Therapeutic Class

68:18 Gonadotropins and Antigonadotropins

Introduction

Gonad-stimulating hormone; biosynthetic (recombinant DNA-derived) form of human chorionic gonadotropin (hCG).Ref

Uses

See the full AHFS monograph for more information.

Female Infertility

Used in conjunction with other infertility agents (e.g., gonadotropin-releasing hormone agonist, FSH) for induction of final follicular maturation and early luteinization in ovulatory, infertile women during assisted reproductive technology (ART) programs.Ref

Use in patients with tubal obstruction only if participating in ART programs.Ref

Choriogonadotropin alfa (r-hCG) is equivalent to urinary-derived hCG with regard to number of oocytes recovered, fertilized oocytes or embryos, and live births.Ref

Used in conjunction with follicle-stimulating agent to induce ovulation in anovulatory, infertile women in whom anovulation is functional and not due to primary ovarian failure.Ref

Choriogonadotropin alfa (r-hCG) is similar to urinary-derived hCG with regard to ovulation rates.Ref

Dosage and Administration

See the full AHFS monograph for more information.

General

• Should be prescribed only by clinicians experienced in infertility treatment and who are familiar with cautions, precautions, and contraindications associated with such therapy.Ref
• Prior to treatment initiation with choriogonadotropin alfa, perform a thorough gynecologic and endocrinologic evaluation; assess pelvic anatomy and rule out early pregnancy, primary ovarian failure (as indicated by increased serum concentrations of FSH and LH and low serum estrogen concentrations), and neoplasms.Ref(See Contraindications under Cautions.) Perform a thorough diagnostic evaluation in patients who demonstrate abnormal uterine bleeding and other signs of endometrial abnormalities.Ref(See Contraindications under Cautions.) Evaluate partner’s infertility.Ref
• When ultrasound assessment and serum estradiol concentrations show sufficient follicular maturation, administer choriogonadotropin alfa 1 day after last dose of follicle-stimulating agent to complete final follicular maturation and induce ovulation.Ref
• Withhold further follicle-stimulating therapy and delay or withhold choriogonadotropin alfa if ovaries show an excessive response to treatment with gonadotropins because of increased risk of ovarian hyperstimulation syndrome (OHSS).Ref (See Ovarian Hyperstimulation Syndrome under Cautions.)
• Encourage daily sexual intercourse beginning 1 day prior to administration of choriogonadotropin alfa until ovulation occurs (as determined by rise in basal body temperature, increase in serum progesterone concentrations, and menstruation following shift in basal body temperature).Ref(See Adequate Patient Evaluation and Monitoring under Cautions.)
• Examine ovaries by ultrasound for persistent cysts, particularly when attempts at stimulation of ovulation follow immediately after unsuccessful stimulated cycle.Ref

Administration

See the full AHFS monograph for more information.

Sub-Q Administration

Administer by sub-Q injection, generally into abdomen using commercially available prefilled syringe;Ref may be self-administered by patient.Ref

Dosage

Adults

Female Infertility

ART

Sub-Q

250 mcg, given 1 day following last dose of follicle-stimulating agent.Ref(See General under Dosage and Administration.)

Ovulation Induction

Sub-Q

250 mcg, given 1 day following last dose of follicle-stimulating agent.Ref(See General under Dosage and Administration.)

If stimulation of ovulation is unsuccessful, adjust dosage of follicle-stimulating agent administered in subsequent cycles based on woman’s response in preceding cycle.Ref

Prescribing Limits

Adults

Female Infertility

Sub-Q

Maximum 500-mcg single dose studied in clinical trials.Ref

Cautions

See the full AHFS monograph for more information.

Contraindications

See the full AHFS monograph for more information.

• Known hypersensitivity to human chorionic gonadotropin preparations (including urinary-derived hCG) or any ingredient in formulation.Ref
• Primary ovarian failure.Ref
• Uncontrolled thyroid or adrenal dysfunction.Ref
• Uncontrolled organic intracranial lesions (e.g., pituitary neoplasms).Ref
• Abnormal intrauterine or vaginal bleeding of undetermined origin.Ref
• Ovarian cysts or enlargement of undetermined origin.Ref
• Sex-hormone-dependent neoplasms of reproductive tract and accessory organs.Ref
• Pregnancy.Ref

Warnings/Precautions

See the full AHFS monograph for more information.

Warnings

See the full AHFS monograph for more information.

Ovarian Enlargement

Risk of mild to moderate uncomplicated ovarian enlargement; may be accompanied by abdominal distention and/or pain, but generally regresses without treatment within 2–3 weeks.Ref Careful monitoring of ovarian response recommended.Ref

If ovaries are abnormally enlarged during controlled ovarian stimulation, withhold choriogonadotropin alfa during current course of therapy to minimize risk of OHSS.Ref(See Ovarian Hyperstimulation Syndrome under Cautions.)

