Clinical UM Guideline
|Guideline #:||CG-DRUG-11||Current Effective Date:||10/14/2014|
|Status:||Reviewed||Last Review Date:||08/14/2014|
This document addresses the use of oral, injectable and topical infertility drugs, including protocols used to treat women with ovulation disorders, drugs used as part of an Assisted Reproductive Technology (ART) treatment (most commonly through in vitro fertilization [IVF]), intrauterine insemination, and as treatment of male infertility with gonadotropins.
Note: Please see the following documents for additional information:
I. Clomiphene Citrate
Clomiphene citrate for a maximum of 6 cycles of therapy is considered medically necessary for ovulation induction in individuals who meet any of the following criteria:
Not Medically Necessary:
Clomiphene citrate is considered not medically necessary for ovulation induction in individuals who meet ANY of the following criteria:
II. Ovulation Stimulation Alone or With Intrauterine Insemination - Injectable Low Dose Follicle Stimulating Hormone (FSH) (Bravelle™, Follistim AQ®, Gonal-f®, Gonal-f®-RFF) or Menotropins (Repronex® and Menopur®)
Ovulation induction with a maximum of 3 cycles of injectable low dose FSH or menotropins, with or without intrauterine insemination, is considered medically necessary in individuals who meet ANY of the following criteria:
Not Medically Necessary:
Ovulation induction with injectable low dose FSH or menotropins is considered not medically necessary in any of the following individuals:
III. Ovarian Stimulation in Conjunction with In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) (Bravelle, Follistim AQ, Gonal-f, Gonal-f RFF, Menopur, Recombinant hCG (Ovidrel) or, Repronex, urinary derived hCG (Pregnyl, Novarel and generics), with GnRH agonists (Lupron Depot, generic leuprolide) or antagonists (Cetrotide, Ganirelix)
A maximum of 3 cycles of ovarian stimulation in conjunction with IVF or ICSI is considered medically necessary in individuals who meet ANY of the following criteria:
Not Medically Necessary:
Ovarian stimulation in conjunction with IVF or ICSI is considered not medically necessary in individuals with greater than 3 cycles of therapy.
IV. Gonadotropins for Male Infertility Associated with Hypogonadotropic Hypogonadism (Follistim AQ, Gonal-f)
Follistim AQ or Gonal-f in combination with hCG, are considered medically necessary for infertile men with hypogonadotropic hypogonadism with onset prior to completion of pubertal development.
The use of hCG alone or in combination with FSH is considered medically necessary to maintain spermatogenesis for infertile men with post-pubertal acquired hypogonadotropic hypogonadism who have previously had normal sperm production.
The use of hCG alone or in combination with FSH is considered medically necessary to maintain spermatogenesis for infertile men with partial gonadotropin deficiency.
Not Medically Necessary:
The use of gonadotropins for male infertility associated with hypogonadotropic hypogonadism is considered not medically necessary when the criteria above are not met.
V. Progesterone Vaginal Supplementation or Replacement for Infertility Treatment (Crinone 8% gel, Endometrin vaginal insert, Prochieve 8% gel)
Progesterone vaginal insert or 8% gel is considered medically necessary as part of an Assisted Reproductive Technology (ART) treatment for infertile women who require progesterone supplementation.
Not Medically Necessary:
The use of progesterone vaginal insert or 8% gel for infertile women is considered not medically necessary when the criteria above are not met.
The use of progesterone 4% gel is considered not medically necessary as part of an ART treatment for infertile women who require progesterone supplementation.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
|J0725||Injection, chorionic gonadotropin; per 1,000 USP units [Novarel, Pregnyl]|
|J1950||Injection, leuprolide acetate (for depot suspension); per 3.75 mg [Lupron]|
|J3355||Injection, urofollitropin, 75 IU [Bravelle]|
|J3490||Unclassified drugs [when specified as lutropin alfa (Luveris), cetrorelix acetate (Cetrotide), Ovidrel or other injectable for infertility treatment]|
|J8499||Prescription drug, oral, non-chemotherapeutic, NOS [when specified as clomiphene citrate (Clomid, Serophene)]|
|S0122||Injection, menotropins; 75 IU [Menopur, Repronex]|
|S0126||Injection, follitropin alfa; 75 IU [Gonal-F]|
|S0128||Injection, follitropin beta; 75 IU [Follistim ]|
|S0132||Injection, ganirelix acetate; 250 mcg [Antagon]|
|No code||Progesterone vaginal insert or gel [Crinone 8%, Endometrin, Prochieve 8%, Crinone 4%, Prochieve 4%]|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
The American Society for Reproductive Medicine (ASRM) (2008) defines infertility and states:
Infertility is a disease, defined by the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse. Earlier evaluation and treatment may be justified based on medical history and physical findings and is warranted after 6 months for women over age 35 years.
