Gonal-f Pen - Product Information
|Manufacture:||EMD Serono, Inc|
|Condition:||Follicle Stimulation, Hypogonadism, Male, Ovulation Induction|
|Form:||Liquid solution, Subcutaneous (SC)|
|Ingredients:||follitropin alfa (r-hFSH), sucrose, meta-cresol, di-sodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, Poloxamer 188, O-phosphoric acid, sodium hydroxide|
Follitropin alpha For Injection
Summary Product Information
|Dosage Form / Strength||Clinically Relevant Nonmedicinal
|Subcutaneous injection||Liquid in prefilled pen
300 IU/0.5 mL (22 µg/0.5 mL),
450 IU/0.75 mL (33 µg/0.75 mL), and
900 IU/1.5 mL (66 µg/1.5 mL)
For a complete listing of the nonmedicinal ingredients see Dosage Forms, Composition and Packaging.
GONAL-f (follitropin alpha for injection) is a gonadotropin preparation of recombinant DNA origin. The active ingredient, recombinant human Follicle Stimulating Hormone (r-hFSH), is a human glycoprotein hormone which consists of two non-covalently linked, non-identical protein components designated as the α- and β-subunits. The physicochemical, immunological, and biological activities of r-hFSH are similar to those of human menopausal urine-derived hFSH, but free of urinary protein and of any luteinizing hormone (LH) component.
Indications and Clinical Use
GONAL-f (follitropin alpha for injection) is indicated for the stimulation of multiple follicular development in ovulatory patients undergoing Assisted Reproductive Technologies (ART) such as in vitro fertilization. To complete follicular maturation in the absence of an endogenous lutenizing hormone (LH) surge, human chorionic gonadotropin (hCG) is given.
GONAL-f is also indicated for the stimulation of follicular development in patients with hypothalamic-pituitary dysfunction who present either oligomenorrhoea or amenorrhoea (WHO Group II). To complete follicular maturation and effect ovulation, hCG is given.
Selection of Patients
- Before treatment with GONAL-f is instituted, a thorough gynaecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy.
- Primary ovarian failure should be excluded by the determination of gonadotropin levels.
- Appropriate evaluation should be performed to exclude 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 before starting GONAL-f therapy.
- Evaluation of the partner’s fertility potential should be included in the initial evaluation.
GONAL-f (follitropin alpha for injection) is contraindicated in women who exhibit:
- High levels of Follicle Stimulating Hormone (FSH) indicating primary ovarian failure.
- Uncontrolled thyroid or adrenal dysfunction.
- An organic intracranial lesion such as a pituitary tumour or tumours of the hypothalamus.
- The presence of any cause of infertility other than anovulation, as stated in Indications and Clinical Use unless the women are candidates for Assisted Reproductive Technologies.
- Abnormal uterine bleeding (see Indications and Clinical Use: Selection of Patients ).
- Ovarian cyst or enlargement of undetermined origin (see Indications and Clinical Use: Selection of Patients ).
- Sex hormone dependent tumours of the reproductive organs and breasts.
- Hypersensitivity to or history of previous allergic reaction to follitropin alpha, FSH or to any of the excipients.
Warnings and Precautions
Careful attention should be given to diagnosis in candidates for GONAL-f (follitropin alpha for injection) therapy (see see Indications and Clinical Use: Selection of Patients ).
GONAL- f should only be used by physicians who are thoroughly familiar with infertility problems and their management. GONAL-f is a potent gonadotrophic 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 Monitoring and Laboratory Tests ). Safe and effective use of GONAL-f requires monitoring of ovarian response with ultrasound, alone or in combination with measurement of serum estradiol levels, on a regular basis.
In patients with porphyria or a family history of porphyria GONAL-f may increase the risk of an acute attack. Deterioration or a first appearance of this condition may require cessation of treatment.
Prior to therapy with GONAL-f, patients should be informed of the duration of treatment and monitoring of their condition that will be required. Possible adverse reactions (see Adverse Reactions ) and the risk of multiple births should also be discussed.
