Puregon

hypermesis, hot flashes, syncope.

PUREGON (follitropin beta) is indicated for:

• development of multiple follicles in ovulatory patients participating in an Assisted Reproduction Technology (ART) program

  
  

• induction of ovulation and pregnancy in anovulatory infertile females in whom the cause of infertility is functional and not due to primary ovarian failure

PUREGON (follitropin beta) is indicated for:

• deficient spermatogenesis due to hypogonadotrophic hypogonadism

Each vial of sterile solution for injection contains: follitropin beta (recombinant FSH) 50 or 100 IU. 50 or 100 FSH activity/0.5 mL. Nonmedicinal ingredients: L-methionine, polysorbate 20, sodium citrate, sucrose. Hydrochloric acid 0.1 N and sodium hydroxide 0.1 N (trace amounts for pH adjustment). Boxes of 1, 5 or 10 vial(s) of PUREGON in 0.5 mL aqueous solution. PUREGON solution for injection is filled in colourless, 3 mL vials of hydrolytic resistant glass, Type 1, and closed with chlorobutyl rubber closures.

Solution for injection in cartridges - 833 IU/mL. Cartridges contain a minimum of 400 IU FSH activity in 0.48 mL aqueous solution which is sufficient for a net deliverable dose of 300 IU, a minimum of 700 IU FSH activity in 0.84 mL aqueous solution which is sufficient for a net deliverable dose of 600 IU or a minimum of 1025 IU FSH activity in 1.23 mL which is sufficient for a net dose of 900 IU. Nonmedicinal ingredients: benzyl alcohol, L-methionine, polysorbate 20, sodium citrate and sucrose. Hydrochloric acid 0.1 N and sodium hydroxide 0.1 N (trace amounts for pH adjustment to pH 7.0). Boxes of Puregon solution for injection contain 1 cartridge of Puregon and 6 (300 IU and 600 IU cartridges) or 9 (900 IU cartridges) needles to be used with the Puregon Pen. The cartridges are of colourless hydrolytic (class 1) glass, with a rubber piston and an aluminium crimp-cap with a rubber inlay.

The net deliverable dose of 300 IU, 600 IU and 900 IU are based upon a maximum of six 50 IU injections, six 100 IU injections and nine 100 IU injections respectively.

When more injections are given the net total dose may be lowered, because each injection has to be preceded by an air shot.

Cartridges contain 833 IU of FSH activity per mL aqueous solution. Cartridges with a net dose of 300 IU contain a minimum of 400 IU in 0.48 mL; those of 600 IU contain a minimum of 700 IU in 0.84 mL; those of 900 IU contain a minimum of 1025 IU in 1.23 mL.

PUREGON displays no mutagenic potential. Carcinogenicity studies have not been performed.

PUREGON (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.

A thorough gynecologic and endocrinologic evaluation must be performed prior to treatment with PUREGON (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. Tumours of the thyroid, adrenals, pituitary, and ovary may cause anovulation and patients with such tumours 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 PUREGON therapy.

Multiple ovulations with resulting multiple births occur (mostly twins) frequently (~20% 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.

Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

Semen analysis is recommended 4 to 6 months after the beginning of treatment to assess the response.

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.

Women with generally recognized risk factors for thrombosis, such as a personal or family history, severe obesity (Body Mass Index >30 kg/m²) or thrombophilia, may have an increased risk of venous or arterial thromboembolic processes upon treatment with gonadotropins. In these women the benefits of IVF treatment need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

There is no relevant indication for use of PUREGON in children.

PUREGON is not intended for use during pregnancy.

PUREGON is not intended for use during lactation.

To minimize the risk associated with abnormal ovarian enlargement in women receiving PUREGON and hCG for the induction of ovulation and pregnancy, the drugs should be administered at the lowest possible effective dosage. Since PUREGON 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 distension 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 PUREGON 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; and 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 of primarily 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.

Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with ovarian hyperstimulation syndrome.

PUREGON may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons.

No effects on ability to drive and use machines have been observed.

For intramuscular or subcutaneous injection. For single use only. Once solution has been taken from a vial, any unused drug (solution) should be discarded.

For subcutaneous injection only.

Store in a refrigerator at 2-8°C. Keep the vial(s)/cartridge(s) in the outer carton. Do not freeze. Protect from light.

Store in a refrigerator (2-8°C) or store at or below 25°C for a maximum of 3 months. Keep the vial(s)/cartridge(s) in the outer carton. Do not use past expiry date. Protect from light.

The volume of distribution of PUREGON in healthy, pituitary-suppressed, female subjects following intravenous administration of 300 IU dose was approximately 8 L.

No studies have been conducted with special populations and conditions.

After i.m. or s.c. administration of follitropin beta, high concentrations of FSH are reached within about 12 hours. After intramuscular administration of PUREGON, the maximum FSH concentrations are higher and reached earlier in men as compared to women. FSH levels remain high for 24-48 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 PUREGON, are approximately 1.5-2.5 times higher than after single dose administration.

The bioavailability of PUREGON following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.

The subcutaneous (455.6±141.4 IU·h/L) and intramuscular (455.7±135.7 IU·h/L) routes of administration were equivalent with respect area under the curve (AUC) in healthy, pituitary-suppressed, female subjects given a single 300 IU dose. However, equivalence could not be established for C_max between the subcutaneous (5.41±0.72 IU/L) and intramuscular (6.86±2.90 IU/L) routes of administration.

The pharmacokinetics and pharmacodynamics of a single, intramuscular dose (300 IU) of PUREGON were also investigated in a group of gonadotropin-deficient, but otherwise healthy women. Peak (C_max) serum FSH levels in these women were 4.3±1.7 IU/L (mean±SD) and they occurred approximately 27 hours after intramuscular administration.

A multiple, dose proportionality, pharmacokinetic study of PUREGON was completed in healthy, pituitary-suppressed, female subjects given intramuscular doses of 75 IU, 150 IU or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all the doses after 4 days of treatment based on the minimum concentrations of FSH just prior to dosing (C_min). Peak blood concentrations with the 75 IU, 150 IU, and 225 IU dose were 4.65±1.49 IU/L, 9.46±2.57 IU/L and 11.30±1.77 IU/L, respectively.

A multiple, dose proportionality, pharmacokinetic study of PUREGON was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75 IU, 150 IU, or 225 IU for 7 days. Steady-state blood concentrations of FSH were reached with all the doses after 5 days of treatment based on the minimum concentrations of FSH just prior to dosing (C_min). Peak blood concentrations with the 75 IU, 150 IU, and 225 IU dose were 4.30±0.60 IU/L, 8.51±1.16 IU/L and 13.92±1.81 IU/L, respectively.

The elimination half-life following a single intramuscular dose (300 IU) of PUREGON in female subjects was 43.9±14.1 hours (mean±SD). The elimination half-life following a 7-day intramuscular treatment with 75 IU, 150 IU or 225 IU was 26.9±7.8 hours (mean±SD), 30.1±6.2 hours (mean±SD) and 28.9±6.5, respectively.

There are no significant pharmacokinetic differences between intramuscular and subcutaneous administration of PUREGON. Both have an absolute bioavailability of approximately 77%. Recombinant FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted in the same way.

The recombinant FSH in PUREGON is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.

PUREGON (follitropin beta) is a sterile solution 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 35-45 kD. 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 (≥99%), 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 beta administration once follicular maturation has occurred.

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