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Mechanism of Action
US Drug Names
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.
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. 
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).
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.
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.
Follitropin, r-FSH products are recombinant versions of human follicle stimulating hormone (FSH), a gonadotropin. Follitropin is available as follitropin alfa (Gonal-F, Gonal-F RFF) and follitropin beta (Follistim AQ), both of which are synthesized using a Chinese hamster ovary cell line. Although the drugs possess slightly different structures, they are indistinguishable based on data derived from physio-chemical tests and bioassay. Neither follitropin alfa nor follitropin beta should be confused with urofollitropin, which is a preparation of FSH obtained from the urine of postmenopausal females and is not a recombinant product. However, the primary and tertiary structures of follitropin alfa and follitropin beta are identical to that of human urinary FSH. Gonal-F, Gonal-F RFF (a reformulated injection), and Follistim QA are indicated in women for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-F and Gonal-F RFF are additionally indicated in women for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program. Follistim AQ is indicated for normal ovulatory women undergoing controlled ovarian stimulation as part of an in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle to promote pregnancy. Selected follitropin products are also used for certain types of male infertility. Gonal-F and Follistim AQ are approved for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of male infertility is not due to primary testicular failure.
For storage information, see specific product information within the How Supplied section.
Subcutaneous Injection - General information
Follitropin Alfa Lyophilisate for Solution for Injection (Gonal-F Multidose Vials)
Follitropin Alfa Lyophilisate for Solution for Injection (Gonal-F RFF Single-Dose Vials)
Follitropin Alfa Solution for Injection (Gonal-F RFF Redi-ject Pen)
Follitropin Beta Solution for Injection (Follistim AQ Cartridge with Follistim Pen)
Follitropin, r-FSH may cause gastrointestinal disorders, including abdominal discomfort (2.9%), abdominal pain (2.9% to 23.2%), lower abdominal pain (2.9%), abdominal distension (2% or more), constipation (2% or more), diarrhea (3.6%), flatulence (3.6% to 5.9%), and nausea (3.6% to 8%). Because some of these symptoms may be associated with ovarian hyperstimulation, female patients should be closely monitored.   
Central and peripheral nervous system adverse events have been reported in patients receiving follitropin, r-FSH including headache (6.7% to 26.5%) and pain (5.1%).   
General adverse events reported in patients taking follitropin, r-FSH include fatigue (2.3% to 10%) and enlarged abdomen (13.9%).   
Gynecomastia (male breast enlargement, 3.3% to 6%) and libido decrease (3%) were reported in male patients receiving follitropin, r-FSH therapy. Mastalgia (reported as breast tenderness) was noted in postmarketing reports.   
Follitropin, r-FSH therapy can result in mild to moderate uncomplicated ovarian enlargement. If substantial ovarian enlargement occurs after ovulation, sexual intercourse should be prohibited because of the risk of hemoperitoneum due to ruptured ovaries.   
Other genitourinary adverse drug reactions that may occur with recombinant follitropin therapy include intermenstrual bleeding/breakthrough bleeding (5.1%), pelvic discomfort (8.3%), pelvic pain (5.5%), uterine enlargement (2% or more), and vaginal bleeding (2% or more). Metrorrhagia has also been noted in postmarketing reports.   
An injection site reaction can occur with follitropin, r-FSH and has included injection site pain (4.8% to 11%), injection site inflammation (2.4% to 4.2%), injection site bruising (9.7%), nonspecific injection site reaction (4.2% to 6.7%), and injection site edema (2.5%).   
Serious systemic hypersensitivity reactions, including anaphylaxis, have been reported with use of follitropin, r-FSH. Symptoms have included dyspnea, facial edema, pruritus, and urticaria in postmarketing reports with follitropin, r-FSH in both men and women. If anaphylactoid reactions or other serious allergic reaction occurs, initiate appropriate supportive measures and discontinue further use of the drug. Dermatologic and hypersensitivity-related adverse reactions reported in men during trials included acne vulgaris (6.7% to 27%), rash (3.3%), and seborrhea (5%).   
Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome (ARDS), and exacerbation of asthma) have been reported in female patients treated with gonadotropins such as follitropin, r-FSH. In rare cases, severe pulmonary complications have resulted in death. Asthma exacerbation (e.g., bronchospasm and wheezing) has been noted in postmarketing reports.   
