported in patients with endometriosis receiving SUPREFACT(r) are hot flushes, vaginal dryness, menorrhagia, headache and loss of libido.
Clinical Trial Adverse Drug Reactions
PATIENTS WITH PROSTATIC CANCER An early in treatment transient increase in serum testosterone levels usually occurs. Occasionally, this may be associated with transient worsening of clinical status with secondary reactions such as: occurrence or exacerbation of bone pain in patients with bone metastases, signs of neurological deficit due to spinal cord 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, General). Serious clinical (flare) reactions were reported in approximately 1% of patients in SUPREFACT(r) efficacy trials. Such reactions can be largely avoided when an antiandrogen is given concomitantly in the initial phase of SUPREFACT(r) treatment. However, even with concomitant anti-androgen therapy, a mild but transient increase in tumor pain as well as a deterioration in general well-being may develop in some patients. In a large, North American multicentre study of SUPREFACT(r), the following reactions were encountered as listed in the table below.
| Listing of adverse reactions, arranged by body system, possibly or probably related to SUPREFACT (r) that occurred at an incidence of 1% or greater in patients with prostatic cancer. | ||
| Adverse reactions | SUPREFACT (r) | |
| Subcutaneous (%) | Intranasal (%) | |
| Gastrointestinal disorders | ||
| Gastrointestinal disturbances | 3.0 | - |
| Dry mouth | - | 1.8 |
| General disorders and administration site conditions | ||
| Transient injection site reactions (1) | 11.9 | 5.4 |
| Pain | 4.6 | - |
| Irritation | 3.3 | 3.6 |
| Swelling | 3.3 | - |
| Urticaria | 2.0 | 1.8 |
| Other | 4.6 | - |
| Clinical flare reaction | 1.3 | - |
| Nervous system disorders | ||
| Headache (2) | - | 28.5 |
| Psychiatric disorders | ||
| Loss of libido (3) | 84.8 | 75.0 |
| Reproductive system and breast disorders | ||
| Impotence (3) | 79.4 | 75.0 |
| Gynecomastia | 2.6 | - |
| Respiratory, thoracic and mediastinal disorders | ||
| Nasal irritation (2) | - | 12.5 |
| Dry nose | - | 1.8 |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 1.3 | - |
| Increased sweating | - | 1.8 |
| Vascular disorders | ||
| Hot flushes | 71.6 | 66.1 |
None of the transient injection site reactions were severe or required discontinuation of therapy.
Not all of the cases were considered (by investigators) to be drug related.
Over 50% of patients enrolled reported loss of libido.
PATIENTS WITH ENDOMETRIOSIS During the first two weeks of treatment with intranasal SUPREFACT(r), 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). In two multicentre, open-label, randomized clinical trials, SUPREFACT(r) was compared to danazol in the treatment of patients with mild to severe endometriosis. Reported adverse reactions, which were considered by the treating physician to have a possible or probable relationship to treatment and which occurred in 5% or more of patients are listed in the table below.
| Possible or probable adverse reactions in >= 5% of patients taking SUPREFACT (r) in two trials in the treatment of mild to severe endometriosis. | ||
| Adverse reaction | SUPREFACT (r) (n=168) | Danazol (n=109) |
| n (%) | n (%) | |
| Hot flushes * | 121 (72.0) | 42 (38.5) |
| Vaginal dryness * | 48 (28.6) | 8 ( 7.3) |
| Menorrhagia | 40 (23.8) | 24 (22.0) |
| Headache * | 34 (20.2) | 18 (16.5) |
| Libido decreased * | 20 (11.9) | 8 ( 7.3) |
| Dizziness | 15 ( 8.9) | 6 ( 5.5) |
| Application site reaction | 13 ( 7.7) | 0 ( 0.0) |
| Depression * | 13 ( 7.7) | 6 ( 5.5) |
| Emotional lability * | 12 ( 7.1) | 15 (13.8) |
| Asthenia | 12 ( 7.1) | 24 (22.0) |
| Nausea | 11 ( 6.5) | 9 ( 8.3) |
| Acne * * | 9 ( 5.4) | 35 (32.1) |
* Physiological effects of decreased estrogen
* * Androgenic-like effects
In addition, in these same studies, other adverse reactions possibly or probably related to SUPREFACT(r) therapy that occurred between 1% and 5% of patients are listed in the table below.
