JATENZO TESTOPEL, Testosterone Form

Testosterone pellet (Testopel®) is an implantable androgen. Testosterone undecanoate capsule (Jatenzo®, Kyzatrex, Tlando™) is an oral androgen. ____ *For Health Insurance Marketplace (HIM), if request is through pharmacy benefit, Testopel is a pharmacy benefit exclusion; refer to evidence of coverage documents. FDA Approved Indication(s) Testopel is indicated for: • Replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone: o Primary hypogonadism (congenital or acquired) - testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome, or orchiectomy o Hypogonadotropic hypogonadism (congenital or acquired) - gonadotropic lutenizing hormone-releasing hormone (LHRH) deficiency, or pituitary - hypothalamic injury from tumors, trauma, or radiation • Treatment of delayed puberty in carefully selected males Jatenzo, Kyzatrex, and Tlando are indicated for: • Replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: o Primary hypogonadism (congenital or acquired) - testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testes syndrome, or orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals o Hypogonadotropic hypogonadism (congenital or acquired) - gonadotropic LHRH deficiency, or pituitary - hypothalamic injury from tumors, trauma, or radiation Limitation(s) of use:
• Testopel: Safety and efficacy of Testopel in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established.
• Jatenzo, Kyzatrex, and Tlando: Safety and efficacy in males less than 18 years old have not been established. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
Page 1 of 11

CLINICAL POLICY Testosterone It is the policy of health plans affiliated with Centene Corporation® that Testopel, Jatenzo, Kyzatrex, and Tlando are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Hypogonadism (must meet all):

1. Diagnosis of primary hypogonadism or hypogonadotropic hypogonadism;
   2. If request is for Jatenzo, Kyzatrex, or Tlando, age ≥ 18 years;
   3. Documentation of serum testosterone level < 300 ng/dL on at least 2 separate days within the last 6 months;
2. Member must use transdermal testosterone (e.g., patch, gel), unless clinically significant adverse effects are experienced or all are contraindicated;
3. Member must use injectable testosterone, unless clinically significant adverse effects are experienced or all are contraindicated;
4. Dose does not exceed one of the following (a, b, c, or d):
   a. For Testopel: 450 mg (6 pellets) every 3 months;
   b. For Jatenzo, both of the following (i and ii):
   i. 792 mg per day; ii. 4 capsules per day; c. For Kyzatrex, both of the following (i and ii):
   i. 800 mg per day; ii. 4 capsules per day; d. For Tlando: 450 mg (4 capsules) per day. Approval duration:
   Testopel – 6 months All other agents – 12 months
   B. Delayed Puberty (must meet all):
   1. Diagnosis of delayed puberty;
   2. Request is for Testopel;
   3. Prescribed by or in consultation with an endocrinologist;
   4. Member must use injectable testosterone, unless clinically significant adverse effects are experienced or all are contraindicated;
5. Dose does not exceed 450 mg (6 pellets) every 3 months. Approval duration: 6 months C. Gender Dysphoria, Female-to-Male Transition (off-label) (must meet all):

6. Diagnosis of gender dysphoria or request is for gender transition;

   2. Prescribed by or in consultation with both of the following (a and b): a. An endocrinologist;
      b. A provider with expertise in gender dysphoria and transgender medicine based on a certified training program or affiliation with local transgender health services Page 2 of 11

   CLINICAL POLICY Testosterone (e.g., mental health professional such as psychologist, psychiatrist, see Appendix D);

