CinnaFact®


(Buserelin Acetate)

A Big triumph for medical society


INDICATIONS AND USAGE

Prostate cancer

 Palliative treatment in patients with hormone-dependent advanced prostate cancer (stage D)

Endometriosis

 Treatment of endometriosis in women who do not require surgical intervention as first-line therapy (length of therapy is usually 6 months, but no longer than 9 months)

DOSAGE AND ADMINISTRATION

Administration

SubQ: Rotate injection sites; administer at equal time intervals.

Hazardous agent; use appropriate precautions for handling and disposal

Dosing

Prostate cancer, advanced

Note: Administration of an antiandrogen agent beginning 7 days prior to initiation of buserelin therapy and continuing for ~5 weeks with buserelin therapy is recommended in patients with prostate cancer.

SubQ:

Buserelin: Initial: 500 mcg every 8 hours for 7 days. Maintenance: 200 mcg once daily

For Endometriosis 

200 mcg buserelin by S.C. injection increasing to 500 mcg daily, depending upon symptomatic response. Treatment should be started on the first or second day of the menstrual period in order to exclude, as far as possible, the existence of pregnancy. Treatment is usually given for 6 months and should not exceed 9 months. The inception of buserelin treatment may cause ovulation and contraceptive measures should be in place.

For Adjunctive use in Ovulation Induction

 600 mcg buserelin by S.C. injection as a divided dose 3 times daily. Treatment should start in the early follicular phase (day 1) or, provided the existence of any early pregnancy has been excluded, in the midluteal phase (day 21). It should continue at least until down-regulation is achieved (ie. serum oestradiol < 50 ng/l and serum progesterone < 1 mcg/l). This will usually take about 2-3 weeks with nasal spray administration, and is less with parenteral use. When down-regulation is achieved stimulation with gonadotrophin is commenced while the dosage of buserelin is maintained. At the appropriate stage of follicular development gonadotrophin and buserelin are stopped and human chorionic gonadotropin (hCG) is given to induce ovulation. Treatment monitoring, oocyte transfer and fertilization techniques are performed according to the normal practice of the individual clinic. Luteal support with hCG or progesterone should be given as appropriate.

DOSAGE FORMS AND STRENGTHS

Solution for SC injection: 1mg/ml buserelin as acetate (5.5 ml)

Each mL of sterile aqueous injection solution contains: 1.05 mg buserelin acetate (equivalent to 1.00 mg pure  anhydrous buserelin free base), benzyl alcohol as preservative, monobasic sodium phosphate buffer, sodium  chloride for tonicity adjustment and sodium hydroxide for pH adjustment.

CinnaFact is packaged in clear glass multi-dose vials of 10 mL containing of 5 mL ready for administration direct from the container.

It is supplied as one carton, containing one vial of 5.5 mL.

CONTRAINDICATIONS

Hypersensitivity to buserelin or any component of the formulation; patients with nonhormone-dependent prostate cancer; patients who have undergone orchiectomy; patients with undiagnosed abnormal vaginal bleeding; pregnancy; breast-feeding.

WARNINGS AND PRECAUTIONS

 Concerns related to adverse effects

• Anaphylactoid reactions: Reactions including allergic asthma with dyspnea as well as rare anaphylactic/anaphylactoid shock have been observed in buserelin treated patients.

• CNS effects: Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Exacerbation of disease: A transient (usual duration <10 days) exacerbation of the signs and symptoms of the disease process may be observed with the initiation of therapy. Adjunctive antiandrogen therapy is recommended for patients with prostate cancer to minimize exacerbations.

• Pituitary adenoma: The development of pituitary adenomas may rarely be seen with long-term therapy.

 Disease related concerns

• Cardiovascular disease: Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine, 2010). Androgen deprivation may increase the QT interval (on ECG); consider benefit/risk ratio in patients with congenital long QT syndrome, concomitant antiarrhythmic therapy, or heart failure.

• Depression: Monitor patients with a history of depression and treat appropriately where indicated.

• Diabetes: Loss of blood glucose control has been reported. Reduced glucose tolerance has been noted in rare cases. Use caution in patients with diabetes; monitor blood glucose.

• Endometriosis: A transient exacerbation of the signs/symptoms may be associated with the initiation of therapy. Oral contraceptives should be discontinued prior to starting therapy; use of a nonhormonal contraceptive is recommended.