Drugs used to enhance infertility include the gonadotropin releasing hormone (GnRH), gonadotropins, human chorionic gonadotropins (hCG), and other ovulation stimulating agents such as the anti-estrogens. These agents may be used for the induction of ovulation, superovulation to produce more than one developing follicle or to stimulate multiple follicular developments in assisted reproductive techniques. Exogenous gonadotropins, in particular, have been used for ovulatory dysfunction, luteal phase defects, unexplained infertility, male factor infertility and assisted reproductive techniques (i.e., in vitro fertilization [IVF]). There are several types of gonadotropins available. Follicle stimulating hormone (FSH) is available commercially in both recombinant (Gonal-f, Gonal-f RFF and Follistim AQ) and a urinary-derived preparation (Bravelle). Products containing both FSH and LH are also available (Menopur, Repronex). A pure luteinizing hormone product (Luveris) is commercially available for the treatment of individuals with hypogonadotropin anovulatory disorders or hypopituitarism.
Categories of infertility drugs with pharmacologic actions are summarized in the following table:
|Menotropins: FSH and LH|
|The FSH and LH present in menotropin products produce ovarian follicular growth and maturation in women without primary ovarian failure.|
|Follitropin and Urofollitropins: FSH|
(Follistim AQ, Gonal-f/ RFF, Bravelle)
|The FSH present in follitropin and urofollitropin products produce ovarian follicular growth and maturation in women without primary ovarian failure.|
|Lutropin alfa: r-LH|
|In the ovaries, during the follicular phase, LH stimulates the cells to secrete androgens which in turn facilitate the production of estradiol. Estradiol helps support FSH-induced follicular development. LH is also thought to help with embryo implantation. Exogenous LH is administered with follitropin or urofollitropins in ART protocols or in infertile women with a documented LH deficiency.|
|Human chorionic gonadotropins (hCG) Urinary-derived hCG|
(Pregnyl, Novarel and generics
Recombinant hCG (Ovidrel)
|Sole use of menotropins, follitropins or urofollitropins will result in an undesirable endogenous LH surge and premature egg release. Administration of hCG after treatment with these products will suppress the LH surge, thus facilitating final follicular development, maturation and ovulation.|
|Gonadotropin-releasing hormone (GnRH) antagonists are used to suppress premature luteinizing hormone (LH) surges during ART. LH surge suppression prevents eggs from being released prematurely. Protocols using GnRH antagonists are referred to as "short protocols" as these agents allow for shorter treatment times.|
|GnRH analogs or agonists|
(Lupron Depot® and generic leuprolide acetate)
|Administration results in an initial release of endogenous LH and FSH release, but chronic daily administration (as in ART) results in suppression of endogenous LH and FSH release. Pre-treatment with GnRH analogs in ART prevents the endogenous LH surge which would occur if menotropins, follitropin or urofollitropin were used alone. Protocols using GnRH analogs are referred to as "long protocols" as use of these agents results in longer treatment times.|
(Clomid®, Serophene® and generics)
|Clomiphene binds to estrogenic receptors and thus decreases the number of available receptors. The hypothalamus and pituitary respond to this antiestrogenic effect by releasing additional LH, FSH and gonadotropins, resulting in ovarian stimulation.|
|Progesterone vaginal supplementation or replacement|
(Crinone 8% gel, Endometrin vaginal inserts, Prochieve 8% gel)
|Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone functions to maintain the pregnancy. Vaginal supplementation or replacement of progesterone is used in ART protocols for infertile women who require progesterone supplementation.|
FSH= Follicle stimulating hormone; LH= luteinizing hormone; r-LH= recombinant luteinizing hormone; hCG= human chorionic gonadotropins; ART= assisted reproductive technology; GnRH = gonadotropin releasing hormone
For women with ovulation failure, or in those with unexplained infertility, typically the initial therapy focuses on ovarian stimulation with clomiphene citrate (CC), with or without intrauterine insemination (IUI). There is a lack of evidence in support of having two IUI's on successive days as compared to a single well timed IUI.