7. Member meets one of the following (a or b): a. For Testopel, both of the following (i and ii):
   i. Medical justification supports inability to use transdermal (e.g., patch, gel) testosterone; ii. Medical justification supports inability to use injectable testosterone; b. For Jatenzo and Kyzatrex, both of the following (i and ii):
   i. Age ≥ 18 years; ii. Failure of two formulary testosterone products (e.g., transdermal, intramuscular or subcutaneous injection), at up to maximally indicated doses, unless clinically significant adverse effects are experienced or all are contraindicated;
8. Member demonstrates understanding of expected testosterone treatment outcomes and has given consent for such treatment;
9. If member has a psychiatric comorbidity, member is followed by mental health provider;
10. Psychosocial support will be provided during treatment;
    7. Dose is within FDA maximum limit for any FDA-approved indication (see Section V) or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
       Approval duration: 6 months D. Other diagnoses/indications (must meet 1 or 2):
11. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or
    2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
       II. Continued Therapy A. Hypogonadism (must meet all):

12. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; Page 3 of 11

    CLINICAL POLICY Testosterone b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);

    2. Member is responding positively to therapy;
    3. If request is for a dose increase, new dose does not exceed one of the following (a, b, c, or d): a. For Testopel: 450 mg (6 pellets) every 3 months;
       b. For Jatenzo, both of the following (i and ii):
       i. 792 mg per day; ii. 4 capsules per day; c. For Kyzatrex, both of the following (i and ii):
       i. 800 mg per day; ii. 4 capsules per day; d. For Tlando: 450 mg (4 capsules) per day. Approval duration:
       Testopel – 6 months All other agents – 12 months
       B. Delayed Puberty:
13. Re-authorization is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable C. Gender Dysphoria, Female-to-Male Transition (off-label) (must meet all):
14. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
15. Member is responding positively to therapy (e.g., developing a masculinized body while minimizing feminine characteristics, consistent with member’s gender goals);
16. If request is for a dose increase, new dose is within FDA maximum limit for any FDA-approved indication (see Section V) or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
    Approval duration: 12 months D. Other diagnoses/indications (must meet 1 or 2):

17. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or Page 4 of 11

    CLINICAL POLICY Testosterone b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or

    2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
       III. Diagnoses/Indications for which coverage is NOT authorized:
       A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid, or evidence of coverage documents; B. Age-related hypogonadism or late-onset hypogonadism.
       IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration LHRH: luteinizing hormone-releasing hormone Appendix B: Therapeutic Alternatives
       This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
       Drug Name Dosing Regimen Dose Limit/ Maximum Dose 400 mg every 2 to 4 weeks 400 mg every 2 to 4 weeks 100 mg/day 81 mg/day 70 mg/day
       testosterone cypionate injection testosterone enanthate injection testosterone 1% gel (AndroGel®) testosterone 1.62% gel (AndroGel®) testosterone 2% gel (Fortesta®) Male hypogonadism: 50 to 400 mg IM once every 2 to 4 weeks Male hypogonadism: 50 to 400 mg IM once every 2 to 4 weeks Males with delayed puberty: 50 to 200 mg every 2 to 4 weeks for a limited duration, for example, 4 to 6 months. Male hypogonadism: Starting dose: 50 mg applied topically QD. Dose may be titrated to a maximum of 100 mg QD based on serum testosterone level. Male hypogonadism: Starting dose: 40.5 mg applied topically QD. Dose may be titrated to a maximum of 81 mg QD based on serum testosterone level. Male hypogonadism: 40 mg (4 pump actuations) applied topically QD to the thighs. Dose may be titrated to a maximum Page 5 of 11