Before starting treatment, the couple’s infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamus tumours, and appropriate specific treatment given.
During training of the patient for self-administration, special attention should be given to specific instructions for the use of the pen.
Overstimulation of the Ovary During FSH Therapy
Use of FSH therapy to stimulate follicular development may result in the recruitment of a number of follicles. This may result in mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain. It is more commonly seen in women with polycystic ovarian syndrome. This degree of enlargement has been reported to occur in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks.
To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with GONAL-f therapy, the lowest dose consistent with the expectation of good results should be used. Careful monitoring of ovarian response can further minimize the risk of ovarian enlargement.
If there is clinical evidence of excessive ovarian response (see Monitoring and Laboratory Tests ), treatment should be discontinued and hCG should not be administered. This will reduce the chances of development of the Ovarian Hyperstimulation Syndrome.
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 marked ovarian enlargement, high serum sex steroids and an apparent dramatic increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural 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 mild manifestation of OHSS: abdominal pain, abdominal distention and enlarged ovaries, severe ovarian enlargement, Moderate OHSS may additionally present nausea, vomiting, diarrhoea, ultrasound evidence of ascites and marked ovarian enlargement. Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnea, or oliguria. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, pleural effusions, or acute pulmonary distress (see Respiratory and Cardiovascular ). Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction. 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 the Ovarian Hyperstimulation Syndrome (OHSS).
Severe OHSS occurred in approximately 6.0% of patients treated with urofollitropin therapy in the initial clinical trials, in patients treated for anovulation due to polycystic ovarian syndrome. In these studies, prospective monitoring of ovarian response using serum estradiol determination or ultrasonographic visualizations was not routinely employed.
In the clinical trials in oligo-anovulatory infertile women treated with GONAL-f in which both estradiol and ultrasound measurements were utilized to monitor follicular development, the incidence of severe OHSS was 1 in 513 treatment cycles (0.2%).
In the clinical trials in ovulatory infertile women treated with GONAL-f for induction of multiple follicular induction for IVF/ET in which both estradiol and ultrasound measurements were utilized to monitor follicular development, there was no incident of severe OHSS.
To minimize the risk of OHSS or of multiple pregnancy, ultrasound scans, as well as serum oestradiol measurements are recommended.
When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered.
Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum estradiol levels and previous episodes of OHSS, large number of developing ovarian follicles and large number of oocytes retrieved in ART cycles.
OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration (see Monitoring and Laboratory Tests ), the hCG must be withheld.
If severe OHSS occurs, treatment should be stopped and the patient should be hospitalized. A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.
Carcinogenesis and Mutagenesis
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of GONAL-f . However, r-hFSH showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosome aberration test and a micronucleus test.
There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the baseline risk of these tumours in infertile women.
Respiratory and Cardiovascular
The following paragraph describes serious medical events reported following gonadotropin therapy. Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported. In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported. Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, myocardial infarction, cerebral vascular occlusion (ischemic stroke), and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events have resulted in death. In women with recent or ongoing thromboembolic disease or women with generally recognized risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events.
In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself as well as OHSS also carries an increase of thromoboembolic events.
There have been no reports of abuse or dependence with GONAL-f .
In patients undergoing ovarian stimulation, the incidence of multiple pregnancies is increased as compared with natural conception. In the event they occur, majority of multiple conceptions are twins. Reports of multiple births have been associated with GONAL- f treatment. The risk of multiple births in patients undergoing ART procedures is related to the number of embryos replaced. In other patients, the incidence of multiple births may be increased by GONAL-f , as has been observed with other gonadotropin preparations. The patient and her partner should be advised of the potential risk of multiple births before starting treatment. To minimize the risk of higher order multiple pregnancy, careful monitoring of ovarian response is recommended.
Since women with infertility 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.
The incidence of pregnancy wastage by miscarriage or abortion may be higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception in the normal population.
The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conception. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.
