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PUREGON™
Organon
Follitropin Beta
Gonadotropin
 
Action And Clinical Pharmacology: Puregon is a freeze-dried preparation containing highly purified human follicle stimulating hormone (hFSH) prepared by recombinant DNA technology. The active substance, follitropin beta, is a heterodimeric glycoprotein with a molecular mass of approximately 35-45kD. It is produced by a Chinese hamster ovary (CHO) cell line transfected with a plasmid containing two subunit genes encoding human FSH. Structural analysis has shown that the amino acid sequence of follitropin beta is identical to that of natural hFSH. The oligosaccharide side chains are very similar to those reported for natural hFSH but not completely identical. These small differences do not affect the degree of charge heterogeneity, receptor binding affinity and bioactivity of follitropin relative to natural hFSH. Follitropin beta, as purified from the CHO cell culture supernatant, is of high biochemical purity (³99%), high specific biological activity (approximately 10 000 IU/mg protein), and devoid of luteinizing hormone (LH) activity.

Follicle stimulating hormone (FSH) is essential for normal female and male gamete growth and maturation, and gonadal steroid production. Deficiencies in the endogenous production of FSH may lead to infertility.

FSH is critical for the onset and duration of follicular development and consequently for the timing and number of follicles reaching maturity in females. The primary action of follitropin beta in women with gonadal dysfunction is the stimulation of follicular development and steroid production. Follitropin may also be used to promote multiple follicular development in medically assisted reproduction programs (i.e., IVF/ET/ISCI) and gamete or zygote intra-fallopian transfer (GIFT/ZIFT). In order to induce ovulation, in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given after follitropin administration once follicular maturation has occurred.

After i.m. or s.c. administration of follitropin beta, high concentrations of FSH are reached within about 12 hours. FSH levels remain high for 24 to 48 hours due to follitropin beta's relatively long elimination half-life of about 40 hours (ranging from 12 to 70 hours). Plasma FSH concentrations, after repeated administration of follitropin beta, are approximately 1.5 to 2.5 times higher than after single dose administration.

There are no significant pharmacokinetic differences between i.m. and s.c. administration of follitropin beta.

Indications And Clinical Uses: For development of multiple follicles in ovulatory patients participating in an Assisted Reproduction Technology (ART) program and for induction of ovulation and pregnancy in anovulatory infertile females in whom the cause of infertility is functional and not due to primary ovarian failure.

Contra-Indications: Women who exhibit a high circulating FSH level indicating primary ovarian failure; uncontrolled thyroid or adrenal dysfunction; tumor of the ovary, breast, uterus, hypothalamus or pituitary gland; pregnancy and lactation; heavy or irregular vaginal bleeding of undetermined origin; ovarian cysts or enlargement not due to polycystic ovary syndrome (PCOD); prior hypersensitivity to follitropin beta or other components of Puregon; and conditions incompatible with pregnancy (e.g., malformation of sexual organs or fibroid tumors of the uterus). tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Follitropin beta is a potent gonadotropic agent that is capable of causing severe adverse effects in women. It should be used only by physicians who are experienced in the management of fertility disorders and only when facilities for appropriate clinical and endocrinologic evaluations are available.

Overstimulation of the Ovary During Therapy: To minimize the risk associated with abnormal ovarian enlargement in women receiving follitropin beta and hCG for the induction of ovulation and pregnancy, the drugs should be administered at the lowest possible effective dosage. Since follitropin beta may cause ovarian enlargement and/or hyperstimulation, patients should be assessed for signs of excessive ovarian stimulation during therapy and for a 2-week post-treatment period. Careful monitoring of ovarian response (i.e., ultrasonography and/or estradiol level determination) can minimize the risk of overstimulation.