Ovarian hyperstimulation syndrome (OHSS) can also occur while receiving follitropin, r-FSH therapy and has been reported in 4.6% to 7.6% of female patients taking follitropin during clinical trials. This syndrome is a medical event distinct from uncomplicated ovarian enlargement. The syndrome is associated with a marked increase in vascular permeability which results in rapid accumulation of fluid in the peritoneal, pleural, and pericardial cavities. Some early warning signs include pelvic pain, nausea, vomiting, and weight gain. Abdominal pain, abdominal distension, diarrhea, severe ovarian enlargement, dyspnea, and oliguria have also been reported. Severe cases produce clinical signs such as gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic reactions. Transient hepatic function test abnormalities suggestive of hepatic dysfunction, with or without morphologic changes on liver biopsy, have been reported in association with OHSS. OHSS occurs after gonadotropin treatment has been discontinued and it can develop rapidly, reaching its maximum about 7 to 10 days after treatment. OHSS usually resolves spontaneously with the onset of menses. If there is evidence of OHSS prior to hCG administration, withhold hCG. Cases are more common, more severe, and more protracted if pregnancy occurs; assess patients for at least 2 weeks after hCG administration. OHSS increases the risk of injury to the ovary. Avoid pelvic examination or intercourse, as these may cause rupture of an ovarian cyst, which may result in hemoperitoneum. If OHSS develops, standard and appropriate management of OHSS should be implemented and followed. If serious OHSS occurs, stop gonadotropins, and consider the need for hospitalization. Treatment is primarily symptomatic, consisting of bed rest, fluid and electrolyte management, and analgesics. Due to the potential accentuation of diminished intravascular volume, avoid the use of diuretics except during the late phase of resolution to combat pulmonary edema. The manufacturer's product labels provide some additional informational guidance to aid OHSS management.    Ovarian torsion has been reported after receipt of follitropin, r-FSH and may be related to OHSS, pregnancy, previous abdominal surgery, ovarian torsion history, or 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.   
Infertile females patients may have tubal abnormalities that may increase the risk of ectopic pregnancy in patients who become pregnant as the result of ART. Use hCG testing and transvaginal ultrasound for early confirmation of an intrauterine pregnancy. Patients who become pregnant after ART should seek medical attention for abdominal/pelvic pain (particularly on one side); should, neck, or rectal pain; or nausea and vomiting. The risk of spontaneous fetal abortion (miscarriage) is increased with gonadotropin products, but the increased risk may be a factor of the underlying infertility.   
Some observational studies and a number of case reports gave rise to the speculation that infertility treatments might enhance the risk of new primary malignancy in female patients (i.e., breast cancer or ovarian cancer). However, infertility alone is an independent risk factor for the development of either breast or ovarian cancer. Case reports and observational studies suggesting an association of cancer to fertility treatments rarely control for other independent confounding factors such as delay in parity or family history. In one long-term cohort study of 1,197 infertile patients, the incidence of ovarian or breast cancer was not significantly elevated in the groups receiving fertility treatments versus those not treated. The breast cancer rate, in particular, was not significantly different in either group versus the general female population. Ovarian cyst (3% to 14.4%) development has been reported in patients taking follitropin, r-FSH. There have been infrequent reports of both benign and malignant ovarian neoplasms in patients who have undergone multiple drug regimens with follitropin for controlled ovarian stimulation; however, a causal relationship has not been established. Dermoid cyst (3.3%) has been reported in male patients taking follitropin, r-FSH.   
Follitropin, r-FSH is contraindicated for use in any patient with a prior history of recombinant follitropin hypersensitivity.    In addition, the Follistim AQ products may contain traces of streptomycin or neomycin and may cause hypersensitivity reactions in patients with a history of neomycin hypersensitivity or streptomycin hypersensitivity; use of Follistim AQ is contraindicated in these patients.
The use of follitropin, r-FSH requires an experienced clinician to supervise therapy. Follitropin should be used only by physicians who are experienced in infertility treatment, as these products contain a potent gonadotropic substance capable of causing various complications, including ovarian, pulmonary or vascular complications and multiple births, particularly in female patients. Follitropin therapy requires the availability of appropriate monitoring facilities.   
Recombinant follitropin, r-FSH is contraindicated in females with primary ovarian failure because it is ineffective in these patients. Prior to initiation of FSH treatment in females, patients should have a complete gynecologic and endocrinologic evaluation and diagnosis for the cause of infertility. When using these products for induction of ovulation, exclude primary ovarian failure and demonstrate tubal patency. The possibility of the patient being pregnant should be excluded. The fertility status of the male partner should be evaluated.   
Follitropin, r-FSH is contraindicated in men with normal serum gonadotropin concentrations, which indicates normal pituitary function; in primary testicular failure (indicated by increased serum gonadotropin concentrations); and for male infertility other than that resulting from hypogonadotropic hypogonadism. Prior to initiation of treatment with FSH, the male patient should have a 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. Finally, the fertility status of the female partner should be evaluated. 
Recombinant follitropin, r-FSH is contraindicated in patients with uncontrolled non-gonadal endocrinopathies (e.g., thyroid, adrenal, or pituitary disorders) and tumors of the pituitary gland or hypothalamus. Examples may include uncontrolled adrenal insufficiency, uncontrolled thyroid disease, pituitary insufficiency, or a pituitary adenoma. Uncontrolled endocrinopathies can compromise the success of fertility treatments.   