Impaired fertility has been reported in rats exposed to pharmacological doses of r-hFSH (40 IU/kg/day) for extended periods through reduced fecundity.
There are no adequate and well-controlled studies in pregnant women. Given in high doses (>5 IU/kg/day), GONAL-f caused an increase in deaths, fetal effects and dystocia in pregnant rats and rabbits, but without being a teratogen. However, since GONAL-f is not indicated in pregnancy, these data are of limited clinical relevance. To date, no particular malformative effect has been reported. No teratogenic effect has been observed in animal studies.
It is not known whether this drug is excreted in human milk, although animal studies have shown that r-hFSH is excreted in milk. Therefore, GONAL-f is contraindicated in lactating mothers. During lactation, the secretion of prolactin can entail a poor prognosis to ovarian stimulation.
Not indicated for treatment in pediatric population.
Not indicated for treatment in the geriatric population.
Renal or hepatic impaired patients
Safety, efficacy, and pharmacokinetics in patients with renal or hepatic impairment have not been established.
Monitoring and Laboratory Tests
In most instances, treatment with GONAL-f results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles.
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 a shift in basal body temperature.
When used in conjunction with the 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.
Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests.
For patients undergoing extended cycles of treatment, PTT and liver enzymes should be monitored.
No studies on the effects on the ability to drive and use machines have been performed.
Adverse Drug Reaction Overview
Safety data on GONAL-f (follitropin alpha for injection) stem from clinical studies, as well as 15 years of post-marketing surveillance.
The most commonly reported adverse reactions with GONAL-f in clinical studies were ovarian cysts, injection site reaction of any severity, headache, mild to moderate ovarian hyperstimulation syndrome (OHSS) manifesting with symptoms such as abdominal swelling and pain, ovarian enlargement, as well as gastrointestinal symptoms such as nausea, vomiting, and diarrhoea.
The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of GONAL-f , adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) was severe OHSS and its associated complications, such as ovarian torsion, thromboembolic events, and pulmonary conditions (see Warnings and Precautions ).
Severe OHSS was also the most frequently reported serious adverse reaction. (see Warnings and Precautions ). Complications of severe OHSS have been reported both in clinical studies and from spontaneous sources.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates .
Summary of Adverse Drug Reactions Reported during Clinical Trials and in Post-Market Experience
More than 1000 patients were exposed to r-hFSH during the clinical development programme of GONAL-f . In addition to the clinical trial patient population, it is estimated that 580 000 to 1 700 000 patients have been exposed to r-hFSH during the post-marketing phase. The following summary presents the adverse drug reactions that have been reported with the use of r-hFSH during clinical trials and during post-market use. These data provide a comprehensive description of the safety profile of GONAL-f
≥ 1% (Common and Very Common)
Reproductive disorders, female
- Ovarian cysts
- Mild to moderate ovarian enlargement
- Breast tenderness
- Mild to moderate OHSS
Application site disorders
- Mild to severe injection site reaction (e.g. pain, redness, bruising, swelling and/or irritation at the site of injection)
Body as a whole, general disorders
Gastro-intestinal system disorders
- Abdominal; pain, distension, cramps, discomfort
< 1% (Uncommon, Rare and Very rare)
Reproductive disorders, female
- Severe OHSS
- Complications of severe OHSS (see Warnings and Precautions)
- Thromboembolism, usually associated with severe OHSS
Respiratory system disorders
- Acute pulmonary distress
- Exacerbation or aggravation of asthma
Immune system disorders
- Mild to severe hypersensitivity reactions including anaphylactic reactions and shock
Common and very common ADR have been reported from clinical studies, as well as in post-marketing surveillance. Severe OHSS has been reported from clinical studies, as well as in post-marketing surveillance. However, rare and very rare ADRs such as complications of severe OHSS and allergic reactions have generally been reported from post-marketing sources.
