CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Women:Follicle-stimulating hormone (FSH), the active component in Follistim AQ Cartridge, is required for normal follicular growth, maturation, and gonadal steroid production.In women, the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. Follistim AQ Cartridge stimulates ovarian follicular growth in women who do not have primary ovarian failure. In order to effect the final phase of follicle maturation, resumption of meiosis and rupture of the follicle in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following treatment with Follistim AQ Cartridge when patient monitoring indicates appropriate follicular development parameters have been reached.. Men:Follistim when administered with hCG stimulates spermatogenesis in men with hypogonadotropic hypogonadism. FSH, the active component of Follistim, is the pituitary hormone responsible for spermatogenesis.. 12.3 Pharmacokinetics. Pharmacokinetic parameters for Follistim AQ Cartridge were evaluated in an open-label, single-center, randomized study in 20 healthy women. Serum FSH values from single subcutaneous injection of reconstituted Follistim lyophilized powder administered by conventional syringe were compared to those values following single subcutaneous injection of Follistim AQ Cartridge administered with the Follistim Pen injector. Administration of follitropin beta with the Follistim Pen resulted an 18% increase in AUC0- and Cmax. The 18% difference in serum FSH concentrations resulting from administration of the two formulations was due to differences between the anticipated and actual volume delivered with the conventional syringe. The pharmacokinetic parameters for Follistim AQ Cartridge are as follows:Table 5: Mean (SD) Pharmacokinetic Parameters of Single Subcutaneous Injection of 150 IU of Follistim AQ Cartridge (n=20)AUC0- (IU/Lh)Cmax (IU/L)tmax (h)t1/2 (h)CLapp (L/h/kg)AUC0- Area under the curveCmax Maximum concentrationtmax Time to maximum concentrationt1/2 Elimination half-lifeCLapp ClearanceFollistim AQ215.13.412.933.40.01Cartridge(45.8)(0.7)(6.2)(4.2)(0.003). Absorption:. Women:The bioavailability of Follistim following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed women given single 300 international units dose. In these women, the area under the curve (AUC), expressed as the mean +- SD, was equivalent between the subcutaneous (455.6 +- 141.4 IUh/L) and intramuscular (445.7 +- 135.7 IUh/L) routes of administration. However, equivalence could not be established with respect to the peak serum FSH levels (Cmax). The Cmax achieved after subcutaneous administration and intramuscular administration was 5.41 +- 0.72 international units/L and 6.86 +- 2.90 international units/L, respectively. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.The pharmacokinetics and pharmacodynamics of single, intramuscular dose (300 international units) of Follistim were also investigated in group (n=8) of gonadotropin-deficient, but otherwise healthy women. In these women, FSH (mean +- SD) AUC was 339 +- 105 international unitsh/L, Cmax was 4.3 +- 1.7 international units/L. Cmax occurred at approximately 27 +- 5.4 hours after intramuscular administration.A multiple dose, dose proportionality, pharmacokinetic study of Follistim was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75, 150, or 225 international units for days. Steady-state blood concentrations of FSH were reached with all doses after days of treatment based on the trough concentrations of FSH just prior to dosing (Ctrough). Peak blood concentrations with the 75, 150, and 225 international units dose were 4.30 +- 0.60 international units/L, 8.51 +- 1.16 international units/L and 13.92 +- 1.81 international units/L, respectively.. Men:No PK studies were conducted using Follistim AQ Cartridge in men. Exposures of follitropin beta from Follistim AQ Cartridge and Follistim are expected to be equivalent after adjusting for the 18% difference in dose [see Dosage and Administration (2)].Serum levels of FSH were measured in clinical study that compared the effects of two different dosing schedules of Follistim (150 international units three times week or 225 international units twice week) administered by subcutaneous injection concurrently with chorionic gonadotropin for induction of spermatogenesis in hypogonadotropic hypogonadal men. Administration of Follistim was started at Week 17. Mean serum trough concentrations of FSH remained fairly constant over the treatment period. At the end of treatment (Week 64), the mean serum trough concentrations of FSH were 2.09 international units/L in the 150 international units group and 3.22 international units/L in the 225 international units group. Serum trough concentrations of FSH measured prior to the first Follistim injection on the Mondays of active treatment period (Weeks 17 to 64) and one week after the end of treatment period are presented in Figure 1.Figure 1: Mean (SD) Serum Trough Concentrations of FSH in Men Following Subcutaneous Administration of Follistim Using Two Different Dosing Schedules (150 International Units Three Times Week or 225 International Units Twice Week). Figure 1. Distribution:The volume of distribution of Follistim in healthy, pituitary-suppressed, women following intravenous administration of 300 international units dose was approximately L.. Metabolism:The recombinant FSH in Follistim AQ Cartridge is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.. Elimination:The elimination half-life (t1/2) following single subcutaneous injection of 150 IU of Follistim AQ Cartridge in women was 33.4 (4.2) hours. The clearance was 0.01 (0.003) L/h/kg.. Use in Specific Populations: Body weight: The effect of body weight on the pharmacokinetics of Follistim was evaluated in group of European and Japanese women who were significantly different in terms of body weight. The European women had body weight of (mean +- SD) 67.4 +- 13.5 kg and the Japanese subjects were 46.8 +- 11.6 kg. Following single intramuscular dose of 300 international units of Follistim, the AUC was significantly smaller in European women (339 +- 105 international unitsh/L) than in Japanese women (544 +- 201 international unitsh/L). However, clearance per kg of body weight was essentially the same for the respective groups (0.014 and 0.013 L/hr/kg).Geriatric Use: The pharmacokinetics of Follistim has not been studied in geriatric subjects.Pediatric Use: The pharmacokinetics of Follistim has not been studied in pediatric subjects.Renal Impairment: The effect of renal impairment on the pharmacokinetics of Follistim has not been studied.Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Follistim has not been studied.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ovulation Induction. The efficacy of Follistim for ovulation induction was evaluated in randomized, assessor-blind, parallel-group comparative, multicenter safety and efficacy study of 172 chronic anovulatory women (105 subjects on Follistim) who had previously failed to ovulate and/or conceive during clomiphene citrate treatment. The study results for ovulation rates are summarized in Table and those for pregnancy rates are summarized in Table 7.Table 6: Cumulative Ovulation RatesCycleFollistim(n=105)First treatment cycle72%Second treatment cycle82%Third treatment cycle85%Table 7: Cumulative OngoingAll ongoing pregnancies were confirmed after at least 12 weeks after the hCG injection. Study was not powered to demonstrate this outcome. Pregnancy RatesCycleFollistim(n=105)First treatment cycle14%Second treatment cycle19%Third treatment cycle23%. 14.2 Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle. The efficacy of Follistim AQ Cartridge was evaluated in randomized, double-blind, active-controlled study of 1,509 healthy normal ovulatory women (mean age, body weight, and body mass index of 32 years, 68 kg and 25 kg/m2, respectively) treated for one cycle with controlled ovarian stimulation and pituitary suppression with GnRH antagonist as part of an in vitro fertilization or intracytoplasmic sperm injection cycle. This 2008 study was conducted in Europe and North America (United States and Canada). Approximately 54% of the subjects were from North America. The overall results, as well as the results from North America only, for clinical pregnancy are summarized in Table 8.Table 8: Pregnancy Results from Treatment With Follistim AQ Cartridge and GnRH Antagonist in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization or Intracytoplasmic Sperm Injection Cycle.Single treatment cycle results Intent-to-Treat Population (ITT)ParameterFollistim AQ CartridgeOverall data(n=750)Follistim AQ CartridgeNorth American data(n=403)Clinical pregnancy rate/cycle initiationClinical pregnancy was assessed >=6 weeks after transfer of one or two embryos. 