• Hypertension: Increases in blood pressure (including hypertensive crisis) may occur in patients with preexisting hypertension. Monitor blood pressure regularly.

• Osteoporosis: Treatment inducing a hypoestrogenic state may lead to changes in bone density. The benefits and risks of potential buserelin therapy should be considered before treatment is initiated. Patients at risk for reduced bone density include those with chronic alcohol and/or tobacco use, family history of osteoporosis, and chronic treatment with anticonvulsants or corticosteroids. Use of buserelin for >6 months or in association with other risk factors may contribute to additional bone loss.

• Prostate cancer: Initiation of therapy without a concomitant antiandrogen agent may lead to a transient worsening of symptoms, including bone pain, neuropathy, ureter or bladder obstruction, hematuria, hydronephrosis, lymphostasis, or thrombosis with pulmonary embolus. Caution and close monitoring should be used in patients with vertebral metastases who are at risk for lesion exacerbation with possible spinal cord compression; initiate antiandrogen therapy 7 days prior to beginning buserelin therapy and continue for 5 weeks with buserelin therapy. Reversal of hypogonadism induced by therapy has not been established in this patient population. Testosterone suppression is associated with the development of anemia.

• Urinary obstruction: In patients with prostate cancer, a transient increase in patient symptoms may occur early in therapy. Monitor for signs of urinary obstruction or retention.

ADVERSE REACTIONS

Note: Adverse reaction profile differs based on population/medication and route of administration.

>10%:

Central nervous system: Headache (20% to 29%)

Endocrine & metabolic: Loss of libido (prostatic cancer 75% to 85%), hot flash (14% to 72%), hypermenorrhea (endometriosis 24%), decreased libido (endometriosis 12%, prostatic cancer 2% to 5%)

Gastrointestinal: Flatulence (≤15%)

Genitourinary: Impotence (prostatic cancer 2% to 79%), vaginal dryness (endometriosis 29%)

Neuromuscular & skeletal: Back pain (4% to 28%), weakness (≤14%)

Respiratory: Nasal mucosa irritation (intranasal 13%)

1% to 10%:

Cardiovascular: Edema (≤6%), hypertension (2% to 5%), peripheral edema (2%), palpitations (≤1%)

Central nervous system: Dizziness (9%), depression (8%), malaise (≤8%), emotional lability (7%), insomnia (≤5%), nervousness (≤2%), pain (≤2%), anxiety (1%), hostility (1%), sleep disorder (1%)

Dermatologic: Acne vulgaris (endometriosis 5%), dermatological reaction ( 2%), urticaria at injection site (subcutaneous 2%), xeroderma (2%), diaphoresis (≤2%), pruritus (≤2%)

Endocrine & metabolic: Gynecomastia (prostatic cancer ≤3%), weight gain (≤3%), premenstrual syndrome (endometriosis 2%), weight loss (≤2%), menstrual disease (endometriosis 1%), hirsutism (endometriosis ≤1%), increased testosterone level (clinical flare; prostatic cancer ≤1%)

Gastrointestinal: Diarrhea (≤8%), nausea (≤7%), increased appetite (≤5%), sore throat (≤5%), vomiting (1% to 4%), gastrointestinal fullness (3%), xerostomia (1% to 3%), gastrointestinal distress (≤3%), dysgeusia (2%), constipation (≤1%)

Genitourinary: Leukorrhea (endometriosis 4%), mastalgia (endometriosis 3%), dyspareunia (endometriosis 2%), vaginal discharge (endometriosis 2%), vaginitis (endometriosis 2%), pelvic pain (endometriosis ≤2%), vaginal discomfort (endometriosis 1%)

Hematologic & oncologic: Purpura (1%)

Infection: Infection (7%)

Local: Application site reaction (intranasal 8%), pain at injection site (subcutaneous 5%), injection site reaction (subcutaneous ≤5%), application site irritation (intranasal 4%), irritation at injection site (subcutaneous 3%), swelling at injection site (subcutaneous 3%)

Neuromuscular & skeletal: Arthralgia (≤5%), myalgia (2% to 5%), limb pain (2%), neck stiffness (1%)

Respiratory: Dry nose (intranasal 2%), rhinitis (2%), upper respiratory tract infection (1%)