| Listing of adverse reactions, arranged by body system, possibly or probably related to SUPREFACT (r) that occurred between 1% and 5% in patients with endometriosis. | |
| Body system Adverse reactions (preferred term) | SUPREFACT (r) (n = 168) |
| n (%) | |
| Cardiac disorders | |
| Palpitation | 2 (1.2) |
| Gastrointestinal disorders | |
| Constipation | 2 (1.2) |
| Gastrointestinal fullness | 5 (3.0) |
| Infections and infestations | |
| Rhinitis | 3 (1.8) |
| Upper respiratory infection | 2 (1.2) |
| Vaginitis | 3 (1.8) |
| Investigations | |
| Weight gain | 5 (3.0) |
| Weight loss | 4 (2.4) |
| Metabolism and nutrition disorders | |
| Edema | 5 (3.0) |
| Musculoskeletal and connective tissue disorders | |
| Arthralgia | 8 (4.8) |
| Myalgia | 3 (1.8) |
| Neck rigidity | 2 (1.2) |
| Pain in extremity | 3 (1.8) |
| Nervous system disorders | |
| Migraine | 5 (3.0) |
| Paresthesia | 4 (2.4) |
| Taste perversion | 3 (1.8) |
| Psychiatric disorders | |
| Anxiety | 2 (1.2) |
| Hostility | 2 (1.2) |
| Insomnia | 8 (4.8) |
| Nervousness | 4 (2.4) |
| Reproductive system and breast disorders | |
| Breast pain | 5 (3.0) |
| Dyspareunia | 3 (1.8) |
| Menstrual disorder | 2 (1.2) |
| Skin and subcutaneous tissue disroders | |
| Dry skin | 3 (1.8) |
| Hirsutism | 2 (1.2) |
| Purpura | 2 (1.2) |
| Skin disorder | 3 (1.8) |
In other clinical trials comprising a total of 968 patients with endometriosis treated with SUPREFACT(r), adverse events not listed above which occurred in 1% or more of patients are included in the table below (not all cases were assessed for causality to SUPREFACT(r)).
| Listing of adverse reactions, arranged by body system, that occurred in 1% or more of patients with endometriosis (causality not assessed in all cases). | ||
| Body system Adverse reactions (preferred term) | SUPREFACT (r) (n = 968) | |
| 1200 u g/day (n=152) | 900 u g/day (n=816) * | |
| n (%) | n (%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 12 (7.9) | 8 (1.0) |
| Dry mouth | 4 (2.6) | 9 (1.1) |
| Flatulence | 23 (15.1) | 4 (0.5) |
| Vomiting | 6 (3.9) | 9 (1.1) |
| General disorders and administration site conditions | ||
| Ill-defined symptoms | 23 (15.1) | 16 (2.0) |
| Malaise | 12 (7.9) | 4 (0.5) |
| Infections and infestations | ||
| Infection | 11 (7.2) | - |
| Metabolism and nutrition disorders | ||
| Generalized edema | 9 (5.9) | 1 (0.1) |
| Peripheral edema | 3 (2.0) | 12 (1.5) |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 42 (27.6) | 30 (3.7) |
| Psychiatric disorders | ||
| Sleep disorder | 2 (1.3) | 10 (1.2) |
| Reproductive system and breast disorders | ||
| Leukorrhea | - | 36 (4.4) |
| Pelvic pain | 1 (0.7) | 17 (2.1) |
| Premenstrual syndrome | - | 12 (1.5) |
| Vaginal discharge | - | 14 (1.7) |
| Vaginal discomfort | - | 11 (1.3) |
| Respiratory, thoracic and mediastinal disorders | ||
| Sore throat | 8 (5.3) | 4 (0.5) |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | - | 12 (1.5) |
* : 16 patients received 450-1800ug/day
Less Common Clinical Trial Adverse Drug Reactions (<1%)
PATIENTS WITH PROSTATIC CANCER Other adverse reactions, arranged by body system possibly or probably related to the administration of SUPREFACT(r) that occurred at an incidence below 1% included:
Body as a whole: Digestive system: Endocrine system
fever (subcutaneous), pain (subcutaneous)
(subcutaneous) diarrhea, nausea
: feminization (subcutaneous)
Skin and appendages
: hirsutism (subcutaneous)
Urogenital system
: urinary retention (subcutaneous)
P
ATIENTS WITH ENDOMETRIOSIS