41.1%48.9%. 14.3 Induction of Spermatogenesis. The safety and efficacy of Follistim administered by subcutaneous injection concomitantly with chorionic gonadotropin for injection (hCG) has been examined in multicenter, open-label, non-comparator clinical study for induction of spermatogenesis in hypogonadotropic hypogonadal men. The study compared the effects of two different Follistim dosing schedules on semen parameters and serum levels of follicle stimulating hormone (FSH). The multicenter study involved 16-week pretreatment phase with hCG at dosage of 1,500 international units twice week to normalize serum testosterone levels. If serum testosterone levels did not normalize after weeks of hCG treatment, the hCG dose could have been increased to 3,000 international units twice week. This phase was followed by 48-week treatment phase. Men who were still azoospermic after the pretreatment phase were randomized to receive either 225 international units Follistim together with 1,500 international units hCG twice week or 150 international units Follistim three times week together with 1,500 international units hCG twice weekly. Men who required 3,000 international units of hCG twice week in the pretreatment phase were continued on that dosage during the treatment phase. The mean age of patients in both treatment groups was approximately 30 years (range 18 to 47 years). At baseline, mean left and right testis volumes were 4.61 +- 2.94 mL and 4.57 +- 3.00 mL, respectively, in the group receiving three weekly injections of Follistim. For the group receiving two weekly injections of Follistim, the mean left and right testis volumes were 6.54 +- 2.45 mL and 7.21 +- 2.94 mL, respectively, at baseline. The primary efficacy endpoint was the percentage of patients with mean sperm density of >=1 106/mL on their last two treatment assessments. The outcomes of treatment in the 30 men enrolled in the treatment phase are summarized in Table 9.Table 9: Number of Men Receiving Follistim Who Achieved Mean Sperm Density of >=106/mL on Their Last Two Treatment AssessmentsFollistim 150 international units three times week(n=15)Follistim 225 international units twice week(n=15)Overall(n=30)Sperm Density of >=106/mL n%n%n%Yes6407471343No9608531757Overall, the median time to reach sperm concentration of 106 per mL was 165 days (range 25 to 327 days) in patients who demonstrated sperm concentration of at least 106 per mL. The median time to reach sperm concentration of at least 106 per mL was 186 days (range 25 to 327 days) for the 150 international units group and 141 days (range 43 to 204 days) for the 225 international units group. No pregnancy data were collected during the trial.The local tolerance data were comparable between the two treatment groups. The mean percentage of days without pain calculated for all subjects in the treatment period was 91.3% for patients in the 150 international units (three times week) and 76.0% for patients in the 225 international units (two times week) Follistim treatment groups. In the 225 international units (twice per week) group, local symptoms judged as severe by the investigator were: itching in patient (7%), pain in patients (13%), bruising in patients (13%), swelling in patients (13%), and redness in patient (7%). In the 150 international units (three times per week) group, event in patient (bruising, 7%) was judged as severe. No patient discontinued treatment due to injection site reaction or injection site pain.

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2)] Atelectasis [see Warnings and Precautions (5.3)] Thromboembolism [see Warnings and Precautions (5.3)] Ovarian Torsion [see Warnings and Precautions (5.4)] Multi-fetal Gestation and Birth [see Warnings and Precautions (5.5)] Congenital Anomalies [see Warnings and Precautions (5.6)] Ectopic Pregnancy [see Warnings and Precautions (5.7)] Spontaneous Abortion [see Warnings and Precautions (5.8)] Ovarian Hyperstimulation Syndrome [see Warnings and Precautions (5.2)] Atelectasis [see Warnings and Precautions (5.3)] Thromboembolism [see Warnings and Precautions (5.3)] Ovarian Torsion [see Warnings and Precautions (5.4)] Multi-fetal Gestation and Birth [see Warnings and Precautions (5.5)] Congenital Anomalies [see Warnings and Precautions (5.6)] Ectopic Pregnancy [see Warnings and Precautions (5.7)] Spontaneous Abortion [see Warnings and Precautions (5.8)] The most common adverse reactions (>=2%) in women undergoing ovulation induction are ovarian hyperstimulation syndrome, ovarian cyst, abdominal discomfort, abdominal pain and lower abdominal pain. (6.1)The most common adverse reactions (>=2%) in women undergoing controlled ovarian stimulation as part of an IVF or ICSI cycle are pelvic discomfort, headache, ovarian hyperstimulation syndrome, pelvic pain, nausea and fatigue. (6.1)The most common (>=2%) adverse reactions in men undergoing induction of spermatogenesis are headache, acne, injection site reaction, injection site pain, gynecomastia, rash and dermoid cyst. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Study Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.. Ovulation InductionIn single cycle, multi-center, assessor-blind, parallel group, comparative study, total of 172 chronic anovulatory women who had failed to ovulate and/or conceive with clomiphene citrate therapy, were randomized and treated with Follistim (105) or urofollitropin comparator. Adverse reactions with an incidence of greater than 2% in either treatment group are listed in Table 2.Table 2: Common Adverse Reactions Reported at Frequency of >=2% in an Assessor-Blind, Comparative Study of Anovulatory Women Receiving Ovulation InductionSystem Organ Class/Adverse ReactionsTreatmentNumber (%) of WomenFollistimN=105n (%)ComparatorN=67n (%)Gastrointestinal disorders Abdominal discomfort3 (2.9)1 (1.5) Abdominal pain3 (2.9)2 (3.0) Abdominal pain lower3 (2.9)1 (1.5)Reproductive system and breast disorders Ovarian cyst3 (2.9)2 (3.0) Ovarian hyperstimulation syndrome8 (7.6)3 (4.5)General disorders and administration site conditions Pyrexia0 (0.0)2 (3.0)Adverse reactions reported commonly (greater than or equal to 2% of women treated with Follistim) in other ovulation induction clinical trials were headache, abdominal distension, constipation, diarrhea, nausea, pelvic pain, uterine enlargement, vaginal hemorrhage and injection site reaction.. In Vitro Fertilization/Intracytoplasmic Sperm InjectionIn single cycle, multi-center, double-blind, parallel group, comparative study, total of 1509 women were randomized to receive controlled ovarian stimulation with either Follistim AQ Cartridge (751 women were treated with Follistim AQ Cartridge) or comparator and pituitary suppression with gonadotropin releasing hormone (GnRH) antagonist as part of an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle. Table lists adverse reactions with an incidence of greater than 2% in the group of women treated with Follistim AQ Cartridge.Table 3: Common Adverse Reactions Reported at Frequency of >=2% in Randomized, Double-blind, Active-controlled, Comparative Study of Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization or Intracytoplasmic Sperm Injection CycleSystem Organ Class/Adverse ReactionsFollistim AQ Cartridge TreatmentN 751nn number of women with the adverse reaction (%)Nervous System disorders Headache55 (7.3%)Gastrointestinal disorders Nausea29 (3.9%)Reproductive system and breast disorders Ovarian Hyperstimulation Syndrome48 (6.4%) Pelvic discomfort62 (8.3%) Pelvic Pain41 (5.5%)General disorders and Administration site conditions Fatigue17 (2.3%). Induction of SpermatogenesisIn an open-label, non-comparative clinical trial, 49 men with hypogonadotropic hypogonadism were enrolled to receive pretreatment with hCG, followed by combination therapy with hCG and Follistim for induction of spermatogenesis. Of the 49 men, 30 received weekly Follistim doses of 450 international units; 24 of these 30 men received total of 48 weeks of treatment with Follistim. Adverse reactions occurring with an incidence of greater than 2% in the 30 men treated with Follistim are listed in Table 4.Table 4: Common Adverse Reactions Reported at Frequency of >=2% in an Open-Label Clinical Trial in Men with Hypogonadotropic HypogonadismSystem Organ Class/Adverse ReactionsFollistim TreatmentN=30n (%)Nervous system disorders Headache2 (6.7)General disorders and administration site disorders Injection site reaction2 (6.7) Injection site pain2 (6.7)Skin and cutaneous tissue disorders Acne2 (6.7) Rash1 (3.3)Reproductive system and breast disorders Gynecomastia1 (3.3)Neoplasms benign, malignant and unspecified Dermoid cyst1 (3.3). 6.2Postmarketing Experience. The following adverse reactions have been identified during post approval use of Follistim and/or Follistim AQ Cartridge. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal disordersAbdominal distension, abdominal pain, constipation, diarrheaGeneral disorders and administration site conditionsInjection site reactionReproductive system and breast disordersBreast tenderness, metrorrhagia, ovarian enlargement, vaginal hemorrhageSkin and subcutaneous tissue disordersRashVascular disordersThromboembolism [see Warnings and Precautions (5.3)].

