Follistim AQ

Gonadotropins
Pituitary Hormones

For storage information, see specific product information within the How Supplied section.

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Follitropin, r-FSH should be prescribed only by health care prescribers who are experienced in managing endocrine or fertility disorders and only in facilities where appropriate clinical and endocrinology evaluations are available.

Subcutaneous Injection - General information
Rotate injection sites with each dose.
Follow the manufacturer's "Instructions for Use" for the product prescribed.
For self administration, the health care provider must train the patient how to correctly prepare and inject the product.
Do not share needles or injection devices.
Missed doses: If a dose is missed, do not double the next dose. The patient should call their health care provider for missed dose instruction.
 
Follitropin Alfa Lyophilisate for Solution for Injection (Gonal-F Multidose Vials)
Use prefilled syringe provided to dilute injection powder in vial as directed in package label. Do not shake.
450 International Units multidose vial: Dissolve the contents of 1 vial with 1 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol). The resulting concentration will be 600 International Units/mL.
1,050 International Units multidose vial: Dissolve the contents of 1 vial with 2 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol). The resulting concentration will be 600 International Units/mL.
Inject the proper dose subcutaneously in the abdomen or upper leg taking care not to inject intradermally.
Storage: Store the reconstituted vials at room temperature or under refrigeration, and discard unused portion after 28 days. Protect from light. Do not freeze.
 
Follitropin Alfa Lyophilisate for Solution for Injection (Gonal-F RFF Single-Dose Vials)
Dissolve contents of one or more single-use vials in 1 mL of Sterile Water for Injection as directed in the package label. Use the provided 18-gauge needle.
Do not shake.
After reconstitution, remove the 18-gauge needle and replace it with a 29-gauge needle for injection.
Inject the proper dose subcutaneously in the abdomen, upper arm, or upper leg taking care not to inject intradermally.
Storage: Discard any unused injection solution (do not store).
 
Follitropin Alfa Solution for Injection (Gonal-F RFF Redi-ject Pen)
Use as directed in the package label.
This is a pre-filled disposable auto-injection device intended for multiple dose use. It can be set in 12.5 International Unit increments.
Do not attempt to mix any other medications inside the device.
Do not shake the pen.
Instruct patients to remove the device from the refrigerator at least 30 minutes prior to use in order to allow it to warm to room temperature to avoid the discomfort of a cold injection.
Inject the proper dose subcutaneously in the abdomen taking care not to inject intradermally.
Storage: Upon dispensing, store unopened device refrigerate at 2 to 8 degrees C (36 to 46 degrees F) until the expiration date or at room temperature 20 to 25 degrees C (68 to 77 degrees F) for up to 3 months or until the expiration date, whichever occurs first. After the first injection, store refrigerated or at room temperature, but discard unused portion after 28 days. Protect from light. Do not freeze.
 
Follitropin Beta Solution for Injection (Follistim AQ Cartridge with Follistim Pen)
Use as directed in the package label.
Do not add any other medications to the cartridge.
Instruct patients to remove the device from the refrigerator and allow it to warm to room temperature to avoid the discomfort of a cold injection.
The pen will dial doses in the range of 50 International Units to 450 International Units.
Inject the proper dose subcutaneously in the abdomen or the outer upper thigh taking care not to inject intradermally.
Storage: Upon dispensing, store the unopened cartridges in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) until the expiration date or at room temperature 25 degrees C (77 degrees F) for up to 3 months or until the expiration date, whichever occurs first. Once the rubber stopper of the cartridge has been pierced by a needle, the cartridge can only be stored for a maximum of 28 days under refrigeration or at room temperature. Protect from light. Do not freeze.

ovarian hyperstimulation syndrome / Delayed / 4.6-7.6
anaphylactoid reactions / Rapid / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
ovarian torsion / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
thromboembolism / Delayed / Incidence not known
stroke / Early / Incidence not known
myocardial infarction / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
ectopic pregnancy / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known

constipation / Delayed / 2.0
vaginal bleeding / Delayed / 2.0
ovarian enlargement / Delayed / Incidence not known
dyspnea / Early / Incidence not known
wheezing / Rapid / Incidence not known
phlebitis / Rapid / Incidence not known

acne vulgaris / Delayed / 6.7-27.0
headache / Early / 6.7-26.5
abdominal pain / Early / 2.9-23.2
injection site reaction / Rapid / 2.4-11.0
fatigue / Early / 2.3-10.0
nausea / Early / 3.6-8.0
gynecomastia / Delayed / 3.3-6.0
flatulence / Early / 3.6-5.9
pelvic pain / Delayed / 5.5-5.5
breakthrough bleeding / Delayed / 5.1-5.1
seborrhea / Delayed / 5.0-5.0
diarrhea / Early / 3.6-3.6
rash / Early / 3.3-3.3
libido decrease / Delayed / 3.0-3.0
mastalgia / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known