<1% (Limited to important or life-threatening): Accommodation disturbance, amnesia, anemia, anorexia, arthritis, bleeding at injection site, breast atrophy (endometriosis), breast hypertrophy (endometriosis), cardiac failure, dyslipidemia, ejaculatory disorder (prostatic cancer), extrinsic asthma, fecal incontinence, feminization (prostatic cancer), hyperalgesia, hyperglycemia, hypersensitivity reaction, increased acid phosphatase (transient), increased plasma estradiol concentration (endometriosis; transient), increased serum bilirubin, increased serum transaminases, lactation (endometriosis; female), leukopenia, myelofibrosis, ovarian cyst (endometriosis; during initial phase of therapy), pituitary neoplasm, skin photosensitivity, suicidal tendencies, syncope, tachycardia, testicular atrophy (prostatic cancer), thrombocytopenia, thrombosis, transient blindness (one eye), urinary retention, vaginal hemorrhage (endometriosis)

DRUG INTERACTIONS

Antidiabetic Agents: Luteinizing Hormone-Releasing Hormone Analogs may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Corifollitropin Alfa: Luteinizing Hormone-Releasing Hormone Analogs may enhance the therapeutic effect of Corifollitropin Alfa. Risk X: Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Risk X: Avoid combination

Indium 111 Capromab Pendetide: Luteinizing Hormone-Releasing Hormone Analogs may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk X: Avoid combination

Mifepristone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk X: Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk C: Monitor therapy

USE IN SPECIFIC POPULATIONS

Pregnancy

Buserelin is contraindicated in pregnant women. Patients should employ a nonhormonal method of contraception during therapy. To exclude preexisting pregnancy, begin treatment on the first or second day of menses; if there is doubt, a pregnancy test is recommended. Ovulation may occur with a missed dose; in the event a patient conceives, therapy should be discontinued.

Lactation 

Enters breast milk/contraindicated

Breast-Feeding Considerations 

Small amounts of buserelin can be detected in breast milk. Contains benzyl alcohol, which has been associated with gasping syndrome in premature infants. Breast-feeding is contraindicated by the manufacturer.

OVERDOSAGE

There is no information on the consequences of overdosage with buserelin.

DESCRIPTION

Buserelin acetate is a synthetic peptide analog of the natural gonadotropin releasing hormone (GnRH/LHRH) with enhanced biological activity. After repeated administration of this drug, 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 secre- tion of testosterone.

In female individuals the elimination of pulsatile gonadotrophin release inhibits the secretion of estrogen. Clinical Pharmacology The substitution of glycine in position 6 by D-serine, and that of glycinamide in posi- tion 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) 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.

CinnaFact is supplied at a concentration of 1 mg/mL buserelin as acetate (5.5 ml) multiple use vial.  Each mL of sterile aqueous injection solution contains: 1.05 mg buserelin acetate (equivalent to 1.00 mg pure  anhydrous buserelin free base), benzyl alcohol as preservative, monobasic sodium phosphate buffer, sodium  chloride for tonicity adjustment and sodium hydroxide for pH adjustment.

CLINICAL PHARMACOLOGY

Mechanism of Action

Synthetic peptide analog of Gonadotropin hormone releasing hormone (GnRH) with substitutions at positions 6 and 10; altered peptide structure results in a significantly magnified GnRH agonist effect with an extended duration of activity. Following an initial rise in the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), chronic administration of buserelin results in a sustained suppression of LH and FSH and an interference with the production of ovarian and testicular steroids. Eventually, a decline in gonadal steroids to castration levels is observed.

Pharmacodynamics and Pharmacokinetics

Protein binding: ~15%

Metabolism: Plasma; inactive metabolites

Half-life elimination: SubQ: Immediate release: 80 minutes

Excretion: Urine (50% as unchanged drug)

NONCLINICAL TOXICOLOGY

There is no information for this part.

HOW SUPPLIED/STORAGE AND HANDLING

Stability and Storage

Vials of CinnaFact should be stored between 2-250C in the original container.

Protect from light and heat.

Do not freeze.

Do not use beyond the expiration date printed on the container label.

The product can be kept up to 20 days after the first opening when stored at room temperature.

Keep in a safe place out of reach of children.

FAQs

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