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. See Dose Conversion Table for Follistim AQ Cartridge with Pen Injector (2.1)In Anovulatory Women Undergoing Ovulation Induction (2.2):Starting daily dose of 50 international units of Follistim AQ Cartridge is administered subcutaneously for at least the first days. The dose is increased by 25 or 50 international units at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate response.When an acceptable pre-ovulatory state is achieved, final oocyte maturation is achieved with 5,000 to 10,000 international units of human chorionic gonadotropin (hCG).The woman and her partner should have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent. In Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization or Intracytoplasmic Sperm Injection Cycle (2.3):Starting dose of 200 international units (actual cartridge doses) of Follistim AQ Cartridge is administered subcutaneously for at least the first days of treatment. Subsequent doses can be adjusted down or up based upon ovarian response as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Dosage reduction in high responders can be considered from the 6th day of treatment onward according to individual response.Final oocyte maturation is induced with dose of 5,000-10,000 international units of hCG.Oocyte (egg) retrieval is performed 34 to 36 hours later. Induction of Spermatogenesis in Men (2.4):Pretreatment with hCG alone (1,500 international units twice weekly) is required. If serum testosterone levels have not normalized after weeks of hCG treatment, the dose may be increased to 3,000 international units twice week.After normalization of serum testosterone levels, administer 450 international units per week (225 international units twice weekly or 150 international units three times weekly) of Follistim AQ Cartridge subcutaneously with the same pre-treatment hCG dose used to normalize testosterone levels.. Starting daily dose of 50 international units of Follistim AQ Cartridge is administered subcutaneously for at least the first days. The dose is increased by 25 or 50 international units at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate response.When an acceptable pre-ovulatory state is achieved, final oocyte maturation is achieved with 5,000 to 10,000 international units of human chorionic gonadotropin (hCG).The woman and her partner should have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent. When an acceptable pre-ovulatory state is achieved, final oocyte maturation is achieved with 5,000 to 10,000 international units of human chorionic gonadotropin (hCG).. The woman and her partner should have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent.. Starting dose of 200 international units (actual cartridge doses) of Follistim AQ Cartridge is administered subcutaneously for at least the first days of treatment. Subsequent doses can be adjusted down or up based upon ovarian response as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Dosage reduction in high responders can be considered from the 6th day of treatment onward according to individual response.Final oocyte maturation is induced with dose of 5,000-10,000 international units of hCG.Oocyte (egg) retrieval is performed 34 to 36 hours later. Final oocyte maturation is induced with dose of 5,000-10,000 international units of hCG.. Oocyte (egg) retrieval is performed 34 to 36 hours later.. Pretreatment with hCG alone (1,500 international units twice weekly) is required. If serum testosterone levels have not normalized after weeks of hCG treatment, the dose may be increased to 3,000 international units twice week.. After normalization of serum testosterone levels, administer 450 international units per week (225 international units twice weekly or 150 international units three times weekly) of Follistim AQ Cartridge subcutaneously with the same pre-treatment hCG dose used to normalize testosterone levels.. 2.1General Dosing Information. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the solution is not clear and colorless or has particles in it, the solution should not be used.Do not add any other medicines into the Follistim AQ Cartridge.Follistim AQ Cartridge with the pen injector device delivers on average an 18% higher amount of follitropin beta when compared to reconstituted Follistim delivered with conventional syringe and needle. When administering Follistim AQ Cartridge, lower starting dose and lower dose adjustments (as compared to reconstituted Follistim) should be considered. For that purpose the following Dose Conversion Table is provided:Table 1: Follistim AQ Cartridge Administered Subcutaneously With the Follistim Pen Dose Conversion TableEach value represents an 18% difference rounded to the nearest 25 IU increment. Lyophilized recombinant FSH dosing withampules or vials, using conventional syringeFollistim AQ Cartridgedosing with the Follistim Pen75 IU50 IU150 IU125 IU225 IU175 IU300 IU250 IU375 IU300 IU450 IU375 IU. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the solution is not clear and colorless or has particles in it, the solution should not be used.. Do not add any other medicines into the Follistim AQ Cartridge.. Follistim AQ Cartridge with the pen injector device delivers on average an 18% higher amount of follitropin beta when compared to reconstituted Follistim delivered with conventional syringe and needle. When administering Follistim AQ Cartridge, lower starting dose and lower dose adjustments (as compared to reconstituted Follistim) should be considered. For that purpose the following Dose Conversion Table is provided:. 2.2Recommended Dosing in Anovulatory Women Undergoing Ovulation Induction. The dosing scheme is stepwise and is individualized for each woman [see Clinical Studies (14.1)]. starting daily dose of 50 international units of Follistim AQ Cartridge is administered [see Dosage and Administration (2.1)] subcutaneously daily for at least the first days. Subsequent dosage adjustments are made at weekly intervals based upon ovarian response. If an increase in dose is indicated by the ovarian response, the increase should be made by 25 or 50 international units of Follistim AQ Cartridge at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate ovarian response.The following should be considered when planning the womans individualized dose:Appropriate Follistim AQ Cartridge dose adjustment(s) should be used to prevent multiple follicular growth and cycle cancellation.The maximum, individualized, daily dose of Follistim AQ Cartridge is 250 international units. Treatment should continue until ultrasonic visualizations and/or serum estradiol determinations approximate the pre-ovulatory conditions seen in normal individuals. When pre-ovulatory conditions are reached, 5,000 to 10,000 international units of hCG are used to induce final oocyte maturation and ovulation.The administration of hCG must be withheld in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of Follistim AQ Cartridge therapy [see Warnings and Precautions (5.1, 5.2, 5.10)]. The woman and her partner should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent [see Warnings and Precautions (5.10) ]. During treatment with Follistim AQ Cartridge and during two-week post-treatment period, the woman should be assessed at least every other day for signs of excessive ovarian stimulation.It is recommended that Follistim AQ Cartridge administration be stopped if the ovarian monitoring suggests an increased risk of OHSS or abdominal pain occurs. Most OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days post-ovulation.. starting daily dose of 50 international units of Follistim AQ Cartridge is administered [see Dosage and Administration (2.1)] subcutaneously daily for at least the first days.. Subsequent dosage adjustments are made at weekly intervals based upon ovarian response. If an increase in dose is indicated by the ovarian response, the