RxMed: Pharmaceutical Information – FERTINORM

FERTINORM® HP

Serono

Urofollitropin

Gonadotropin

Action And Clinical Pharmacology: Fertinorm HP is a highly purified preparation of the gonadotropin, Follicle Stimulating Hormone (FSH) extracted from the urine of postmenopausal women. The principal action of Fertinorm HP is the induction of follicular growth in infertile women who do not have primary ovarian failure. Treatment in most instances results only in follicular growth and maturation. In order to effect ovulation in the absence of an endogenous LH surge, human Chorionic Gonadotropin (hCG) must be given following the administration of Fertinorm HP once follicular maturation has occurred.

Pharmacokinetics: Following a single s.c. or i.m. administration of Fertinorm HP 150 IU, to male volunteers: Peak serum FSH levels were reached 15±7 (s.c.) and 10±4 (i.m.) hours later with an increase of 4.0±2 IU/L of FSH over baseline values, for both the s.c. and i.m. routes; 72 hours after administration, serum FSH levels were still significantly higher than baseline values. The elimination half-life of FSH was estimated to be between 30 to 40 hours.

Indications And Clinical Uses: Fertinorm HP followed by chorionic gonadotrophin (hCG), stimulates follicular development and ovulation in women with hypothalamic-pituitary dysfunction who present with either oligomenorrhea or amenorrhea. These women are classified as WHO Group II patients and usually receive clomiphene citrate as primary therapy. They have evidence of endogenous estrogen production and thus will either spontaneously menstruate or experience withdrawal bleeding after progesterone administration. Polycystic ovarian disease is part of the WHO II classification and is present in the majority of these patients.

Contra-Indications: Women who exhibit: high levels of FSH indicating primary ovarian failure, uncontrolled thyroid or adrenal dysfunction, an organic intracranial lesion such as a pituitary tumor, the presence of any cause of infertility other than anovulation as stated in the Indications, abnormal uterine bleeding (see Precautions), ovarian cyst or enlargement of undetermined origin, a prior hypersensitivity to menotropins/urofollitropin, or any excipients used in the formulation, sex hormone dependent tumors of the reproductive tract and accessory organs.

Pregnancy and Lactation: Fertinorm HP should not be administered in case of pregnancy and lactation.

Manufacturers’ Warnings In Clinical States: Caution: Fertinorm HP should only be used by physicians who are thoroughly familiar with infertility problems and their management. It is a potent gonadotropic substance capable of causing mild to severe adverse reactions. Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see Precautions, Laboratory Tests). In female patients it must be used with a great deal of care.

Overstimulation of the Ovary During Fertinorm HP Therapy: Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within 2 or 3 weeks.

The Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an apparent dramatic increase in vascular permeability which can result in an accumulation of fluid in the peritoneal cavity, thorax and rarely in the pericardial cavities. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea and oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress and thromboembolic events (see Thromboembolic Events).

OHSS occurred in approximately 6% of patients treated with urofollitropin therapy in the initial clinical trials, in patients treated for anovulation due to polycystic ovarian syndrome. OHSS develops rapidly and most often after treatment with urofollitropin or hCG has been discontinued, reaching its maximum at about 7 to 10 days following treatment. Patients, therefore, should be followed for at least 2 weeks after urofollitropin or hCG administration. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see Precautions, Laboratory Tests), the hCG should be withheld.

If OHSS occurs, treatment should be stopped and the patient hospitalized. Treatment is primarily symptomatic, consisting of bed rest, fluid and electrolyte management, and analgesics if needed. The phenomenon of hemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity, and pericardial cavity has been seen to occur and should be thoroughly assessed in the following manner: 1) fluid intake and output, 2) weight, 3) hematocrit, 4) serum and urinary electrolytes, 5) urine specific gravity, 6) BUN and creatinine and 7) abdominal girth. These determinations are to be performed daily or more often if the need arises.

With OHSS there is an increased risk of injury to the ovary. The ascitic, pleural, and pericardial fluids should not be removed unless absolutely necessary to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in hemoperitoneum, and should therefore be avoided. If this does occur, and if bleeding becomes such that surgery is required, the surgical treatment should be designed to control bleeding and to retain as much ovarian tissue as possible. Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts.

The management of OHSS may be divided into three phases: the acute, the chronic and the resolution phases. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution.

Acute Phase: Management during the acute phase should be designed to prevent hemoconcentration due to loss of intravascular volume to the third space and to minimize the risk of thromboembolic phenomena and kidney damage. Treatment is designed to normalize electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Management includes administration of limited i.v. fluids, electrolytes and human serum albumin. Monitoring for the development of hyperkalemia is recommended.

Chronic Phase: After stabilizing the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium and fluid restriction.