Ovarian Hyperstimulation Syndrome

Risk of potentially severe OHSS, characterized by apparent dramatic increase in vascular permeability that may result in rapid accumulation of fluid in peritoneal cavity, thorax, and potentially, pericardium.Ref

May progress rapidly (within 24 hours to several days).Ref Initial manifestations include severe pelvic pain, nausea, vomiting, and weight gain.Ref Other symptoms include abdominal pain/distention, diarrhea, severe ovarian enlargement, dyspnea, and oliguria.Ref Hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events may occur.Ref

Transient liver function test abnormalities, which may be accompanied by morphologic changes (as detected by liver biopsy), reported.Ref

Occurs most often after completion of gonadotropin therapy, reaching maximum severity after 7–10 days; usually resolves spontaneously with onset of menses.Ref Monitor patients for ≥2 weeks after hCG administration.Ref OHSS may be more severe and protracted if pregnancy occurs.Ref

If severe OHSS develops, discontinue therapy, hospitalize patient, and consult clinician experienced in management of OHSS or fluid and electrolyte imbalances.Ref

Multiple Births

Multiple ovulations resulting in multiple gestations reported in 30.9 or 13.3% of women during ART programs or ovulation induction, respectively.Ref

Risk of multiple births correlates with number of embryos transferred.Ref

Thromboembolism

See the full AHFS monograph for more information.

Potential for arterial thromboembolism exists.Ref

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; exclude pregnancy before initiating treatment.Ref

Animal studies indicate adverse effects on pregnancy outcomes and/or labor.Ref(See Contraindications under Cautions.)

General Precautions

See the full AHFS monograph for more information.

Adequate Patient Evaluation and Monitoring

Administer only under supervision of qualified clinicians experienced in fertility disorders and interpretation of indices of ovulation.Ref

Monitor follicular development (e.g., using transvaginal ultrasound, serum estradiol concentrations) to correctly identify follicular maturation, determine timing of choriogonadotropin alfa administration, detect ovarian enlargement, and minimize risks of OHSS and multiple gestation.Ref

Obtain clinical confirmation of ovulation from direct and indirect indices of progesterone production, including rise in basal body temperature, an increase in serum progesterone concentrations, and menstruation following shift in basal body temperature.Ref Sonographic evidence of ovulation includes findings of fluid in cul-de-sac, ovarian stigmata, collapsed follicle, and secretory endometrium.Ref

Specific Populations

See the full AHFS monograph for more information.

Pregnancy

Category X.Ref (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)

Lactation

Not known whether choriogonadotropin alfa is distributed into milk.Ref Use caution.Ref

Pediatric Use

Safety and efficacy not established.Ref

Geriatric Use

Safety and efficacy not established.Ref

Hepatic Impairment

Safety and efficacy not established.Ref

Renal Impairment

Safety and efficacy not established.Ref

Common Adverse Effects

See the full AHFS monograph for more information.

ART: Injection site reactions (i.e., pain, bruising),Ref abdominal pain,Ref nausea,Ref vomiting,Ref postoperative pain.Ref

Ovulation induction: Injection site reactions (i.e., pain, inflammation, bruising, other injection site reaction),Ref ovarian cysts,Ref ovarian hyperstimulation,Ref abdominal pain.Ref

Drug Interactions

See the full AHFS monograph for more information.

No formal drug interaction studies to date.Ref

Laboratory Tests

Test

Interaction

Comments

Radioimmunoassays for gonadotropins

Possible cross-reaction with radioimmunoassays for gonadotropins, particularly LHRef

Individual laboratories should establish degree of cross-reactivity with their gonadotropin assayRef

When requesting gonadotropin concentration determinations, inform laboratory of choriogonadotropin alfa therapyRef

Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, absolute bioavailability is 40%.Ref Peak serum concentrations attained in 12–24 hours; detectable in serum for 10 days.Ref

Onset

Following midcycle administration, peak stimulation of luteal-phase progesterone production (as indicated by serum progesterone concentrations) occurs in approximately 5–7 days.Ref(See Actions.)

Duration

Following midcycle administration, stimulation of luteal-phase progesterone production persists for approximately 10 days.Ref

Distribution

Extent

Median apparent volume of distribution is 21.4 L in women undergoing in vitro fertilization.Ref

Elimination

Metabolism

Urinary-derived hCG extensively metabolized, principally in the liver and kidneys, to active metabolites; urinary-derived choriogonadotropin alfa (r-hCG) exhibits similar pharmacokinetics as hCG.Ref

Elimination Route

Excreted in urine principally as metabolites.Ref

Half-life

Biphasic; median terminal half-life is 29.2 hours in women undergoing in vitro fertilization.Ref

Special Populations

Pharmacokinetics not evaluated in patients with renal or hepatic impairment.Ref

Stability

Storage

Parenteral

Injection

2–8°C until dispensed.Ref Once dispensed, refrigerate prefilled syringe at 2–8°C, but may be stored at ≤25°C for ≤30 days; protect from light.Ref Discard unused portion.Ref

Actions

• A recombinant DNA-derived form of hCG prepared from genetically modified mammalian (Chinese hamster ovary) cells.Ref
• An analog of LH; has physicochemical, immunologic, and biologic activities comparable to those of urinary-derived hCG.Ref
• Substitutes for the endogenous LH surge responsible for ovulation and stimulates late maturation of the ovarian follicle, resumption of oocytic meiosis, and initiation of rupture of the preovulatory ovarian follicle.Ref Spontaneous midcycle LH surges are inconsistent during controlled ovarian stimulation.Ref
• Induces and maintains corpus luteum (as evidenced by increased serum progesterone concentrations).Ref

Advice to Patients

See the full AHFS monograph for more information.