increase should be made by 25 or 50 international units of Follistim AQ Cartridge at weekly intervals until follicular growth and/or serum estradiol levels indicate an adequate ovarian response.The following should be considered when planning the womans individualized dose:Appropriate Follistim AQ Cartridge dose adjustment(s) should be used to prevent multiple follicular growth and cycle cancellation.The maximum, individualized, daily dose of Follistim AQ Cartridge is 250 international units. Appropriate Follistim AQ Cartridge dose adjustment(s) should be used to prevent multiple follicular growth and cycle cancellation.. The maximum, individualized, daily dose of Follistim AQ Cartridge is 250 international units.. Treatment should continue until ultrasonic visualizations and/or serum estradiol determinations approximate the pre-ovulatory conditions seen in normal individuals.. When pre-ovulatory conditions are reached, 5,000 to 10,000 international units of hCG are used to induce final oocyte maturation and ovulation.The administration of hCG must be withheld in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of Follistim AQ Cartridge therapy [see Warnings and Precautions (5.1, 5.2, 5.10)].. The woman and her partner should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG and until ovulation becomes apparent [see Warnings and Precautions (5.10) ].. During treatment with Follistim AQ Cartridge and during two-week post-treatment period, the woman should be assessed at least every other day for signs of excessive ovarian stimulation.It is recommended that Follistim AQ Cartridge administration be stopped if the ovarian monitoring suggests an increased risk of OHSS or abdominal pain occurs. Most OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days post-ovulation.. 2.3Recommended Dosing in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle. The dosing scheme follows stepwise approach and is individualized for each woman.A starting dose of 200 international units (actual cartridge doses) of Follistim AQ Cartridge is administered [see Dosage and Administration (2.1)] subcutaneously daily for at least the first days of treatment.Subsequent to the first days of treatment, the dose can be adjusted down or up based upon the womans ovarian response as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Dosage reduction in high responders can be considered from the 6th day of treatment onward according to individual response. The following should be considered when planning the womans individualized dose: For most normal responding women, the daily starting dose can be continued until pre-ovulatory conditions are achieved (seven to twelve days). For low or poor responding women, the daily dose should be increased according to the ovarian response. The maximum, individualized, daily dose of Follistim AQ Cartridge is 500 international units. For high responding women [those at particular risk of abnormal ovarian enlargement and/or ovarian hyperstimulation syndrome (OHSS)], decrease or temporarily stop the daily dose, or discontinue the cycle according to individual response [see Warnings and Precautions (5.1, 5.2, 5.10)]. When sufficient number of follicles of adequate size are present, dosing of Follistim AQ Cartridge is stopped and final maturation of the oocytes is induced by administering hCG at dose of 5,000 to 10,000 international units. The administration of hCG should be withheld in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of Follistim AQ Cartridge therapy [see Warnings and Precautions (5.1, 5.2, 5.10)]. Oocyte (egg) retrieval should be performed 34 to 36 hours following the administration of hCG.. starting dose of 200 international units (actual cartridge doses) of Follistim AQ Cartridge is administered [see Dosage and Administration (2.1)] subcutaneously daily for at least the first days of treatment.. Subsequent to the first days of treatment, the dose can be adjusted down or up based upon the womans ovarian response as determined by ultrasound evaluation of follicular growth and serum estradiol levels. Dosage reduction in high responders can be considered from the 6th day of treatment onward according to individual response. The following should be considered when planning the womans individualized dose: For most normal responding women, the daily starting dose can be continued until pre-ovulatory conditions are achieved (seven to twelve days). For low or poor responding women, the daily dose should be increased according to the ovarian response. The maximum, individualized, daily dose of Follistim AQ Cartridge is 500 international units. For high responding women [those at particular risk of abnormal ovarian enlargement and/or ovarian hyperstimulation syndrome (OHSS)], decrease or temporarily stop the daily dose, or discontinue the cycle according to individual response [see Warnings and Precautions (5.1, 5.2, 5.10)]. For most normal responding women, the daily starting dose can be continued until pre-ovulatory conditions are achieved (seven to twelve days).. For low or poor responding women, the daily dose should be increased according to the ovarian response. The maximum, individualized, daily dose of Follistim AQ Cartridge is 500 international units.. For high responding women [those at particular risk of abnormal ovarian enlargement and/or ovarian hyperstimulation syndrome (OHSS)], decrease or temporarily stop the daily dose, or discontinue the cycle according to individual response [see Warnings and Precautions (5.1, 5.2, 5.10)].. When sufficient number of follicles of adequate size are present, dosing of Follistim AQ Cartridge is stopped and final maturation of the oocytes is induced by administering hCG at dose of 5,000 to 10,000 international units. The administration of hCG should be withheld in cases where the ovarian monitoring suggests an increased risk of OHSS on the last day of Follistim AQ Cartridge therapy [see Warnings and Precautions (5.1, 5.2, 5.10)].. Oocyte (egg) retrieval should be performed 34 to 36 hours following the administration of hCG.. 2.4Recommended Dosing for Induction of Spermatogenesis in Men. Pretreatment with hCG is required prior to concomitant therapy with Follistim AQ Cartridge and hCG. An initial dosage of 1,500 international units of hCG should be administered at twice weekly intervals to normalize serum testosterone levels. If serum testosterone levels have not normalized after weeks of hCG treatment, the hCG dose can be increased to 3,000 international units twice weekly [see Clinical Studies (14.3)].After normal serum testosterone levels have been reached, Follistim AQ Cartridge should be administered by subcutaneous injection concomitantly with hCG treatment. Follistim is given at dosage of 450 international units per week, as either 225 international units twice weekly or 150 international units three times per week, in combination with the same hCG dose used to normalize testosterone levels. Based on delivery of higher dose of follitropin beta with the Follistim AQ Cartridge and pen injector [see Dosage and Administration (2.1)], lower dose of Follistim AQ Cartridge may be considered. The concomitant therapy should be continued for at least to months before any improvement in spermatogenesis can be expected. If man has not responded after this period, the combination therapy may be continued. Treatment response has been noted at up to 12 months.. Pretreatment with hCG is required prior to concomitant therapy with Follistim AQ Cartridge and hCG. An initial dosage of 1,500 international units of hCG should be administered at twice weekly intervals to normalize serum testosterone levels. If serum testosterone levels have not normalized after weeks of hCG treatment, the hCG dose can be increased to 3,000 international units twice weekly [see Clinical Studies (14.3)].. After normal serum testosterone levels have been reached, Follistim AQ Cartridge should be administered by subcutaneous injection concomitantly with hCG treatment. Follistim is given at dosage of 450 international units per week, as either 225 international units twice weekly or 150 international units three times per week, in combination with the same hCG dose used to normalize testosterone levels. Based on delivery of higher dose of follitropin beta with the Follistim AQ Cartridge and pen injector [see Dosage and Administration (2.1)], lower dose of Follistim AQ Cartridge may be considered. The concomitant therapy should be continued for at least to months before any improvement in spermatogenesis can be expected. If man has not responded after this period, the combination therapy may be continued. Treatment response has been noted at up to 12 months.