Resolution Phase: A fall in hematocrit and an increasing urinary output without an increased intake are observed due to the return of third space fluid to the intravascular compartment. Peripheral and/or pulmonary edema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilized. Diuretics may be indicated during the resolution phase if necessary to combat pulmonary edema.

Thromboembolic Events: Thromboembolic events, both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported following gonadotropin therapy. These included thrombophlebitis, pulmonary embolism, stroke and arterial occlusion resulting in the loss of a limb. In rare cases, thromboembolic events have resulted in death.

Multiple Births: Multiple births have been associated with Fertinorm HP therapy, as with other agents used to stimulate ovulation; however, the majority of multiple conceptions are twins. The patient and her husband should be advised of the potential risk of multiple births before starting therapy.

Precautions: General: Careful attention should be given to diagnosis in the selection of candidates for Fertinorm HP therapy.

Before treatment with Fertinorm HP is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include a hysterosalpingogram (to rule out uterine and tubal pathology) and documentation of anovulation by means of basal body temperature, serial vaginal smears, examination of cervical mucus, determination of serum (or urinary) progesterone, and endometrial biopsy.

Primary ovarian failure should be excluded by the determination of gonadotropin levels.

Careful examination should be made to rule out the presence of an early pregnancy.

Patients in late reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities.

Evaluation of the husband’s fertility potential should also be performed before starting Fertinorm HP therapy.

In order to minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with Fertinorm HP hCG therapy, the lowest dose consistent with expectation of good results should be used. Careful monitoring of ovarian response can further minimize risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Fertinorm HP therapy, hCG should not be administered in this course of therapy; this will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.

Laboratory Tests: In most instances, treatment with Fertinorm HP results only in follicular growth and maturation. In order to effect ovulation in the absence of an endogenous LH surge, hCG must be given following the administration of Fertinorm HP when clinical assessment of the patient indicates that sufficient follicular maturation has occurred.

This may be estimated by measuring serum (or urinary) estrogen levels and sonographic visualization of the ovaries. The combination of both estradiol levels and ultrasonography is useful for monitoring the growth and development of follicles, timing hCG administration, as well as for detecting ovarian enlargement and minimizing the risk of OHSS and multiple gestation.

Urinary and/or plasma estrogen determinations provide an indirect index of follicular maturity since as the follicles grow and develop, they secrete estrogens in increasing amounts. However, plasma and/or urinary estrogen levels represent the sum of ovarian activity. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma and/or urinary estrogens do not give an indication of the number of follicles.

Other clinical parameters which may have potential use for monitoring Fertinorm HP therapy include: changes in the vaginal cytology, appearance and volume of the cervical mucus, spinnbarkeit and ferning of the cervical mucus.

The above clinical indices provide an indirect estimate of the estrogenic effect upon the target organs and, therefore, should only be used adjunctively with more direct estimates of follicular development, i.e., serum estradiol and ultrasonography.

The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows: a rise in basal body temperature, increase in serum progesterone and menstruation following the shift in basal body temperature.

When used in conjunction with indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following: fluid in the cul-de-sac, ovarian stigmata, collapsed follicle and secretory endometrium.

Because of the subjectivity of the various tests for the determination of follicular maturation and ovulation, it cannot be overemphasized that the physician should choose tests with which he/she is thoroughly familiar.

Drug Interactions: No clinically significant drug/drug or drug/food interactions have been reported during Fertinorm HP therapy.

Carcinogenesis and Mutagenesis: Carcinogenicity studies have not been performed. Fertinorm HP exhibited no mutagenic activity in a range of mutagenicity studies.

Pregnancy: Contraindicated in pregnancy.

Lactation: Fertinorm HP should not be administered during lactation.

Dependence Liability: There have been no reports of abuse or dependence with Fertinorm HP.

Adverse Reactions: The following adverse reactions, reported during urofollitropin and menotropin therapy, are listed in decreasing order of potential severity: thromboembolic events (see Warnings), Ovarian Hyperstimulation Syndrome (see Warnings), mild to moderate ovarian enlargement, abdominal pain; sensitivity to Fertinorm HP (Febrile reactions which may be accompanied by chills, musculoskeletal aches, joint pains, malaise, headache and fatigue have occurred after the administration of urofollitropin/menotropin. It is not clear whether or not these were pyrogenic responses or possible allergic reactions); ovarian cysts; gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramps, bloating); pain, rash, swelling, and/or irritation at the site of the injection; breast tenderness; headache; dermatological symptoms (dry skin, body rash, hair loss, hives), and hemoperitoneum has been reported during menotropins therapy and, therefore, may also occur during Fertinorm HP therapy.