The following adverse reactions reported during gonadotropin therapy are listed in decreasing order of potential severity:
- Pulmonary and vascular complications (see Warnings and Precautions )
- Ovarian Hyperstimulation Syndrome (see Warnings and Precautions )
- Adnexal torsion (as a complication of ovarian enlargement)
- Mild to moderate ovarian enlargement
- Abdominal pain
- Ovarian cysts
- Gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal cramps, bloating),
- Pain, rash, swelling, and/or irritation at the site of injection
- Breast tenderness
- Dermatological symptoms (body rash, hives/urticaria)
Subjective assessments indicated minimal or mild transient pain in two and five subjects who received GONAL-f single-dose and GONAL-f multi-dose, respectively .
The following medical events have been reported subsequent to pregnancies resulting from GONAL-f therapy in controlled clinical trials:
- Spontaneous Abortion
- Ectopic Pregnancy
- Premature Labour
- Postpartum Fever
- Congenital abnormalities
Two incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with GONAL-f and hCG in clinical studies. In addition, a pregnancy occurring in a study following treatment with GONAL-f and hCG was characterized by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made.
Three incidents of chromosomal abnormalities and four birth defects have been reported following urofollitropin- hCG or urofollitropin, Pergonal (menotropins for injection, USP)-hCG therapy in clinical trials for stimulation prior to in vitro fertilization. The aborted pregnancies included one Trisomy 13, one Trisomy 18, and one fetus with multiple congenital anomalies (hydrocephaly, omphalocele, and meningocele). One meningocele, one external ear defect, one dislocated hip and ankle, and one dilated cardiomyopathy in presence of maternal Systemic
Lupus Erythematosus were reported. None of these events were thought to be drug-related. The incidence does not exceed that found in the general population.
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established.
Clomiphene citrate, LH and hCG used with GONAL-f (follitropin alpha for injection) may enhance follicular response, and caution is indicated when using these drugs together.
Use of GnRH agonist or antagonist to induce pituitary desensitization may alter the dosage of GONAL-f needed.
No other clinically significant drug/drug or drug/food interactions have been reported during GONAL-f therapy.
Dosage and Administration
Treatment with GONAL-f Pen (follitropin alpha for injection) should be initiated under the supervision of a physician experienced in the treatment of fertility problems.
GONAL-f Pen is intended for subcutaneous administration.
Recommended Dose and Dosage Adjustment
The dose of GONAL-f to stimulate development of the follicle must be individualized for each patient and the particular indication. To minimize the hazard associated with the occasional abnormal ovarian enlargement which may occur with GONAL-f therapy, the lowest dose consistent with the expectation of good results should be used. GONAL-f should be administered subcutaneously until adequate follicular development is indicated by ultrasound alone or in combination with measurement of serum estradiol levels.
The dosage recommendations given for GONAL-f are those in use for urinary FSH. Clinical assessment of GONAL-f indicates that its daily doses, regimens of administration, and treatment monitoring procedures should not be different from those currently used for urinary FSH-containing preparations. However, when these doses were used in a clinical study comparing GONAL-f and urinary FSH, GONAL-f was more effective than urinary FSH in terms of a lower total dose and a shorter treatment period needed to achieve pre-ovulatory conditions.
Over the course of treatment, doses may range between 75 to 450 IU depending on the indication and the individual patient response. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. If the ovaries are abnormally enlarged or significant abdominal pain occurs, GONAL- f 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 and, should spontaneous ovulation occur, reduce the chances of multiple gestation. While individual dosing regimens will differ between patients, typical treatment regimens are presented below.
Assisted Reproductive Technologies
In patients undergoing Assisted Reproductive Technologies (ART) whose endogenous gonadotropin levels are not suppressed, GONAL-f should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, administered subcutaneously. Treatment should be continued until adequate follicular development is indicated as determined by either ultrasound alone or in combination with measurement of serum estradiol levels. Adjustments to dose, based on the patient's response, should only be considered after the first five days of treatment; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 37.5-150 IU additionally at each adjustment. Treatment should be continued until adequate follicular development is indicated. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval.