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. Follistim(R) AQ (follitropin beta injection) Cartridge is indicated:In Women for:. Follistim AQ Cartridge is gonadotropin indicated:In Women for:Induction of Ovulation and Pregnancy in Anovulatory Infertile Women in Whom the Cause of Infertility is Functional and Not Due to Primary Ovarian Failure (1.1)Pregnancy in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle (1.2)In Men for:Induction of Spermatogenesis in Men with Primary and Secondary Hypogonadotropic Hypogonadism (HH) in Whom the Cause of Infertility is Not Due to Primary Testicular Failure (1.3). Induction of Ovulation and Pregnancy in Anovulatory Infertile Women in Whom the Cause of Infertility is Functional and Not Due to Primary Ovarian Failure (1.1). Pregnancy in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle (1.2). Induction of Spermatogenesis in Men with Primary and Secondary Hypogonadotropic Hypogonadism (HH) in Whom the Cause of Infertility is Not Due to Primary Testicular Failure (1.3). 1.1 Induction of Ovulation and Pregnancy in Anovulatory Infertile Women in Whom the Cause of Infertility is Functional and Not Due to Primary Ovarian Failure. Prior to initiation of treatment with Follistim AQ Cartridge:Women should have complete gynecologic and endocrinologic evaluation.Primary ovarian failure should be excluded.The possibility of pregnancy should be excluded.Tubal patency should be demonstrated.The fertility status of the male partner should be evaluated.. Women should have complete gynecologic and endocrinologic evaluation.. Primary ovarian failure should be excluded.. The possibility of pregnancy should be excluded.. Tubal patency should be demonstrated.. The fertility status of the male partner should be evaluated.. 1.2 Pregnancy in Normal Ovulatory Women Undergoing Controlled Ovarian Stimulation as Part of an In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Cycle. Prior to initiation of treatment with Follistim AQ Cartridge:Women should have complete gynecologic and endocrinologic evaluation and diagnosis of cause of infertility.The possibility of pregnancy should be excluded.The fertility status of the male partner should be evaluated.In Men for:. Women should have complete gynecologic and endocrinologic evaluation and diagnosis of cause of infertility.. The possibility of pregnancy should be excluded.. The fertility status of the male partner should be evaluated.. 1.3 Induction of Spermatogenesis in Men with Primary and Secondary Hypogonadotropic Hypogonadism (HH) in Whom the Cause of Infertility is Not Due to Primary Testicular Failure. Prior to initiation of treatment with Follistim AQ Cartridge:Men should have complete medical and endocrinologic evaluation.Hypogonadotropic hypogonadism should be confirmed and primary testicular failure should be excluded.Serum testosterone levels should be normalized with human chorionic gonadotropin (hCG) treatment.The fertility status of the female partner should be evaluated.. Men should have complete medical and endocrinologic evaluation.. Hypogonadotropic hypogonadism should be confirmed and primary testicular failure should be excluded.. Serum testosterone levels should be normalized with human chorionic gonadotropin (hCG) treatment.. The fertility status of the female partner should be evaluated.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Follistim AQ Cartridge should be used only by physicians who are experienced in infertility treatment. Follistim AQ Cartridge contains potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) [see Warnings and Precautions (5.2)] with or without pulmonary or vascular complications [see Warnings and Precautions (5.3)] and multiple births [see Warnings and Precautions (5.5)]. Gonadotropin therapy requires the availability of appropriate monitoring facilities [see Warnings and Precautions (5.10)].Careful attention should be given to the diagnosis of infertility and in the selection of candidates for Follistim AQ Cartridge therapy [see Indications and Usage (1.1, 1.2, 1.3) and Dosage and Administration (2.2, 2.3, 2.4)].Switching to Follistim AQ Cartridge from other brands (manufacturer), types (recombinant, urinary), and/or methods of administration (Follistim Pen, conventional syringe) may necessitate an adjustment of the dose [see Dosage and Administration (2)]. Treatment with Follistim AQ may result in:Abnormal Ovarian Enlargement (5.1)Ovarian Hyperstimulation Syndrome (OHSS) (5.2)Pulmonary and Vascular Complications (5.3)Ovarian Torsion (5.4)Multi-fetal Gestation and Birth (5.5)Congenital Anomalies (5.6)Ectopic Pregnancy (5.7)Spontaneous Abortion (5.8)Ovarian Neoplasms (5.9). Abnormal Ovarian Enlargement (5.1). Ovarian Hyperstimulation Syndrome (OHSS) (5.2). Pulmonary and Vascular Complications (5.3). Ovarian Torsion (5.4). Multi-fetal Gestation and Birth (5.5). Congenital Anomalies (5.6). Ectopic Pregnancy (5.7). Spontaneous Abortion (5.8). Ovarian Neoplasms (5.9). 5.1Abnormal Ovarian Enlargement. In order to minimize the hazards associated with abnormal ovarian enlargement that may occur with Follistim AQ therapy, treatment should be individualized and the lowest effective dose should be used [see Dosage and Administration (2.2, 2.3) ]. Use of ultrasound monitoring of ovarian response and/or measurement of serum estradiol levels is important to minimize the risk of overstimulation [see Warnings and Precautions (5.8)] .If the ovaries are abnormally enlarged on the last day of Follistim AQ therapy, hCG should not be administered in order to reduce the chances of developing Ovarian Hyperstimulation Syndrome (OHSS). Intercourse should be prohibited in patients with significant ovarian enlargement after ovulation because of the danger of hemoperitoneum resulting from ruptured ovarian cysts [see Warnings and Precautions (5.3)]. 5.2Ovarian Hyperstimulation Syndrome (OHSS). OHSS is medical entity distinct from uncomplicated ovarian enlargement and may progress rapidly to become serious medical condition. OHSS is characterized by dramatic increase in vascular permeability, which can result in rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium. The early warning signs of OHSS developing are severe pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria have been reported with OHSS. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions [see Warnings and Precautions (5.3)]. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy have also been reported in association with OHSS.OHSS occurs after gonadotropin treatment has been discontinued, and it can develop rapidly, reaching its maximum about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is risk for OHSS evident prior to hCG administration [see Warnings and Precautions (5.1)], the hCG must be withheld. Cases of OHSS are more common, more severe, and more protracted if pregnancy occurs; therefore, women should be assessed for the development of OHSS for at least two weeks after hCG administration.If serious OHSS occurs, gonadotropins, including hCG, should be stopped and consideration should be given as to whether the patient needs to be hospitalized. Treatment is primarily symptomatic and overall should consist of bed rest, fluid and electrolyte management, and analgesics (if needed). Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below. The management of OHSS may be divided into three phases as follows:Acute Phase: Management should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, and human serum albumin is intended 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.Chronic Phase: After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.Resolution Phase: As third space fluid returns to the intravascular compartment, fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. 