Women with stage I-II endometriosis who undergo IUI and controlled ovarian hyperstimulation are typically more likely to conceive than those who try conceiving without such assistance. The ASRM (2012) in an opinion paper on endometriosis and infertility issued conclusions including the following:
In 2013, the ASRM reported the following summary and conclusions regarding the use of CC in women:
In addition, the ASRM (2013) stated that if CC is used to induce ovulation, pregnancy is most likely to occur in the first 3 to 6 cycles, and therapy beyond 6 cycles is generally not recommended. ACOG (2002) advises that there is no benefit to increasing the dosage of clomiphene once ovulation has occurred or to continuing beyond six months of treatment.
Zain and colleagues (2009) reported on a randomized controlled trial comparing clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with PCOS. The authors concluded their study demonstrated that clomiphene citrate is superior to metformin in inducing ovulation in anovulatory women with PCOS.
IVF procedures require initial ovarian stimulation with menotropins, FSH products, either gonadotropin release hormone (GnRH) agonists or antagonists to prevent the normal endogenous LH surge, and finally human urinary or recombinant chorionic gonadotropin at the end of the cycle to cause final follicle maturation. Protocols vary, and during the last decade the trend in infertility management has been toward a greater use of recombinant products. For example, recombinant FSH (rFSH) products (Gonal-f, Gonal f- RFF, Follistim AQ) are now available and are an alternative to the purified urine-derived FSH (Bravelle) and the urine-derived menotropins (Repronex, Menopur). It was anticipated that the use of rFSH products would result in better, more consistent clinical outcomes, such as clinical pregnancy rate and live birth rate, the final health outcome. However, a recent Cochrane review reported that there was no significant difference in live birth rates or other secondary outcomes, including number of oocytes retrieved. Safety and tolerability of urine-derived and recombinant products appear to be similar (Van Wely, 2005). All gonadotropin cycles should be carefully monitored with ultrasound to decrease the risk of multiple pregnancies and ovarian hyperstimulation syndrome (Aboulghar, 2001; ACOG 2002; Dickey, 2005; Eijkemans, 2003; Hughes, 2003; Yang, 1998). Protocols may include the use of either urine derived formulations of FSH (Bravelle) or menotropins containing FSH and LH (Repronex, Menopur) or recombinant FSH products (Gonal-f, Gonal-f RFF, Follistim AQ). Reviews and meta-analysis have shown that urine derived and recombinant products have equivalent outcomes (clinical pregnancy, live birth rate, number of oocytes retrieved). The safety and tolerability are also similar (Al-Inany, 2005; Von Welty, 2005).
Another key component of an IVF cycle is suppression of the normal endogenous LH surge in order to suppress premature release of eggs. As noted in the above table, either GnRH agonists or antagonists can be used. When agonists are used, the protocol is known as a "long protocol," since longer treatment times are required, compared to the use of GnRH antagonists, known as a "short protocol." In the United States, leuprolide (Lupron Depot) is the only available GnRH agonist, while two GnRH antagonist products (Cetrotide, Ganirelix) are available. The use of GnRH antagonists is associated with a shorter treatment cycle compared to agonists (i.e., short vs. long protocol), however, recent reviews have reported that use of GnRH antagonists (i.e., short protocol) is associated with a lower clinical pregnancy rate compared to GnRH agonists (i.e., long protocol) (Al-Inany, 2002).
In the final stage of IVF protocols, human chorionic gonadotropin (hCG) is administered to prompt final follicle maturation. HCG is available in a urine-derived formula (Pregnyl, Novarel and generic urinary hCG) and a recombinant form (Ovidrel). Similarly, a Cochrane review found no difference in follicular maturation/quality and live birth rates between the urine-derived and recombinant formulations (Al-Inany, 2005). Safety and tolerability of urine-derived and recombinant products appear to be similar.