Mild to moderate uncomplicated ovarian enlargement, which may be accompanied by abdominal distention and/or abdominal pain, occurs in approximately 20% of patients treated with gonadotropins and hCG, and generally regresses without treatment within 2 to 3 weeks. If unwanted hyperstimulation occurs, the administration of follitropin beta should be discontinued immediately. In this case, hCG must not be given because the administration of an LH-active gonadotropin at this stage may induce ovarian hyperstimulation syndrome, in addition to multiple ovulations. This warning is particularly important with respect to patients with anovulation or oligoovulation (polycystic ovarian disease and hypothalamic hypogonadism).

Clinical symptoms of mild ovarian hyperstimulation syndrome are gastrointestinal problems (abdominal distention, nausea, diarrhea), painful breasts, and mild to moderate enlargement of ovaries because of ovarian cysts.

Severe ovarian hyperstimulation syndrome (OHSS) is characterized by ovarian enlargement (large cysts prone to rupture) accompanied by hemoconcentration, decreased urinary output, ascites with or without pain and/or pleural effusion.

If severe OHSS occurs, treatment should be stopped and the patient hospitalized. Ovarian hyperstimulation syndrome develops rapidly within 3 to 4 days and generally during the 2-week period following the hCG injection.

Hemoconcentration associated with fluid loss into the abdominal cavity has been observed to occur and should be thoroughly assessed as follows: 1) fluid intake and output; 2) weight and abdominal girth; 3) hematocrit; 4) serum and urinary electrolytes; 5) urine specific gravity. Other monitoring should include serum albumin and total proteins. These determinations should be performed daily or more often if needed. Treatment consists primarily of bed rest, fluid, electrolyte and albumin replacement, and analgesics as needed. Generally, removal of ascitic fluid (paracentesis) should be reserved for the more severe cases of third space fluid shift or abdominal discomfort.

Hemoperitoneum may occur from ruptured ovarian cysts. This is usually the result of sexual intercourse or a vigorous pelvic examination. Should this occur and be accompanied by bleeding to the extent that surgery is necessary, partial resection of the enlarged ovary or ovaries may be required. Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation due to the risk of hemoperitoneum resulting from ruptured ovarian cysts.

Arterial Thromboembolism: Arterial thromboembolism has been reported in patients who have received gonadotropin and hCG, both in association with and separate from ovarian hyperstimulation syndrome. Complications resulting from thromboembolism have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, stroke, arterial occlusion necessitating limb amputation, and (rarely) death.

Other Reproductive Complications: Multiple ovulations with resulting multiple births occur (mostly twins) frequently (Žsl20% of pregnancies) following treatment with gonadotropins and hCG. Prior to gonadotropin and hCG therapy, the patient and her male sexual partner should be informed of the possibility and potential risks associated with multiple births.

Spontaneous abortion rates have been reported from 10 to 25% of all patients following gonadotropin treatment. Increased abortion rates are more common in women over 35 years of age, in women with polycystic ovarian disease, and are more common in the infertile couple. The increased frequency of multiple pregnancy is also associated with an increased rate of abortion.

Precautions: A thorough gynecologic and endocrinologic evaluation must be performed prior to treatment with follitropin beta. The evaluation may include hysterosalpinography to detect uterine and tubal pathology. Anovulation should be confirmed by menstrual history, observation of the basal body temperature pattern, determination of serum progesterone concentration in the luteal phase, or an endometrial biopsy. Tumors of the thyroid, adrenals, pituitary and ovary may cause anovulation and patients with such tumors should be excluded from follitropin beta therapy.

Determination of serum gonadotropin concentrations should be obtained to rule out primary ovarian failure.

The presence of early pregnancy should be ruled out by a biochemical pregnancy test. Evaluation of the fertility potential of the male sexual partner should also be performed (a semen analysis) before starting follitropin beta therapy.

Lactation: Follitropin beta is not intended for use during lactation.

Carcinogenesis and Mutagenesis: Follitropin beta displays no mutagenic potential. Carcinogenicity studies have not been performed.

Drug Interactions: Concurrent use of follitropin beta and clomiphene may enhance the follicular response. After pituitary desensitization effected by a GnRH agonist, a higher dose of follitropin beta may be necessary to elicit an adequate follicular response.