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.OHSS increases the risk of injury to the ovary. The ascitic, pleural, and pericardial fluid should not be removed unless there is the necessity 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 bleeding occurs and requires surgical intervention, the clinical objective should be to control the bleeding and retain as much ovarian tissue as possible.During clinical trials with Follistim or Follistim AQ Cartridge therapy, OHSS occurred in 7.6% of 105 women (OI) and 6.4% of 751 women (IVF or ICSI) treated with Follistim and Follistim AQ Cartridge, respectively.. Acute Phase: Management should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, and human serum albumin is intended 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 should be directed at preventing hemoconcentration due to loss of intravascular volume to the third space and minimizing the risk of thromboembolic phenomena and kidney damage. Fluid intake and output, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, total proteins with albumin: globulin ratio, coagulation studies, electrocardiogram to monitor for hyperkalemia, and abdominal girth should be thoroughly assessed daily or more often based on the clinical need. Treatment, consisting of limited intravenous fluids, electrolytes, and human serum albumin is intended 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.. Chronic Phase: After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.. After the acute phase is successfully managed as above, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium, and fluid restriction.. Resolution Phase: As third space fluid returns to the intravascular compartment, fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. 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.. As third space fluid returns to the intravascular compartment, fall in hematocrit and increasing urinary output are observed in the absence of any increase in intake. 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.. 5.3Pulmonary and Vascular Complications. Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome) have been reported in women treated with gonadotropins. In addition, thromboembolic reactions both in association with, and separate from OHSS have been reported following gonadotropin therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Women with generally recognized risk factors for thrombosis, such as personal or family history, severe obesity, or thrombophilia, may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotropins. Sequelae of such reactions have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb and rarely in myocardial infarction. In rare cases, pulmonary complications and/or thromboembolic reactions have resulted in death. In women with recognized risk factors, the benefits of ovulation induction, in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment need to be weighed against the risks. It should be noted, that pregnancy itself also carries an increased risk of thrombosis.. 5.4Ovarian Torsion. Ovarian torsion has been reported after treatment with Follistim AQ Cartridge and after intervention with other gonadotropins. This may be related to OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.. 5.5Multi-fetal Gestation and Birth. Multi-fetal gestation and births have been reported with all gonadotropin treatments including Follistim AQ Cartridge treatment. The woman and her partner should be advised of the potential risk of multi-fetal gestation and births before starting treatment.. 5.6Congenital Anomalies. The incidence of congenital malformations after IVF or ICSI may be slightly higher than after spontaneous conception. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g., maternal age, sperm characteristics) and to the higher incidence of multi-fetal gestations after IVF or ICSI. There are no indications that the use of gonadotropins during IVF or ICSI is associated with an increased risk of congenital malformations.. 5.7Ectopic Pregnancy. Since infertile women undergoing IVF or ICSI often have tubal abnormalities, the incidence of ectopic pregnancies might be increased. Early confirmation of an intrauterine pregnancy should be determined by -hCG testing and transvaginal ultrasound.. 5.8Spontaneous Abortion. The risk of spontaneous abortions (miscarriage) is increased with gonadotropin products. However, causality has not been established. The increased risk may be factor of the underlying infertility.. 5.9Ovarian Neoplasms. There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for controlled ovarian stimulation; however, causal relationship has not been established.. 5.10Laboratory Tests. For Women:In most instances, treatment with Follistim AQ Cartridge will result only in follicular growth and maturation. In order to complete the final phase of follicular maturation and to induce ovulation, hCG must be given following the administration of Follistim AQ Cartridge or when clinical assessment indicates that sufficient follicular maturation has occurred. The degree of follicular maturation and the timing of hCG administration can both be determined with the use of sonographic visualization of the ovaries and endometrial lining in conjunction with measurement of serum estradiol levels. The combination of transvaginal ultrasonography and measurement of serum estradiol levels is also useful for minimizing the risk of OHSS and multi-fetal gestations.The clinical confirmation of ovulation is obtained by the following direct or indirect indices of progesterone production as well as sonographic evidence of ovulation.Direct or indirect indices of progesterone production are:Urinary or serum luteinizing hormone (LH) riseA rise in basal body temperatureIncrease in serum progesteroneMenstruation following the shift in basal body temperatureThe following provide sonographic evidence of ovulation:Collapsed follicleFluid in the cul-de-sacFeatures consistent with corpus luteum formationSonographic evaluation of the early pregnancy is also important to rule out ectopic pregnancy.. Urinary or serum luteinizing hormone (LH) rise. rise in basal body temperature. Increase in serum progesterone. Menstruation following the shift in basal body temperature. Collapsed follicle. Fluid in the cul-de-sac. Features consistent with corpus luteum formation. For Men:Clinical monitoring for spermatogenesis utilizes the following indirect or direct measures:Serum testosterone levelSemen analysis. Serum testosterone level. Semen analysis. 5.11 Follistim Pen. The Follistim Pen is intended only for use with Follistim AQ Cartridge. The Follistim Pen is not recommended for the blind or visually impaired without the assistance of an individual with good vision who is trained in the proper use of the injection device.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetic parameters for Follistim AQ Cartridge were evaluated in an open-label, single-center, randomized study in 20 healthy women. Serum FSH values from single subcutaneous injection of reconstituted Follistim lyophilized powder administered by conventional syringe were compared to those values following single subcutaneous injection of Follistim AQ Cartridge administered with the Follistim Pen injector. Administration of follitropin beta with the Follistim Pen resulted an 18% increase in AUC0- and Cmax. The 18% difference in serum FSH concentrations resulting from administration of the two formulations was due to differences between the anticipated and actual volume delivered with the conventional syringe. The pharmacokinetic parameters for Follistim AQ Cartridge are as follows:Table 5: Mean (SD) Pharmacokinetic Parameters of Single Subcutaneous Injection of 150 IU of Follistim AQ Cartridge (n=20)AUC0- (IU/Lh)Cmax (IU/L)tmax (h)t1/2 (h)CLapp (L/h/kg)AUC0- Area under the curveCmax Maximum concentrationtmax Time to maximum concentrationt1/2 Elimination half-lifeCLapp ClearanceFollistim AQ215.13.412.933.40.01Cartridge(45.8)(0.7)(6.2)(4.2)(0.003). Absorption:. Women:The bioavailability of Follistim following subcutaneous and intramuscular administration was investigated in healthy, pituitary-suppressed women given single 300 international units dose. In these women, the area under the curve (AUC), expressed as the mean +- SD, was equivalent between the subcutaneous (455.6 +- 141.4 IUh/L) and intramuscular (445.7 +- 135.7 IUh/L) routes of administration. However, equivalence could not be established with respect to the peak serum FSH levels (Cmax). The Cmax achieved after subcutaneous administration and intramuscular administration was 5.41 +- 0.72 international units/L and 6.86 +- 2.90 international units/L, respectively. After subcutaneous or intramuscular injection the apparent dose absorbed was 77.8% and 76.4%, respectively.The pharmacokinetics and pharmacodynamics of single, intramuscular dose (300 international units) of Follistim were also investigated in group (n=8) of gonadotropin-deficient, but otherwise healthy women. In these women, FSH (mean +- SD) AUC was 339 +- 105 international unitsh/L, Cmax was 4.3 +- 1.7 international units/L. Cmax occurred at approximately 27 +- 5.4 hours after intramuscular administration.A multiple dose, dose proportionality, pharmacokinetic study of Follistim was completed in healthy, pituitary-suppressed, female subjects given subcutaneous doses of 75, 150, or 225 international units for days. Steady-state blood concentrations of FSH were reached with all doses after days of treatment