One recombinant luteinizing hormone (r-LH) formulation is available (Luveris). The labeled indication for Luveris identifies only a very small subset of infertile women, i.e. those hypogonadal women with a profound LH deficiency (Burgues, 2001; European Recombinant Human LH Study Group, 1998). While Luveris is useful for this small population, there is no data to support its use for other more common causes of infertility. For example, purified urine preparation of FSH will contain some LH, while recombinant FSH contains none. Therefore, some physicians may suggest that Luveris has a role in "adding back" LH to those women treated with recombinant FSH. There is inadequate data to support this practice as studies have shown no benefit in improving pregnancy or live birth rates by the addition of Luveris to ART protocols (De Placido, 2005; Fabregues, 2006; Sauer, 2004).
Progesterone intravaginal supplementation has been found in several studies to have benefits in promoting fertility (Ho, 2008; Check, 2009). Crinone 8% and Prochieve 8% are both vaginal progesterone gels and Endometrin is a vaginal progesterone tablet. Crinone 8% and Prochieve 8% are FDA approved for progesterone supplementation or replacement as part of an ART treatment for women with a progesterone deficiency who are undergoing fertility treatment. Crinone 4% and Prochieve 4% are not FDA approved for use as part of an ART treatment. Endometrin is FDA approved to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an ART treatment program for infertile women.
Assisted reproductive technology (ART): Refers to fertility treatments in which embryos, eggs, or both the eggs and sperm are handled. Not included in ART is artificial insemination using sperm from either a woman's partner or a sperm donor.
Fecundity: The ability to produce offspring.
Intrauterine insemination: A procedure for treating infertility in which washed and concentrated sperm are placed directly into the uterus.
In vitro fertilization (IVF): A fertility treatment that involves the transfer of fertilized human eggs into a woman's uterus.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
Assisted Reproductive Technology (ART)
Chorionic Gonadotropin Alfa, Recombinant
Follicle Stimulating Hormone
Follicle Stimulating Hormone/Luteinizing Hormone
Intracytoplasmic sperm injection (ICSI)
Intrauterine insemination (IUI)
In Vitro Fertilization (IVF)
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||08/14/2014||Medical Policy & Technology Assessment Committee (MPTAC) review. Discussion and Reference sections updated.|
|Revised||08/08/2013||MPTAC review. Position statement for clomiphene citrate updated to include stage I or II endometriosis as medically necessary. Description, Rationale, and Reference sections updated.|
|Reviewed||11/08/2012||MPTAC review. Reference section updated.|
|Revised||11/17/2011||MPTAC review. Coding, Description, Discussion, Reference, and Index sections updated. Definition section added. Reformatted clinical indications. Clarified clinical indication II by replacing "gonadotropins" with "menotropins". Updated clinical indication III with additional drugs. Minor clarifications made to clinical indications IV and V. Title updated to Infertility Drugs.|
|Revised||11/18/2010||MPTAC review. Title updated to Oral, Injectable and Topical Infertility Drugs. Discussion, References, Coding and Index sections updated. Added a medically necessary statement for progesterone vaginal insert or 8% gel. Added a not medically necessary statement for progesterone vaginal insert or 8% gel and a not medically necessary statement for progesterone 4% gel.|
|Reviewed||11/19/2009||MPTAC review. Discussion, references and note under description updated. Place of service and case management sections removed from document.|
|Reviewed||11/20/2008||MPTAC review. Description, references and index updated. Added the word "induction" after "ovulation" in the not medically necessary statement of clinical indication II for clarification. Position stance was not changed.|
|Revised||11/29/2007||MPTAC review. References, index and coding updated. Added not medical necessary statement to clinical indication IV. Gonadotropins for Male Infertility Associated with Hypogonadotropic Hypogonadism.|
|Revised||12/07/2006||MPTAC review. References updated. Added index. Coding updated; removed HCPCS Q2018 deleted 12/31/05.|
|Revised||12/01/2005||MPTAC review. Removed age limits; added clarification to some clinical indications.|
|New||09/22/2005||MPTAC initial guideline development.|