In patients undergoing ART, whose endogenous gonadotropin levels are suppressed indicating a hypogonadotrophic state, GONAL-f should be initiated at a dose of 225 IU per day, administered subcutaneously. Treatment should be continued until adequate follicular development is indicated as determined by either ultrasound alone or in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 37.5-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not generally recommended. As before, once adequate follicular development is evident hCG should be administered to induce final follicular maturation in preparation for oocyte retrieval.
The majority of patients who require ovulation induction are patients with Polycystic Ovarian Syndrome (PCO). Patients with PCO tend to show a more rapid and exaggerated response to treatment. Therefore, in this patient population, particular care should be employed to ensure that patients are adequately monitored and that the lowest dose consistent with the expectation of good results is employed.
It is recommended that treatment of any patient be initiated at a dose of 75 IU GONAL-f per day, administered subcutaneously. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an estradiol rise indicates imminent follicular development. Once adequate follicular development is evident, hCG should be administered to induce final follicular maturation and effect ovulation. The patient should attempt to have intercourse at a consistent frequency of at least three times/week from the day prior to administration of hCG until ovulation becomes apparent.
If there is evidence of ovulation but pregnancy does not ensue, this regimen should be repeated for at least two more courses before increasing the dose of GONAL-f to 150 IU per day for 7 to 12 days. As before, this dose should be followed by the administration of hCG when adequate follicular development is evident. If evidence of ovulation is present but pregnancy does not ensue, repeat the same dose for two more courses. Doses larger than this are not routinely recommended.
For patients who miss a dose, it is not recommended to double the next dose. The patients should be reminded to contact the physician monitoring their treatment.
Each GONAL-f Pen is designed to administer multiple doses liquid solution of GONAL-f subcutaneously.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Aside from possible ovarian hyperstimulation and multiple gestations (see Warnings and Precautions), little is known concerning the consequences of acute overdosage with GONAL-f (follitropin alpha for injection). Apart from expected ovarian and endometrial effects, no acute toxicity was seen in animals given doses of r-hFSH up to 1000-fold the human dose.
Action and Clinical Pharmacology
Mechanism of Action
Follicle stimulating hormone (FSH, follitropin) is one of the key hormones regulating reproductive functions both in females and in males. In females, it stimulates the development of ovarian follicles that carry the oocytes, while in males it promotes spermatogenesis.
FSH is synthesized by gonadotrophic cells of the anterior pituitary gland and secreted into the general circulation through which it reaches specific target cells in the ovaries and testes. The synthesis and the secretion of FSH are stimulated by a hypothalamic peptide named gonadotropin-releasing hormone (GnRH). In the target organ, FSH binds to the FSH receptor, a protein component of ovarian granulosa cells and testicular Sertoli cell plasma membranes. FSH binding to its receptor triggers intracellular mechanisms that regulate steroidogenesis, cell replication, and expression of specific proteins and growth factors that modulate gametogenesis.
GONAL- f (follitropin apha for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure. FSH is the primary hormone responsible for follicular recruitment and development. To complete follicular maturation and effect ovulation in the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. There may be a degree of interpatient variability in response to FSH administration, with lack of response to FSH in some patients.
One main PD study has been performed in healthy female volunteers down-regulated with a GnRH agonist (Study 5117). The aim of this study was to assess PD characteristics of r-hFSH administered sc daily for one week. After s.c. administration over one week, the first PD marker of ovarian response to FSH was serum inhibin, followed by plasma E2 and follicular growth. When FSH administration was stopped, inhibin levels dropped, while E2 continued to rise for one day and follicle size further increased during four days.