• Importance of informing patient of potential adverse effects (e.g., OHSS, multiple gestation).Ref
• Importance of discussing duration of treatment and required monitoring procedures.Ref
• Importance of patients informing clinician if severe pain or bloating in abdominal or pelvic area, severe upset stomach, vomiting, or weight gain occurs.Ref
• Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.Ref
• Importance of women informing their clinician if they plan to breast-feed.Ref
• Importance of informing patient of other important precautionary information.Ref(See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Choriogonadotropin Alfa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use only

257.5 mcg/0.515 mL (delivers 250 mcg)

Ovidrel® (available as a 0.515-mL, disposable prefilled syringe)

Serono

References

Serono Inc. Ovidrel® (choriogonadotropin alfa) injection prescribing information. Randolph, MA; 2004 Jan.

European Recombinant Human Chorionic Gonadotropin Study Group. Induction of final follicular maturation and early luteinization in women undergoing induction for assisted reproduction treatment—recombinant HCG versus urinary HCG. Hum Reprod. 2000; 15:1446-51. [PubMed 10875887]

Driscoll GL, Tyler JP, Hanagan JT et al. A prospective, randomized, controlled, double-blind, double-dummy comparison of recombinant and urinary HCG for inducing oocyte maturation and follicular luteinization in ovarian stimulation. Hum Reprod. 2000; 15:1305-10. [PubMed 10831560]

Serono Laboratories Inc. Gonal-F® (follitropin alfa) for injection prescribing information. Randolph, MA; 1997 Sep.

Organon. Follistim® (follitropin beta) for injection prescribing information. West Orange, NJ; 1997 Sep.

Practice Committee, American Society of Reproductive Medicine. Induction of ovarian follicle development and ovulation with exogenous gonadotropins. A technical bulletin. Birmingham, AL; 1998. From ASRM website. [Web]

Institute for Clinical Systems Improvement. Diagnosis and management of infertility. Bloomington, MN; 2000 July. From the ICSI website. [Web]

Yoshida TM. Infertility update: use of assisted reproductive technology. J Am Pharm Assoc. 1999; 39:65-72.

Serono Inc: Personal communication.

Norman RJ, Buchholz MM, Somogyi AA et al. hCGβ core fragment is a metabolite of hCG: evidence from infusion of recombinant hCG. J Endocrinol. 2000; 164:299-305. [PubMed 10694369]

Trinchard-Lugan I, Khan A, Porchet HC et al. Pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotropin in healthy male and female volunteers. Reprod Biomed Online. 2002; 4:106-15.

EMD Serono. Ovidrel® (choriogonadotropin alfa) prefilled syringe FAQ’s. Rockland, MA; 2007. Available from website. Accessed 2007 Nov 27. [Web]

Serono Inc. Ovidrel® (choriogonadotropin alfa) injection prescribing information. Rockland MA; 2006 Jul.

Beckers NGM, Macklon NS, Eijkemans MJ et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab. 2003; 88:4186-92. [PubMed 12970285]

Chan CCW, Ng EHY, Tang OS et al. A prospective, randomized, double-blind study to compare two doses of recombinant human chorionic gonadotropin in inducing final oocyte maturity and the hormonal profile during the luteal phase. J Clin Endocrinol Metab. 2005; 90:3933-8. [PubMed 15870129]

European Recombinant LH Study Group. Recombinant human leuteinizing hormone is as effective as, but safer than, urinary human choriogonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study. J Clin Endocrinol Metab. 2001; 86:2607-18. [PubMed 11397861]

International Recombinant Human Chorionic Gonadotropin Study Group. Induction of ovulation in World Health Organization group II anovulatory women undergoing follicular stimulation with recombinant human follicle-stimulating hormone: a comparison of recombinant human chorionic gonadotropin (rHCG) and urinary HCG. Fertil Steril. 2001; 75:1111-8. [PubMed 11384635]

Practice Committee, American Society of Reproductive Medicine. Ovarian hyperstimulation syndrome. An educational bulletin. Fertil Steril. 2006; 86:S178-83. [PubMed 17055817]

Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update. 2002; 8:559-77. [PubMed 12498425]

Stenman U, Tiitinen A, Alfthan H et al. The classification, functions and clinical use of different isoforms of HCG. Hum Reprod Update. 2006; 12:769-84. [PubMed 16877746]

EMD Serono Laboratories Inc. Gonal-F® (follitropin alfa) for injection prescribing information. Randolph, MA; 2005 Aug.

AHFS Drug Information. McEvoy GK, ed. Choriogonadotropin Alfa. Bethesda, MD: American Society of Health-System Pharmacists.

Copyright

AHFS® DI Essentials™. © Copyright, 2004-2020, Selected Revisions June 1, 2008, American Society of Health-System Pharmacists®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

Last Updated 3/2/20