Other adverse reactions possibly or probably related to SUPREFACT(r) therapy reported in less than 1% of patients included:
Body as a whole:
abdominal pain, allergic reaction, pain, photosensitivity
Cardiovascular system:
syncope, vasodilatation
Digestive system:
gastrointestinal disorder, gastrointestinal pain, increased appetite, mouth ulceration
Nervous system:
amnesia, somnolence, sweating increased, thinking abnormal, tremor, vertigo
Respiratory system:
epistaxis
Skin & appendages:
breast atrophy, breast enlargement, rash
Special senses:
abnormality of accommodation, dry eyes, ear disorder, ear pain, eye disorder, parosmia, tinnitus
Urogenital system:
vaginal hemorrhage
Abnormal Hematologic and Clinical Chemistry Findings
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 and estradiol can be expected. With chronic drug administration, these elevated values of these variables will fall below baseline. In addition, changes in blood lipids, increase in bilirubin levels, increase in serum liver enzymes levels (e.g. transaminases), leucopenia, thrombopenia have been observed with the use of SUPREFACT(r).
Post-Market Adverse Drug Reactions
Very rare cases of pituitary adenomas were reported during treatment with LHRH agonists, including SUPREFACT(r).
PATIENTS WITH PROSTATIC CANCER In the international adverse effect database other adverse events have been observed in patients treated with buserelin with all reports probably or possibly related to the administration of SUPREFACT(r):
Special senses:
eye dryness and irritation
Metabolic & nutritional disorders:
mild edemas of the ankles and lower legs
Nervous system:
mood changes
Respiratory system:
rhinorrhea
Skin and appendages
: articular pains, skin reaction (wheal) allergy.
PATIENTS WITH ENDOMETRIOSIS In the international database, other adverse events have been observed in patients treated with buserelin, as itemized below (not all events were considered to be related to buserelin therapy):
Digestive system:
increased thirst
Haemic and lymphatic system
: leucopenia, thrombopenia
Nervous system
: concentration and memory disturbances, drowsiness, tiredness
Skin and appendages
: articular pains, application site pain, irritation of the mucosa in the nasopharynx due to nasal solution administration (which may lead to nosebleeds, hoarseness, disturbances of smell or taste), brittle finger nails, female lactation, decrease or increase in scalp
hair, decrease in body hair.
Special senses
: feeling of pressure behind the eyes, impaired vision (e.g. blurred vision).
Urogenital system
: ovarian cysts (during the initial phase of therapy).
Drug-Drug Interactions
During treatment with SUPREFACT(r), the effect of antidiabetic agents may be attenuated. PATIENTS WITH ENDOMETRIOSIS In concomitant treatment with sexual hormones ("add-back"), the dosage is to be selected so as to ensure that the overall therapeutic effect is not affected.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Administration of SUPREFACT(r) in therapeutic doses results in suppression of the pituitary- gonadal system. Normal function is usually restored after a few weeks of last dose of SUPREFACT(r). Diagnostic tests of pituitary-gonadal function conducted during the treatment and within a few weeks after discontinuation of SUPREFACT(r) therapy may therefore be misleading.
Dosing Considerations
SUPREFACT(r) should be administered at approximately equal time intervals to ensure that the desired therapeutic effect is maintained.