Follistim AQ, Gonal-f, Gonal-f RFF, Gonal-f RFF Redi-ject

Rx

Products ar recombinant versions of human follicle stimulating hormone (FSH), a gonadotropin; available as follitropin alfa or follitropin beta
Used for infertility protocols for ovulation induction in selected females and for induction of spermatogenesis in selected males
Used in combination with human chorionic gonadotropin (hCG)

The initial dose for the first cycle is 75 International Units subcutaneously once daily. An incremental dose adjustment of up to 37.5 International Units may be considered after 14 days. Further dose increases of up to 37.5 International Units may be made, if necessary, every 7 days. The initial dose administered in the subsequent cycles is based on the individual response in the preceding cycle. Max: 300 International Units/day. For each cycle, FSH is administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography (generally 5 to 7 days). Subsequent monitoring is individualized to patient response. Treatment duration should not exceed 35 days unless the serum estradiol rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin (hCG) should be given after the last dose of FSH with each cycle. The couple should be encouraged to have intercourse daily, beginning on the day prior to hCG administration and until ovulation is apparent. REDUCING Ovarian Hyperstimulation Syndrome (OHSS) RISK: Withhold hCG if ovarian monitoring suggests an increased risk of OHSS on the last day of FSH therapy. Do not give hCG dose if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, discontinue FSH, do not administer hCG, and advise the patient not to have intercourse; this may reduce the chance of development of OHSS and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase.

For the first cycle, initiate with 50 International Units subcutaneously once daily for at least 7 days. May increase by 25 to 50 International Units at weekly intervals if needed until follicular growth, monitored by transvaginal ultrasound, indicates an ovarian response. Serum estradiol concentrations may also be useful. The initial dose administered in the subsequent cycles is based on the individual response in the preceding cycle. Max: 250 International Units/day. Once adequate response is evident, administer hCG to complete follicular development and effect ovulation. The woman and her partner should have intercourse daily, beginning the day prior to the administration of hCG and until ovulation becomes apparent. REDUCING Ovarian Hyperstimulation Syndrome (OHSS) RISK: Follow current clinical practice for reducing the risk of OHSS. If the ovaries are abnormally enlarged or abdominal pain occurs, discontinue FSH, do not administer hCG, and advise the patient not to have intercourse; this may reduce the chance of development of OHSS and, should spontaneous ovulation occur, reduce the chance of multiple gestation.

Initiate in the early follicular phase (cycle day 2 or 3). In patients undergoing ART less than 35 years old, whose endogenous gonadotropin levels are suppressed, give 150 International Units per day subcutaneously as the initial dose. In patients 35 years and older whose endogenous gonadotropin levels are suppressed, initiate at 225 International Units/day. Continue daily until adequate follicular development is indicated by ultrasound and serum estradiol levels. In most cases, therapy should not exceed 10 days. May adjust dose after 5 days based on response; then adjust further every 3 to 5 days, by no more than 75 to 150 International Units at each adjustment. Max: 450 International Units/day. Once adequate follicular development is evident, administer hCG to induce final follicular maturation in preparation for oocyte retrieval. Do not give hCG in cases where the ovaries are abnormally enlarged on the last day of therapy; this should reduce the chance of developing OHSS.

Individualize dosage for each patient. Initially, 200 units subcutaneously once daily for at least the first 7 days. The dose may then be adjusted (up or down) based upon the individual ovarian response as determined by ultrasound evaluation. Concurrent determination of serum estradiol may also be useful. In most normal responders, continue treatment for 7 to 12 days until pre-ovulatory conditions are achieved. In patients who are low or poor responders, increase the daily dose according to ovarian response. Max: 500 International Units/day. In high responders [those at risk of abnormal ovarian enlargement and/or ovarian hyperstimulation syndrome (OHSS)], consider dosage reduction at day 6 of treatment onward. For high-responding women, may decrease or temporarily stop the daily dose, or discontinue the cycle as indicated. When a sufficient number of follicles of adequate size are present, discontinue FSH and administer hCG to induce final follicular maturation for oocyte retrieval. Oocyte retrieval is performed 34 to 36 hours following the administration of hCG. REDUCING OHSS RISK: Follow current clinical practice for reducing the risk of OHSS. Do not give hCG in cases where the ovaries are abnormally enlarged of if abdominal pain occurs.