based on the trough concentrations of FSH just prior to dosing (Ctrough). Peak blood concentrations with the 75, 150, and 225 international units dose were 4.30 +- 0.60 international units/L, 8.51 +- 1.16 international units/L and 13.92 +- 1.81 international units/L, respectively.. Men:No PK studies were conducted using Follistim AQ Cartridge in men. Exposures of follitropin beta from Follistim AQ Cartridge and Follistim are expected to be equivalent after adjusting for the 18% difference in dose [see Dosage and Administration (2)].Serum levels of FSH were measured in clinical study that compared the effects of two different dosing schedules of Follistim (150 international units three times week or 225 international units twice week) administered by subcutaneous injection concurrently with chorionic gonadotropin for induction of spermatogenesis in hypogonadotropic hypogonadal men. Administration of Follistim was started at Week 17. Mean serum trough concentrations of FSH remained fairly constant over the treatment period. At the end of treatment (Week 64), the mean serum trough concentrations of FSH were 2.09 international units/L in the 150 international units group and 3.22 international units/L in the 225 international units group. Serum trough concentrations of FSH measured prior to the first Follistim injection on the Mondays of active treatment period (Weeks 17 to 64) and one week after the end of treatment period are presented in Figure 1.Figure 1: Mean (SD) Serum Trough Concentrations of FSH in Men Following Subcutaneous Administration of Follistim Using Two Different Dosing Schedules (150 International Units Three Times Week or 225 International Units Twice Week). Figure 1. Distribution:The volume of distribution of Follistim in healthy, pituitary-suppressed, women following intravenous administration of 300 international units dose was approximately L.. Metabolism:The recombinant FSH in Follistim AQ Cartridge is biochemically very similar to urinary FSH and it is therefore anticipated that it is metabolized in the same manner.. Elimination:The elimination half-life (t1/2) following single subcutaneous injection of 150 IU of Follistim AQ Cartridge in women was 33.4 (4.2) hours. The clearance was 0.01 (0.003) L/h/kg.. Use in Specific Populations: Body weight: The effect of body weight on the pharmacokinetics of Follistim was evaluated in group of European and Japanese women who were significantly different in terms of body weight. The European women had body weight of (mean +- SD) 67.4 +- 13.5 kg and the Japanese subjects were 46.8 +- 11.6 kg. Following single intramuscular dose of 300 international units of Follistim, the AUC was significantly smaller in European women (339 +- 105 international unitsh/L) than in Japanese women (544 +- 201 international unitsh/L). However, clearance per kg of body weight was essentially the same for the respective groups (0.014 and 0.013 L/hr/kg).Geriatric Use: The pharmacokinetics of Follistim has not been studied in geriatric subjects.Pediatric Use: The pharmacokinetics of Follistim has not been studied in pediatric subjects.Renal Impairment: The effect of renal impairment on the pharmacokinetics of Follistim has not been studied.Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Follistim has not been studied.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONFollistim(R) (Fol-lis-tim) AQ Cartridge(follitropin beta injection)Read the Patient Information that comes with Follistim(R) AQ Cartridge before you start using it and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.What is Follistim AQ CartridgeFollistim AQ is prescription medicine that contains follicle-stimulating hormone (FSH). The medicine is taken with the Follistim Pen(R).Follistim AQ Cartridge is used:In women:to help healthy ovaries to develop (mature) and release eggsas part of treatment programs that use special techniques (skills) to help women get pregnant by causing their ovaries to produce more mature eggsIn men:to help bring about the production and development of spermWho should not take Follistim AQ CartridgeDo not take Follistim AQ Cartridge if you are Woman or Man who:is allergic to recombinant human FSH productshas high level of FSH in your blood indicating that your ovaries (women only) or testes (men only) may be permanently damaged and do not work at allhas uncontrolled thyroid, pituitary, or adrenal gland problemsis allergic to streptomycin or neomycin (types of antibiotics)has tumor of the hypothalamus, pituitary gland, breast, uterus (women only), ovary (women only), or testis (men only)Do not take Follistim AQ Cartridge if you are Woman who:is pregnant or think you may be pregnanthas heavy or irregular vaginal bleeding and the cause is not knownhas ovarian cysts or enlarged ovaries, not due to polycystic ovary syndrome (PCOS)Talk to your healthcare provider before taking this medicine if you have any of the conditions listed above.What should tell my healthcare provider before taking Follistim AQ CartridgeBefore you take Follistim AQ, tell your healthcare provider if you:have an increased risk of blood clots (thrombosis)have ever had blood clot (thrombosis), or anyone in your immediate family has ever had blood clot (thrombosis)had stomach (abdominal) surgeryhad twisting of your ovary (ovarian torsion)had or have cyst in your ovaryhave polycystic ovary diseasehave any other medical conditionsare breastfeeding or plan to breastfeed. It is not known if the medicine in Follistim AQ Cartridge passes into your breast milk. You and your healthcare provider should decide if you will take Follistim AQ Cartridge or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of them and show your healthcare provider and pharmacist when you get new medicine.How should use Follistim AQ CartridgeBe sure that you read, understand, and follow the Patient Instructions for Use that come with Follistim AQ Cartridge.Use Follistim AQ Cartridge exactly as your healthcare provider tells you to.Your healthcare provider will tell you how much Follistim AQ Cartridge to use, how to inject it, and how often it should be injected.Do not inject Follistim AQ Cartridge at home until your healthcare provider has taught you the right way to put the cartridge and pen device together and to inject yourself.Do not mix any other medicines into the cartridge.Do not change your dose of Follistim AQ Cartridge unless your healthcare provider tells you to.Call your healthcare provider immediately if you use too much Follistim AQ Cartridge.If you miss or forget to take dose, do not double your next dose. Ask your healthcare provider for instructions.Use Follistim AQ Cartridge only with the Follistim Pen.Do not use the Follistim Pen if you are blind or visually impaired unless you have assistance from an individual with good vision who is trained in the right way to use the pen.Do not re-use the BD Micro-Fine(TM) Pen Needle.Your healthcare provider will do blood and urine hormone tests while you are taking Follistim AQ Cartridge. Make sure you follow-up with your healthcare provider to have your blood and urine tested when told to do so.Women:Your healthcare provider may do ultrasound scans of your ovaries. Make sure you follow-up with your healthcare provider to have your ultrasound scans.Men:Your healthcare provider may test your semen while you are taking Follistim AQ Cartridge. Make sure you follow-up with your healthcare provider to give semen sample for testing.What are the possible side effects of Follistim AQ CartridgeFollistim AQ Cartridge may cause serious side effects.Serious side effects in women include:Ovarian enlargementOvarian hyperstimulation syndrome (OHSS). OHSS is serious medical problem that can happen when the ovaries are over stimulated. In rare cases it has caused death. OHSS causes fluid to build up suddenly in your stomach and chest areas and can cause blood clots to form. Call your healthcare provider right away if you have:pain in your lower stomach areanauseavomitingweight gaindiarrheadecreased urine outputtrouble breathing Lung problems. Follistim AQ Cartridge can cause you to have fluid in your lungs (atelectasis) and trouble breathing (acute respiratory distress syndrome).Blood clots. Follistim AQ Cartridge may increase your chance of having blood clots in your blood vessels. Blood clots can cause:blood vessel problems (thrombophlebitis)strokeloss of your arm or legblood clot in your lungs (pulmonary embolus)heart attack Ovarian torsion. Follistim AQ Cartridge may increase the chance of twisting of the ovaries in women with certain conditions such as OHSS, pregnancy and previous abdominal surgery. Twisting of the ovary could cause the