Adverse Reactions: The most frequently reported adverse events in clinical trials were related to the reproductive (total 8.8%; ovarian hyperstimulation syndrome 5%, ectopic pregnancy 2.1%, vaginal hemorrhage 1%) and gastrointestinal system (total 3.6%, abdominal pain 2%). Miscarriages were reported in 3.1% of the study population. The incidence of adverse reactions was similar to that observed with urinary gonadotropin. Table I shows adverse events, listed by body system, which have been reported in clinical studies evaluating the efficacy and safety of follitropin beta.

In addition, each of the following adverse events were reported by 1 to 3 patients receiving follitropin beta: eczema, itching, rash, hyperemesis, bloating, constipation, gastroesophageal reflux, vomiting, tooth disorder, increased bilirubin, dyspnea, hematoma, cystitis, dysuria, face edema, frequent micturition, premature labor, metrorrhagia, ovarian disorder, vaginal discharge, vulvovaginitis, hydatidiform mole, back pain, feeling unwell, hot flushes, influenza-like symptoms, lumbar pain, pain, swollen abdomen, syncope, abscess, Herpes zoster, otitis media, sepsis and genital infection.

Post-treatment sera were analyzed following 3 treatment cycles and no evidence of induction of anti-FSH or anti-CHO cell-derived protein antibodies were found.

The following adverse reactions have been reported with gonadotropin therapy in general: mild to moderate ovarian enlargement; febrile reactions which may be associated with chills, musculoskeletal aches, joint pains, malaise, headache and fatigue; breast tenderness; dry skin; hair loss; hives; and hemoperitoneum.

The following adverse events have been reported subsequent to pregnancies resulting from gonadotropin therapy: ectopic pregnancy; congenital abnormalities including chromosomal abnormalities and birth defects (imperforate anus, aplasia of the sigmoid colon, hypospadias, cecovesical fistula, bifid scrotum, bilateral internal tibial torsion, right metatarsus adductus, cardiac lesions, supernumerary digit, exstrophy of the bladder, Down's syndrome, Trisomy 13, Trisomy 18, hydrocephaly, omphalocele, meningocele, external ear defect, dislocated ankle and hip, dilated cardiomyopathy). None of these events were considered drug-related and the incidence does not exceed that found in the general population. Spontaneous abortion was also observed in patients receiving urinary gonadotropin therapy.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The acute toxicity of gonadotropin preparations has been shown to be very low. However, too high a dosage for more than 1 day may lead to hyperstimulation of the ovaries (see Warnings). tag_DosageDosage

Dosage And Administration: Ovulation Induction: The dosage of follitropin beta required to produce follicular maturation must be individualized according to ovarian response. The growth and development of follicles, timing of hCG administration, detection of ovarian enlargement and minimization of the risk of OHSS and multiple gestation requires careful clinical assessment. This may be achieved through pelvic ultrasonography, monitoring of estrogen levels, and/or clinical evaluation of estrogen activity.

Generally, an initial dose of 75 IU/day, administered i.m. or s.c., for 5 to 7 days is recommended. If there is no apparent ovarian response, the daily dose is gradually increased until estrogen levels start to rise. A daily ascent rate of 40 to 100% is considered to be optimal. The maximum individualized daily dose of follitropin beta safely used in clinical trials was 300 IU. The daily effective dose is maintained until preovulatory conditions are reached. If estrogen levels rise too rapidly (i.e., more than a daily doubling for 2 consecutive days), the daily dose should be decreased. Preovulatory conditions are reached when plasma estradiol levels of 1 000 to 3 000 pmol/L are attained, and/or when there is ultrasonographic evidence of a dominant follicle of at least 18 mm in mean diameter. Usually, 7 to 14 days of treatment is sufficient to reach this state. Once preovulatory conditions are reached, the administration of follitropin beta should be discontinued and ovulation induced by administration of 5 000 to 10 000 IU human chorionic gonadotropin (hCG).

Beginning the day prior to administration of human chorionic gonadotropin the couple should be encouraged to have intercourse at least 3 times per week until ovulation occurs.