NOTE: Follitropin alfa (Gonal-F) is designated an orphan drug by the FDA for this indication.

Follitropin alfa 150 International Units subcutaneously 3 times per week, in combination with human chorionic gonadotropin (hCG). Use this regimen after normal serum testosterone has been attained using hCG alone and continue hCG at the same dose used to normalize testosterone concentrations. If azoospermia persists, may increase follitropin alfa to a maximum of 300 International Units 3 times per week. Serum testosterone concentrations and semen analysis are used for clinical monitoring of spermatogenesis. Complete a medical and endocrinologic evaluation before starting follitropin alfa. Exclude primary testicular failure and confirm hypogonadotropic hypogonadism. Lastly, evaluate the fertility status of the female partner.

Follitropin beta 450 International Units/week, dosed as either 225 International Units subcutaneously twice per week or 150 International Units subcutaneously 3 times per week, in combination with human chorionic gonadotropin (hCG). Use this regimen after normal serum testosterone has been attained using hCG alone and continue hCG at the same dose used to normalize testosterone concentrations. Continue combined treatment for at least 3 to 4 months before any improvement in spermatogenesis can be expected. If a patient has not responded after this period, the combination therapy may be continued. Treatment response was noted at up to 12 months in clinical trials. Serum testosterone concentrations and semen analysis are used for clinical monitoring of spermatogenesis. Complete a medical and endocrinologic evaluation before starting follitropin beta. Exclude primary testicular failure and confirm hypogonadotropic hypogonadism. Lastly, evaluate the fertility status of the female partner.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Follitropin, r-FSH products.

Follistim AQ Intramuscular Inj Sol: 0.5mL, 75IU
Follistim AQ/Gonal-f RFF Redi-ject Subcutaneous Inj Sol: 0.5mL, 0.75mL, 1mL, 1.5mL, 75IU, 300IU, 450IU, 833IU, 900IU
Gonal-f/Gonal-f RFF Subcutaneous Inj Pwd F/Sol: 75IU, 450IU, 1050IU

No specific maximum dosage limit recommendations are available. Dosage regimens of follitropin, r-FSH depend upon the patient's age, sex, weight, condition being treated or ART procedure to be used, the specific product used, the patient's response to treatment, and the prescribing clinician's judgment. The following maximum dosages are reflective of common recommendations in the package inserts.

Females:
Anovulatory patients: 300 International Units/day subcutaneously for Gonal-f or Gonal-f RFF Redi-ject (follitropin alfa products); 250 International Units/day for Follistim AQ (follitropin beta).
ART indications: 450 International Units/day subcutaneously for Gonal-f or Gonal-f RFF Redi-ject (follitropin alfa products); 500 International Units/day for Follistim AQ (follitropin beta).
 
Males:
Spermatogenesis: 450 International Units/week subcutaneously for Gonal-f or Follistim AQ products, given in divided doses throughout the week as specified for each product.

Not usually indicated; see adult dosing for rare exceptions.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Recombinant follitropin (r-FSH) mimics the actions of endogenous FSH, a gonadotropin which is required for normal follicular growth, maturation, and gonadal steroid production.
 
In females, FSH is critical for the onset and duration of ovarian follicular development, and consequently for the timing and number of follicles reaching maturity. R-FSH stimulates ovarian follicular growth in patients who do not have primary ovarian failure. In order to bring about final maturation of the follicle and ovulation in the absence of an endogenous luteinizing hormone (LH) surge, human chorionic gonadotropin (hCG) must be given following the administration of r-FSH once monitoring of the patient indicates that sufficient follicular development is achieved.
 
In males, endogenous FSH plays a key role in sustaining spermatogenesis. In male patients, r-FSH stimulates spermatogenesis in men with hypogonadotropic hypogonadism when r-FSH is administered with hCG.

Follitropin alfa and follitropin beta are administered subcutaneously.
Follitropin alfa (Gonal-F): The volume of distribution in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET) after subcutaneous administration was 10 L. The elimination rate after subcutaneous administration is dependent on the absorption rate. The mean terminal elimination half-life varied by population. The half-life was 24 hours in healthy female volunteers receiving single or multiple subcutaneous doses. The half-life in IVF/ET patients was 32 hours after multiple subcutaneous doses. In healthy male volunteers, the half-life was 41 hours after a single subcutaneous dose and 32 hours after multiple subcutaneous doses. Metabolism has not been studied.
Follitropin alfa (Gonal-F RFF products): The mean elimination half-life is 53 hours after a single subcutaneous dose in healthy female volunteers and is dependent on the absorption rate. Human tissue or organ distribution has not been determined. Metabolism and excretion have not been studied.
Follitropin beta (Follistim AQ): The volume of distribution in healthy, pituitary-suppressed female patients following IV administration was approximately 8 L. The mean half-life is 33.4 hours after a single subcutaneous dose in healthy female volunteers.
 