The following medical events have been reported subsequent to pregnancies resulting from urofollitropin therapy: Ectopic pregnancy, congenital malformations have been reported in pregnancies after the use of urofollitropin for ovulation induction or ovarian stimulation prior to IVF. The prevalence of these malformations does not exceed the prevalence in spontaneous pregnancies. Pregnancy loss is higher than that in the normal population, but comparable with the rates found in women with other fertility problems.

Ovarian cancer has been reported in a very small number of infertile women who have been treated with fertility drugs. A causal relationship between treatment with fertility drugs and ovarian cancer has not been established.

Overdosage: Symptoms and Treatment: Aside from possible OHSS and possible multiple gestations (see Warnings), little is known concerning the consequences of acute overdosage with Fertinorm HP.

Dosage And Administration: The dose to produce follicular maturation must be individualized. To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with Fertinorm HP therapy, the lowest dose consistent with the expectation of good results should be used. An initial dose of 75 IU/day, administered s.c. or i.m. for 7 to 12 days, is generally recommended. In the absence of an endogenous LH surge, the ovulating dose of hCG (5 000 to 10 000 U) should be administered 1 day after the last day of Fertinorm HP therapy.

In the ovaries of patients with polycystic ovarian syndrome, follicles are found in all stages of development and atresia. The reaction of these ovaries to Fertinorm HP stimulation depends on the stage of development of the follicle at the time Fertinorm HP stimulation is begun. The duration of treatment to induce follicular maturation may vary. The importance of careful and prospective monitoring cannot be overemphasized.

The patient should be treated until indices of estrogenic activity, as indicated under Precautions, are equivalent to or greater than those of the normal individual. If the ovaries are abnormally enlarged or significant abdominal pain occurs, Fertinorm HP treatment should be discontinued, hCG should not be administered and the patient should be advised to refrain from intercourse until resolution of the cycle. This will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.

If there is evidence of ovulation but not pregnancy, repeat this dosage regimen for at least 2 more courses before increasing the dose of Fertinorm HP to 150 IU/day for 7 to 12 days or longer. As before, this dose should be followed by 5 000 to 10 000 U of hCG on the day after the last dose of Fertinorm HP. If evidence of ovulation is present but pregnancy does not ensue, repeat the same dose for 2 or more courses. Doses larger than this are not routinely recommended.

During treatment with both Fertinorm HP and hCG and during the 2-week post-treatment period, patients should be examined at least every other day for signs of excessive ovarian stimulation (see Warnings). In most cases, OHSS occurs after treatment has been completed and reaches its maximum on the 7th to 10th day after hCG administration.

Patients should be followed for at least 2 weeks after hCG administration. The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity.

Preparation of Solution: Open the diluent ampul. Withdraw diluent (0.5 or 1.0 mL depending on dosage prescribed). Open Fertinorm HP ampul and inject syringe containing diluent into the ampul of powder. The powder will dissolve very quickly to form a clear solution. Do not shake the solution, as this may cause air bubbles.

Withdraw the Fertinorm HP solution from the ampul. Repeat procedure with other powder ampuls, until you have the prescribed number of powder ampuls dissolved in the solution. See Table I for further instructions.

To minimize the possibility of irritation, change to a new 1 mL needle before injection. Administer immediately by s.c. or i.m. injection.

Although the reconstituted Fertinorm HP has been shown to be stable for at least 24 hours, the solution should be used immediately after reconstitution and any unused material should be discarded after use.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the reconstituted solution if it appears cloudy, lumpy or discolored.

Reconstitution: Up to 5 ampuls of Fertinorm HP (75 IU) or up to 2 ampuls of Fertinorm HP (150 IU) can be reconstituted in 1 mL of diluent (Sodium Chloride Injection, USP). A smaller volume of diluent can be used for the reconstitution of 1 or 2 ampuls of Fertinorm HP (75 IU).

Stability and Storage of Parenteral Solutions: To minimize potential losses of FSH due to adsorption onto the syringe, Fertinorm HP should preferably be administered immediately after reconstitution. The degree of adsorption which may occur has been shown to have no significant effect on the dose required for clinical efficacy. Any unused solution should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use the reconstituted solution if it appears cloudy, lumpy or discolored.

Availability And Storage: Each 3 mL ampul of sterile lyophilized powder contains: urofollitropin 75 or 150 IU and lactose 10 mg as excipient. Supplied with a 2 mL ampul of Sodium Chloride Injection, USP, for reconstitution. One IU of human urinary FSH is equivalent to the activity contained in 0.11388 mg of the First International Standard. Single dose ampuls of 3 mL, cartons of 1 and 10 with diluent. Lyophilized powder in unopened ampuls is stable up to the expiry date shown on the label. Store refrigerated or at room temperature (3 to 25°C). Protect from light.

FERTINORM® HP Serono Urofollitropin Gonadotropin

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