Recommended Dose and Dosage Adjustment
PATIENTS WITH PROSTATIC CANCER
For the first seven days of treatment give SUPREFACT(r) 500 mcg (0.5 mL) every 8 hours by subcutaneous injection. For patient comfort, vary the injection site.
Depending upon patient preference, or physician recommendation, maintenance treatment may be by daily subcutaneous injection or by intranasal administration three times daily. During maintenance dosing by the subcutaneous injection route, the SUPREFACT(r) dose is 200 mcg (0.2 mL) daily. For patient comfort, vary the site of injection. During maintenance dosing by the intranasal administration route, the SUPREFACT(r) dose is 400 mcg (200 mcg into each nostril) three times daily using the metered-dose pump (nebulizer) provided. Each pump action delivers 100 mcg buserelin (as buserelin acetate) or 0.1 mL solution.
PATIENTS WITH ENDOMETRIOSIS The dose of SUPREFACT(r) in patients with endometriosis is 400 mcg (200 mcg into each nostril) three times daily using the metered-dose pump (nebulizer) provided. Each pump action delivers 100 mcg buserelin (as buserelin acetate) or 0.1 mL solution. The treatment duration is usually six months and should not exceed nine months.
Missed Dose
Should the patient forget to take a dose, the dose should be administered as soon as they remember. However, if it is almost time for the next dose, the patients should skip the missed dose and go back to their regular dosing schedule. The patient should not double doses.
Administration
SUPREFACT(r) Injection The SUPREFACT(r) vial is supplied with a plastic cap which can be removed by pressing upwards with the thumb. This cap serves to ensure that the vial has not been previously entered. After removal (the cap can be discarded) the rubber diaphragm of the vial is exposed. Proceed as follows:
Wash your hands, with soap and water, and dry on a clean towel.
Clean the rubber diaphragm of the SUPREFACT(r) vial with a cotton swab previously dipped in alcohol. Leave to dry.
Select an appropriate sterile, disposable syringe and needle assembly and remove it from its sterile packaging.
Draw the syringe piston as far back as the volume (see syringe cylinder graduation) of solution you wish to withdraw from the vial.
Remove the needle sheath (protector).
Without touching the needle with your fingers, push the needle through the centre of the rubber diaphragm of the vial.
Push on the syringe plunger so that the selected air volume is expelled into the vial.
Keeping the needle in the vial, invert the vial into the vertical position adjusting the needle tip to a position below the surface of the solution in the vial.
Draw the required solution from the vial by withdrawing the syringe piston.
Carefully withdraw the needle and syringe assembly from the vial.
Choose the injection site (vary the site for each injection) and clean the skin with an alcohol impregnated swab
Pinch the site, if you wish, between index finger and thumb and, with the needle at an angle introduce the needle quickly under the skin as far as possible.
Withdraw the syringe piston a little and, if no blood is withdrawn into the syringe, then push on the piston steadily to inject the solution.
Upon completion of the injection, and resting the alcohol-impregnated swab over the needle entry site, remove the needle in a reverse fashion of the entry motion. Hold swab to injection site for a few seconds, then remove.
Discard needle and syringe assembly along with the swab in a safe manner. Return the SUPREFACT(r) vial to its storage area.
There is no information available on possible incompatibilities between SUPREFACT(r) solution or SUPREFACT(r) injection and other agents.
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 26-40 years and 31-40 years respectively, were given 1 mg buserelin or 5 mg buserelin orally as a single dose. No luteinizing hormone (LH) or follicle stimulating hormone (FSH) release was observed. No clinical effects were observed. Overdose may lead to signs and symptoms such as asthenia, headache, nervousness, hot flushes, dizziness, nausea, abdominal pain, edemas of the lower extremities, and mastodynia. For the injectable formulation, local reactions at the injection site such as pain, haemorrhage and induration. Therapy for overdose is directed to the symptoms.