There is inter-female variability in response to follitropin alfa administration. Serum inhibin, estradiol, and total follicular volume responded as a function of time in healthy female volunteers administered Gonal-F. Pharmacodynamic effect lagged behind FSH serum concentration. Serum inhibin levels responded with the least delay and declined rapidly after discontinuation of Gonal-F. Follicular growth was most delayed and continued even after discontinuation of Gonal-F, and after serum FSH levels had declined. Maximum follicular volume correlated better with inhibin and estradiol peak levels than with FSH concentration. Inhibin rise was an early index of follicular development. FSH serum levels after fixed (during the first 5 days) and then adjusted doses of Gonal-F were found to be poor predictors of follicular growth rate. High pre-treatment serum FSH levels may predict lower follicular growth rates. The pharmacodynamics of reformulated (i.e., Gonal-F RFF) products in females have not been fully characterized. In healthy male volunteers, inhibin levels reached a plateau during the entire Gonal-F administration period and then returned to baseline despite high inter-male variation and the absence of down-regulation.
 
Affected cytochrome P450 isoenzymes and drug transporters: None

Follitropin alfa (Gonal F): The mean absolute bioavailability in healthy female volunteers after a single subcutaneous dose was 66%. The mean AUC was 176 International Units x hour/mL in healthy female volunteers after a single subcutaneous dose, 187 International Units x hour/mL in healthy female volunteers after multiple subcutaneous doses, 220 International Units x hour/mL in healthy male volunteers after a single subcutaneous dose, and 186 International Units x hour/mL in healthy male volunteers after multiple subcutaneous doses. The mean Cmax was 3 International Units/L in healthy female volunteers after a single subcutaneous dose, 9 International Units/L in healthy female volunteers after multiple subcutaneous doses, 2.5 International Units/L in healthy male volunteers after a single subcutaneous dose, and 8.3 International Units/L in healthy male volunteers after multiple subcutaneous doses. The mean Tmax was 16 hours in healthy female volunteers after a single subcutaneous dose, 8 hours in healthy female volunteers after multiple subcutaneous doses, 20 hours in healthy male volunteers after a single subcutaneous dose, and 10.7 hours in healthy male volunteers after multiple subcutaneous doses.
Follitropin alfa (Gonal-F RFF): In healthy female volunteers after a single subcutaneous dose who had previously received a GnRH agonist for pituitary down-regulation, the mean AUC was 884 International Units x hour/mL and the mean Cmax was 9.83 International Units/L. The mean Tmax was 15.5 hours.
Follitropin alfa (Gonal-f RFF Redi-ject): The absorption rate after subcutaneous administration is slower than the elimination rate; therefore, the pharmacokinetics are absorption rate-limited. In healthy female volunteers after a single subcutaneous dose who had previously received a GnRH agonist for pituitary down-regulation, the mean AUC was 884 International Units x hour/mL and the mean Cmax was 9.83 International Units/L. The mean Tmax was 15.5 hours.
Follitropin beta: In healthy, pituitary-suppressed female volunteers after a single subcutaneous dose, the bioavailability was 77.8%. The mean AUC was 455.6 International Units x hour/mL and the mean Cmax was 5.41 International Units/L. Peak blood concentrations after subcutaneous doses of 75 International Units, 150 International Units, and 225 International Units were roughly 4.3 International Units/L, 8.51 International Units/L, and 13.92 International Units/L, respectively. In hypogonadotropic hypogonadal male patients receiving follitropin, r-FSH with chorionic gonadotropin for induction of spermatogenesis, mean serum trough FSH concentration remained fairly constant over the treatment period. At the end of the treatment period, the mean serum FSH trough concentration was 2.09 International Units/L in patients receiving 150 International Units and 3.22 International Units/L in patients receiving 225 International Units.

There are no data on the presence of follitropin, r-FSH in human milk, the effects on the breastfed infant, or the effects on milk production. Because the secretion of prolactin during lactation can result in inadequate response to ovarian stimulation, advise patients against breast-feeding during treatment with follitropin, r-FSH.