    CLINICAL POLICY Testosterone Drug Name Dosing Regimen Dose Limit/ Maximum Dose of 70 mg (4 pump actuations on one thigh and 3 pump actuations on the other thigh) QD based on serum testosterone level. Dose should be titrated to maintain serum testosterone in the range of 500-1250 ng/dL. Male hypogonadism: 1 patch topically nightly for 24 hours testosterone transdermal patch (Androderm®) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. 1 patch/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
    o Men with known carcinoma of the breast or known or suspected carcinoma of the prostate o Pregnant women o Jatenzo, Kyzatrex: hypersensitivity to product or ingredients o Tlando: hypogonadal conditions not associated with structural or genetic etiologies • Boxed warning(s):
    o Jatenzo, Kyzatrex: increases in blood pressure Appendix D: General Information • Per the Endocrine Society (2018), the diagnosis of hypogonadism requires unequivocally and consistently low testosterone levels on at least 2 separate mornings. Although the lower limit of normal for testosterone can vary depending on the laboratory used, clinical trials for a number of testosterone agents defined it as < 300 ng/dL. Additionally, the American Urological Association suggests < 300 ng/dL as a reasonable cut-off in support of low testosterone diagnosis (2018). • Patients with primary hypogonadism usually have low serum testosterone concentrations and gonadotropins (follicle stimulating hormone and luteinizing hormone) above the normal range. Patients with hypogonadotropic hypogonadism have low serum testosterone concentrations but have gonadotropins in the normal or low range.
    • Androgens may be used cautiously to stimulate puberty in carefully selected patients with clearly delayed puberty. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support.
    • Testopel implantation has much less flexibility for dosage adjustment than oral administration or intramuscular injections of oil solutions or aqueous suspensions, requires surgical removal if testosterone should be discontinued, and carries a risk of sloughing out of the skin. • WPATH offers their Global Education Institute (GEI) Certified Training Courses: Best Practices in Transgender Medical and Mental Health Care. Additionally, the following link provides a search tool to locate WPATH member providers: https://www.wpath.org/provider/search Page 6 of 11

    CLINICAL POLICY Testosterone • Transgender Care Therapy Certification Training is also offered by the International Transgender Certification Association (ITCA). Professionals with expertise in transgender care can be located using the following search tool: https://transgendercertification.com/locate-a-professional/ • The WPATH Standards of Care Version 8 recommend that adolescents are managed by a multidisciplinary care team that involves both medical and mental health professionals. The list of key disciplines includes but is not limited to: adolescent medicine/primary care, endocrinology, psychology, psychiatry, speech/language pathology, fertility, social work, support staff, and the surgical team. The need to include a healthcare professional with some expertise in mental health does not dictate the inclusion of a psychologist, psychiatrist or social work in every assessment. Instead, a general practitioner, nurse or other qualified clinician could fulfill this requirement as long as they have sufficient expertise to diagnose gender incongruence, recognize mental health concerns, distinguish between these concerns and gender dysphoria, incongruence or diversity, assist a transgender person in care planning and preparing for gender affirmative medical and surgical treatments, and refer to a mental health professional if needed. V. Dosage and Administration
    Drug Name Dosing Regimen Testopel 150 to 450 mg (2 to 6 pellets) SC every 3 to 6 months Maximum Dose 450 mg (6 pellets) every 3 months For every 25 mg/week of testosterone propionate, 150 mg (2 pellets) should be implanted every 3 to 6 months.
    If testosterone therapy needs to be discontinued (e.g., for severe adverse reactions), the pellets may need to be removed by a health care professional. Dosages in delayed puberty generally are in the lower range of that listed above and, for a limited duration, for example 4 to 6 months. Starting dose: 237 mg PO BID Adjust the dose based on serum testosterone levels Starting dosage: 200 mg PO BID Adjust the dosage to a minimum of 100 mg once in the morning and a maximum of 400 mg BID based on serum testosterone drawn 3 to 5 hours after the morning dose at least 7 days after starting treatment or following dose adjustment and periodically thereafter 225 mg (two 112.5 mg capsules) PO BID 792 mg/day 800 mg/day 450 mg/day Jatenzo Kyzatrex Tlando Page 7 of 11

    CLINICAL POLICY Testosterone VI. Product Availability
    Drug Name Availability Testopel Jatenzo Kyzatrex Tlando Pellet for implantation: 75 mg Oral capsules: 158 mg, 198 mg, 237 mg Oral capsules: 100 mg, 150 mg, 200 mg Capsules: 112.5 mg VII.