Two thirds of the volunteers developed significant follicular growth followed by corresponding decreasing levels of inhibin and increasing levels of E2 secretion. Moreover, no correlation was found between maximal serum FSH concentrations during administration and the maximal E2 responses, inhibin responses and follicular growth responses
Single dose pharmacokinetics of r-hFSH were determined following intravenous, administration of 150 IU and 300 IU of GONAL-f to 12 healthy, down-regulated female volunteers (Study 5007). Single pharmacokinetics of r-hFSH were determined following intravenous, subcutaneous and intramuscular administration of 150 IU GONAL-f to 12 healthy, down-regulated female volunteers. Steady-state pharmacokinetics were also determined in the same 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days (Study 5117). The pharmacokinetic parameters from these studies are included in the tables below.
|Cmax (IU/L)||t½ (h)||AUC00-∞
|Volume of distribution
|Single dose IV (150 IU)||32 ± 10||14 ± 7||274 ± 71||0.6 ± 0.2||10 ± 6|
|Single dose IV (300 IU)||59 ± 18||17 ± 3||598 ± 126||0.6 ± 0.1||11 ± 6|
|Cmax (IU/L)||t½ (h)||AUC
|Clearance (L/h)||Volume of distribution
|Single dose IV (150 IU)||33 ± 9||15 ± 5||286 ± 78||0.6 ± 0.2||9 ± 3|
|Single dose IM (150 IU)||3 ± 1||50 ± 27||206 ± 66||---||---|
|Single dose SC (150 IU)||3 ± 1||24 ± 11||176 ± 87||---||---|
|Multiple dose SC (7x150 IU)||4 ± 1(1)
9 ± 3(2)
|24 ± 8||187 ± 61#||---||---|
# Steady-state AUC144-168 (After the 7th daily SC dose)
(1) After the frst dose
(2) After the last dose
Following intravenous administration, GONAL-f is distributed to the extracellular fluid space with an initial half-life of approximately 2 hours and eliminated from the body with a terminal half-life of approximately 1 day. The steady-state volume of distribution and total clearance are 10 L and 0.6 L/h, respectively. One-eighth of the GONAL-f dose is excreted in the urine.
Following subcutaneous or intramuscular administration, the absolute bioavailability is 70%. Following repeated administration, GONAL-f accumulates 3-fold at steady-state within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, GONAL-f has been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
Special Populations and Conditions
No studies have been conducted with special populations and conditions.
Storage and Stability
Pharmacy: Store at 2 - 8 °C (in a refrigerator) for up to 2 years.
Patient: Store at 2 - 8 °C (in a refrigerator) or store for a single period between 2 and 25 °C (in the refrigerator or at room temperature) for a maximum of 3 months. After first use, the pen may be stored 25 °C (room temperature) for a maximum of 28 days.
Do not use the GONAL-f prefilled pen if the solution contains particles or is not clear.
Do not freeze. Protect from light.
Keep in a safe place out of the reach of children.
Do not use after the expiry date.
Special Handling Instructions
The GONAL-f (follitropin alpha for injection) solution should not be administered if it contains particles or is not clear.
GONAL-f Pen is not designed to allow the cartridge to be removed or any other drug to be mixed in the cartridge.
Discard used needles immediately after injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
Dosage Forms, Composition and Packaging
GONAL-f (follitropin alpha for injection) Pen is presented as solution for injection in 3 mL cartridge (Type I glass), with a plunger stopper (halobutyl rubber) and a rubber crimp cap (halobutyl rubber). The cartridge is preassembled with the prefilled pen. GONAL-f Pen is shatterproof per EN ISO 11608-1:2000 standards.
GONAL-f Pen is available in the following strengths and packages are available:
- 300 IU/0.5 mL (22 µg/0.5 mL Filled by Mass: 1 prefilled pen and 5 needles to be used with the pen for subcutaneous administration,
- 450 IU/0.75 mL (33 µg/0.75 mL) Filled by Mass: 1 prefilled pen and 7 needles to be used with the pen for subcutaneous administration,
- 900 IU/1.5 mL (66 µg/1.5 mL) Filled by Mass: 1 prefilled pen and 14 needles to be used with the pen for subcutaneous administration.
Each pen also contains the following non-medicinal ingredients: disodium phosphate dihydrate, L-methionine, m-cresol, phosphoric acid, poloxamer 188, sodium dihydrogen phosphate monohydrate, sodium hydroxide, sucrose and water for injection
There is no latex in the components of the prefilled pen.