Clinical confirmation of ovulation is obtained through the indices of progesterone production. Increasing progesterone secretion by the corpus luteum and a concomitant increase in basal body temperature are indirect signs of ovulation. A serum progesterone level over 30 nmol/L also provides adequate proof of a functional corpus luteum. Lower concentrations of serum progesterone may be supplemented by luteal phase injections of hCG. Within the following 9 days after the initial hCG administration, 2 to 3 injections of 1 000 to 3 000 IU hCG each may be given to prevent insufficiency of the corpus luteum.

Patients should be closely monitored for 2 weeks following follitropin beta and hCG treatment to ensure that hyperstimulation does not occur. If the ovaries become abnormally enlarged, there is more than a 1 kg/day gain in weight, or abdominal pain occurs, administration of hCG should be stopped. Most ovarian hyperstimulation occurs after follitropin beta treatment has been completed and reaches its maximum at about 7 to 10 days after hCG administration (see Warnings).

Controlled Ovarian Hyperstimulation in Medically Assisted Reproduction Programs: The dosage regimen may vary according to the physician's preference or the patient's response. In general, stimulation of follicular growth is achieved by starting with daily i.m. or s.c. administration of 150 to 225 IU follitropin beta for a period of 4 days. Thereafter, the dose may be adjusted according to the individual's ovarian response.

Maturation of follicles is monitored by pelvic ultrasonography and measurement of plasma estrogen levels. In responding patients, daily maintenance doses of 75 to 300 IU for 6 to 12 days are usually sufficient, although longer treatment may be necessary. The maximum individualized daily dose safely used in clinical studies was 450 IU. There is limited experience with higher doses. When ultrasonic evaluation indicates the presence of at least 3 follicles of sufficient size and there is evidence of a good estradiol response, the final phase of maturation of the follicles is induced by administration of hCG. HCG is given 30 to 40 hours after the last administration of follitropin beta in a dose of 5000 to 10 000 IU.

After embryo transfer, up to 3 repeat injections of 1 000 to 3000 IU hCG each may be given within the following 9 days to provide luteal phase support.

Follitropin beta may be given alone, or in combination with clomiphene citrate to stimulate the endogenous production of gonadotropins, (see Precautions, Drug Interactions) or in combination with a GnRH agonist to prevent premature luteinization.

Administration: To prepare the solution, inject 1 mL of the solvent (sodium chloride injection, 4.5 mg/mL) into the ampul of follitropin beta. Swirl gently until the solution is clear. Do not shake. Do not use if the liquid is not clear.

Immediately administer the reconstituted follitropin beta either s.c. or i.m. Any unused reconstituted material should be discarded.

S.C. Administration: The best site for s.c. injection is in the abdomen around the navel. Pinch up a large area of skin between the finger and thumb. Vary the injection site with each injection. The needle should be inserted at the base of the pinched-up skin at a 45° angle. S.C. injection of follitropin beta may be carried out by patients or their partners, provided proper instructions are given by the physician. Self-administration of follitropin beta should only be performed by patients who are well motivated, adequately trained and with access to expert advice.

I.M. Administration: The best site for i.m. administration is the upper outer quadrant of the buttock muscle. Stretching the skin helps the needle to go in more easily and pushes the tissue beneath the skin out of the way. This helps the solution to disperse correctly. The needle should be inserted right up to the hilt at an angle of 90° to the skin surface. Pushing in with a quick thrust causes the least discomfort.



Availability And Storage: Each ampul of lyospheres contains: follitropin beta (recombinant FSH) 50 or 100 IU. Nonmedicinal ingredients: hydrochloric acid, polysorbate 20, sodium citrate anhydrous, sodium hydroxide and sucrose. Ampuls of 2 mL. Each ampul of sovlent contains: sodium chloride 4.5 mg/mL. Ampuls of 1 mL. Boxes of 3“3.

Store at 2 to 30°C Protect from light. For single use only. Discard unused portion.