blood flow to the ovary to be cut off.Pregnancy and birth of multiple babies. Having pregnancy with more than one baby at time increases the health risk for you and your babies. Discuss your chances of multiple births with your healthcare provider.Birth defects. womans age, certain sperm problems, genetic background of both parents and pregnancy with multiple babies can increase the chance that your baby might have birth defects.Ectopic pregnancy (pregnancy outside of the womb). The chance of pregnancy outside of the womb is increased in women with damaged fallopian tubes.Miscarriage. The chance of loss of an early pregnancy may be increased in women who have difficulty with becoming pregnant at all.The most common side effects of Follistim AQ Cartridge include:In women:headachenauseastomach paindiscomfort or pain in the lower stomach areacyst (closed sac) in the ovaryfeeling tiredIn men:headachepain at the injection sitebruising, swelling or redness at the injection sitebreast enlargementacneThese are not all the possible side effects of Follistim AQ Cartridge. For more information, ask your healthcare provider or pharmacist.Call your healthcare provider immediately if you get worsening or strong pain in the lower stomach area (abdomen). Also, call your healthcare provider immediately if this happens some days after the last injection has been given.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Follistim AQ CartridgeStore Follistim AQ Cartridge in the refrigerator between 2-8C (36-46F) until the expiration date.Follistim AQ can be stored at or below 25C (77F) for months or until the expiration date, whichever comes first. Once the rubber inlay of the Follistim AQ Cartridge has been pierced by needle, the product may be stored only for maximum of 28 days at 2-25C (36-77F).Keep Follistim AQ Cartridge away from light.Do not freeze.Keep Follistim AQ Cartridge and all medicines out of the reach of children.General information about Follistim AQ CartridgeMedicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Follistim AQ for condition for which it was not prescribed. Do not give Follistim AQ Cartridge to other people, even if they have the same condition that you have. It may harm them.This Patient Information leaflet summarizes the most important information about Follistim AQ Cartridge. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for more information about Follistim AQ Cartridge that is written for healthcare professionals.For more information, go to www.follistim.com or call 1-866-836-5633.What are the ingredients in Follistim AQ CartridgeActive ingredient: follitropin betaInactive ingredients: sucrose, sodium citrate, benzyl alcohol NF-10 mg/mL, L-methionine, polysorbate 20, water for injection, hydrochloric acid, and/or sodium hydroxide.. to help healthy ovaries to develop (mature) and release eggs. as part of treatment programs that use special techniques (skills) to help women get pregnant by causing their ovaries to produce more mature eggs. to help bring about the production and development of sperm. is allergic to recombinant human FSH products. has high level of FSH in your blood indicating that your ovaries (women only) or testes (men only) may be permanently damaged and do not work at all. has uncontrolled thyroid, pituitary, or adrenal gland problems. is allergic to streptomycin or neomycin (types of antibiotics). has tumor of the hypothalamus, pituitary gland, breast, uterus (women only), ovary (women only), or testis (men only). is pregnant or think you may be pregnant. has heavy or irregular vaginal bleeding and the cause is not known. has ovarian cysts or enlarged ovaries, not due to polycystic ovary syndrome (PCOS). have an increased risk of blood clots (thrombosis). have ever had blood clot (thrombosis), or anyone in your immediate family has ever had blood clot (thrombosis). had stomach (abdominal) surgery. had twisting of your ovary (ovarian torsion). had or have cyst in your ovary. have polycystic ovary disease. have any other medical conditions. are breastfeeding or plan to breastfeed. It is not known if the medicine in Follistim AQ Cartridge passes into your breast milk. You and your healthcare provider should decide if you will take Follistim AQ Cartridge or breastfeed. You should not do both.. Be sure that you read, understand, and follow the Patient Instructions for Use that come with Follistim AQ Cartridge.. Use Follistim AQ Cartridge exactly as your healthcare provider tells you to.. Your healthcare provider will tell you how much Follistim AQ Cartridge to use, how to inject it, and how often it should be injected.. Do not inject Follistim AQ Cartridge at home until your healthcare provider has taught you the right way to put the cartridge and pen device together and to inject yourself.. Do not mix any other medicines into the cartridge.. Do not change your dose of Follistim AQ Cartridge unless your healthcare provider tells you to.. Call your healthcare provider immediately if you use too much Follistim AQ Cartridge.. If you miss or forget to take dose, do not double your next dose. Ask your healthcare provider for instructions.. Use Follistim AQ Cartridge only with the Follistim Pen.. Do not use the Follistim Pen if you are blind or visually impaired unless you have assistance from an individual with good vision who is trained in the right way to use the pen.. Do not re-use the BD Micro-Fine(TM) Pen Needle.. Your healthcare provider will do blood and urine hormone tests while you are taking Follistim AQ Cartridge. Make sure you follow-up with your healthcare provider to have your blood and urine tested when told to do so.. Your healthcare provider may do ultrasound scans of your ovaries. Make sure you follow-up with your healthcare provider to have your ultrasound scans.. Your healthcare provider may test your semen while you are taking Follistim AQ Cartridge. Make sure you follow-up with your healthcare provider to give semen sample for testing.. Ovarian enlargement. Ovarian hyperstimulation syndrome (OHSS). OHSS is serious medical problem that can happen when the ovaries are over stimulated. In rare cases it has caused death. OHSS causes fluid to build up suddenly in your stomach and chest areas and can cause blood clots to form. Call your healthcare provider right away if you have:pain in your lower stomach areanauseavomitingweight gaindiarrheadecreased urine outputtrouble breathing pain in your lower stomach area. nausea. vomiting. weight gain. diarrhea. decreased urine output. trouble breathing. Lung problems. Follistim AQ Cartridge can cause you to have fluid in your lungs (atelectasis) and trouble breathing (acute respiratory distress syndrome).. Blood clots. Follistim AQ Cartridge may increase your chance of having blood clots in your blood vessels. Blood clots can cause:blood vessel problems (thrombophlebitis)strokeloss of your arm or legblood clot in your lungs (pulmonary embolus)heart attack blood vessel problems (thrombophlebitis). stroke. loss of your arm or leg. blood clot in your lungs (pulmonary embolus). heart attack. Ovarian torsion. Follistim AQ Cartridge may increase the chance of twisting of the ovaries in women with certain conditions such as OHSS, pregnancy and previous abdominal surgery. Twisting of the ovary could cause the blood flow to the ovary to be cut off.. Pregnancy and birth of multiple babies. Having pregnancy with more than one baby at time increases the health risk for you and your babies. Discuss your chances of multiple births with your healthcare provider.. Birth defects. womans age, certain sperm problems, genetic background of both parents and pregnancy with multiple babies can increase the chance that your baby might have birth defects.. Ectopic pregnancy (pregnancy outside of the womb). The chance of pregnancy outside of the womb is increased in women with damaged fallopian tubes.. Miscarriage. The chance of loss of an early pregnancy may be increased in women who have difficulty with becoming pregnant at all.. headache. nausea. stomach pain. discomfort or pain in the lower stomach area. cyst (closed sac) in the ovary. feeling tired. headache. pain at the injection site. bruising, swelling or redness at the injection site. breast enlargement. acne. Store Follistim AQ Cartridge in the refrigerator between 2-8C (36-46F) until the expiration date.. Follistim AQ can be stored at or below 25C (77F) for months or until the expiration date, whichever comes first. Once the rubber inlay of the Follistim AQ Cartridge has been pierced by needle, the product may be stored only for maximum of 28 days at 2-25C (36-77F).. Keep Follistim AQ Cartridge away from light.. Do not freeze.