Mechanism of Action
Buserelin acetate is a synthetic peptide analog of the natural gonadotropin releasing hormone (GnRH/LHRH) with enhanced biological activity. After repeated administration of SUPREFACT(r), the secretion of gonadotrophin release and gonadal steroids is significantly inhibited. The pharmacological effect is attributable to the down-regulation of pituitary LHRH receptors. In male individuals the elimination of gonadotrophin release results in a reduction in the synthesis and secretion of testosterone. In female individuals the elimination of pulsatile gonadotrophin release inhibits the secretion of estrogen.
Pharmacodynamics
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 FSH and 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 (50-500 mcg SC/day or 300-1200 mcg IN/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.
Pharmacokinetics
SUPREFACT(r) is water-soluble; when administered by subcutaneous injection it is reliably absorbed. After subcutaneous injection of 200 ug, SUPREFACT(r) is 70% bioavailable; in contrast, after oral administration, SUPREFACT(r) is ineffective. If administered correctly by the nasal route, it is absorbed via the nasal mucosa in such a way that sufficiently high plasma levels are guaranteed. The nasal absorption of SUPREFACT(r) from SUPREFACT(r) nasal solution is 1 to 3%.
SUPREFACT(r) circulates in serum predominantly in intact active form. SUPREFACT(r) accumulates preferentially in the liver and kidneys as well as in the anterior pituitary lobe, the biological target organ. Protein binding is approximately 15%.
SUPREFACT(r) is metabolized and subsequently inactivated by peptidase (pyroglutamyl peptidase and chymotrypsin-like endopeptidase) in the liver and kidneys as well as in the gastrointestinal track. In the pituitary gland, receptor-bond SUPREFACT(r) is inactivated by membrane-located enzymes.
SUPREFACT(r) and inactive SUPREFACT(r) metabolites are excreted via the renal and biliary routes. In man approximately 50% of SUPREFACT(r) excreted in urine is intact. The elimination half-life is approximately 50 to 80 minutes following intravenous administration, 80 minutes after subcutaneous administration and approximately 1 to 2 hours after intranasal administration.
Special populations and conditions
The effect of hepatic impairment on the pharmacokinetics of SUPREFACT(r) has not been studied.
The effect of renal impairment on the pharmacokinetics of SUPREFACT(r) has not been studied.
Store at controlled room temperature 15-25 degC in the original container, protect from heat and light, do not freeze. Do not use beyond the expiration date printed on the container label. The product can be kept up to 14 days after the first opening when stored at room temperature. Keep in a safe place out of reach of children.
Store at controlled room temperature 15-25 degC in the original container, protect from heat and light, do not freeze. Do not use beyond the expiration date printed on the container label. The product can be kept up to 5 weeks after the first opening when stored at room temperature. Keep in a safe place out of reach of children.
Each mL of sterile aqueous injection solution contains: 1.05 mg buserelin acetate (equivalent to 1.00 mg pure anhydrous buserelin free base), 10 mg benzyl alcohol as preservative, monobasic sodium phosphate buffer, 4.5 mg sodium chloride for tonicity adjustment and sodium hydroxide for pH adjustment. SUPREFACT(r) is packaged in clear glass multi-dose vials of 10 mL containing of 5.5 mL (net) ready for administration direct from the container. It is supplied as two cartons, each containing one vial of 5.5 mL.
Each mL of aqueous intranasal solution contains: 1.06 mg buserelin acetate (equivalent to 1.00 mg pure anhydrous buserelin free base), 0.10 mg benzalkonium chloride as preservative, citric acid/sodium citrate buffer and 8.1 mg sodium chloride for tonicity adjustment. SUPREFACT(r) is packaged in amber glass bottles of 10.0 mL (net) for intranasal administration via the metered-dose pump (nebulizer) provided. SUPREFACT(r) solution for intranasal administration is provided ready for administration direct from the container. It is supplied in cartons of 1 x 10.0 mL bottle and 1 metered-dose pump. The metered-dose pump (nebulizer) provided has a mechanical action and contains no propellants.