Prior to initiation of follitropin, r-FSH treatment in females, a full gynecologic exam and endocrine assessment should be performed. Except for those patients enrolled in ART programs, this should include an exam to rule out tubal pathology. Follitropin is contraindicated in female patients with ovarian enlargement or a preexisting ovarian cyst that is not due to polycystic ovarian syndrome (PCOS). Follitropin therapy should not be initiated until the diagnostic cause of the cyst or enlargement has been determined and ovary size has returned to normal. Follitropin is contraindicated for use in female patients with ovarian tumors (e.g., ovarian cancer), breast tumors (e.g., breast cancer), and uterine tumors (e.g., uterine cancer). Infrequent reports of ovarian neoplasms, both benign and malignant, have been documented in women who have undergone multiple drug regimens for controlled ovarian stimulation; however, a causal relationship has not been established.   
The use of recombinant follitropin in patients with vaginal bleeding of unknown origin is contraindicated. This may indicate the presence of endometrial hyperplasia or carcinoma which can be exacerbated by increased estrogen serum concentrations due to ovulation. Any possibility of uterine neoplasms should be ruled out before considering follitropin use. Endometrial growth may be stimulated by these fertility protocols; fertility medications should be used cautiously in patients with uterine leiomyomata (uterine fibroids) or endometriosis.   
Follitropin, r-FSH should be used extremely cautiously in female patients with active thrombophlebitis or other active thromboembolic disease. Thromboembolic events, both in association with, and separate from OHSS have been reported in female patients during and following gonadotropin therapy. Intravascular thrombosis can result in reduced blood flow to vital organs or the extremities. Women with risk factors for thrombosis (e.g. personal or family history, severe obesity, or thrombophilia) may have an increased risk of venous or arterial thromboembolic events, possibly resulting in venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), or 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 risk factors, consider the benefits of ovulation induction, in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment versus the risks of therapy. Also consider that being pregnant also carries an increased risk of thrombosis.   
Recombinant follitropin, r-FSH use is contraindicated during pregnancy. Since infertile women undergoing ART often have tubal abnormalities, the incidence of ectopic pregnancy may be increased. Early confirmation of intrauterine pregnancy should be determined by beta-hCG (pregnancy testing) and transvaginal ultrasound. Pregnancy should be ruled out prior to the administration of follitropin with each fertility treatment course. Ovarian hyperstimulation syndrome (OHSS), which may be induced by follitropin therapy, is more common, more severe, and protracted in patients who conceive. In addition to potential effects on the fetus, protocols using follitropin inherently increase the risk of multiple gestation and the risks associated with such pregnancies. The woman and her partner should be advised of the potential risks for the mother (pregnancy and delivery complications) and the neonate (low birth weight) before starting treatment. For anovulatory women undergoing ovulation induction, monitoring follicular development with transvaginal ultrasonography may aid in determining whether or not to continue the cycle in order to reduce the risk of multi-fetal gestations. The concurrent determination of serum estradiol levels may also be useful. In women undergoing IVF or ICSI procedures, the risk of multiple pregnancy is mainly related to the number of embryos transferred. The incidence of congenital malformations after IVF or ICSI may be slightly higher than after spontaneous conception, and 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. Spontaneous abortions (miscarriage) have been reported for all gonadotropin products; however, causality has not been established, but may be related to a number of factors, including the underlying infertility.   
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.   
All female patients undergoing follitropin, r-FSH treatment should be instructed to report symptoms of ovarian enlargement, including abdominal pain or pelvic pain; nausea; vomiting; ascites (fluid and distension in the abdomen); or weight gain immediately. The current cycle of fertility agents should be halted and sexual intercourse should be avoided if ovarian enlargement or ovarian hyperstimulation syndrome (OHSS) occurs or if an ovarian cyst develops. OHSS is a medical entity distinct from uncomplicated ovarian enlargement. Female patients with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment. Some patients with polycystic ovary syndrome (PCOS) are unusually sensitive to gonadotropins and may have an exaggerated response to ovarian hyperstimulation protocols. Ovarian torsion may be related to OHSS, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst, pregnancy, or polycystic ovaries.   
The safety and efficacy of recombinant follitropin have not been established in postmenopausal females and the products are not FDA-approved in this population.   
The use of follitropin pen or injector devices is not recommended for the blind or those with visual impairment without the assistance of an individual with good vision who is trained in the proper use of the injection device. 
Tobacco smoking is a lifestyle choice that may decrease fertility or the effectiveness of fertility treatments in some women and/or men. Patients should be encouraged to avoid tobacco consumption and pursue smoking cessation while pursuing fertility therapies such as the use of follitropin.
Follitropin, r-FSH is not indicated for use in adolescents, children, or infants less than 18 years of age.   
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.
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
The effect of hepatic impairment on the pharmacokinetics of follitropin, r-FSH has not been studied.
The effect of renal impairment on pharmacokinetics of follitropin, r-FSH has not been studied.
The pharmacokinetics of follitropin, r-FSH has not been studied in pediatric patients.
The pharmacokinetics of follitropin, r-FSH has not been studied in geriatric patients.
The absorption of follitropin alfa lowers as body mass index (BMI) increases.
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