Nafarelin Acetate

Pharmacy Benefit Coverage Criteria

Effective Date ...... 11/1/2020 Next Review Date… ...... 11/1/2021 Coverage Policy Number ...... P0082

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 Somatropin FDA Approved Indications ...... 2 Treatment of Gender Dysphoria Recommended Dosing ...... 2 Background ...... 3 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria

Nafarelin acetate (Synarel®) nasal solution is considered medically necessary when EITHER of the following criteria are met (1 or 2):

1. Treatment of children with central precocious puberty (CPP) with onset of secondary sexual characteristics earlier than 8 years in females and 9 years in males when ONE of the following criteria is met: • Pubertal basal level of luteinizing hormone (LH) greater than or equal to 0.3 mIU/ml • Pubertal luteinizing hormone (LH) response to GnRH stimulation confirming the diagnosis of central precocious puberty.

2. Management of endometriosis

For central precocious puberty (CPP), initial authorization is up to 12 months.

Reauthorization of nafarelin acetate (Synarel) nasal solution for central precocious puberty (CPP) is considered medically necessary when the following are met: • Pretreatment clinical condition met the initial criteria

Page 1 of 4 Pharmacy Benefit Clinical Criteria: P0082 • Individual is younger than the appropriate time point for the onset of puberty (for example: 11 years for females and 12 years for males)

For central precocious puberty (CPP), reauthorization is up to 12 months.

For endometriosis, authorization is for a single course of therapy up to 6 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Nafarelin acetate (Synarel) nasal solution is considered experimental, investigational or unproven for ANY other use including the following: • Concomitant use with recombinant growth hormone (GH) to prolong the pre-pubertal state

Note: Receipt of sample product does not satisfy any criteria requirements for coverage

FDA Approved Indications

FDA Approved Indication Synarel is indicated for treatment of central precocious puberty (CPP) (gonadotropin-dependent precocious puberty) in children of both sexes.

The diagnosis of central precocious puberty (CPP) is suspected when premature development of secondary sexual characteristics occurs at or before the age of 8 years in girls and 9 years in boys, and is accompanied by significant advancement of bone age and/or a poor adult height prediction. The diagnosis should be confirmed by pubertal gonadal sex steroid levels and a pubertal LH response to stimulation by native GnRH. Pelvic ultrasound assessment in girls usually reveals enlarged uterus and ovaries, the latter often with multiple cystic formations. Magnetic resonance imaging or CT-scanning of the brain is recommended to detect hypothalamic or pituitary tumors, or anatomical changes associated with increased intracranial pressure. Other causes of sexual precocity, such as congenital adrenal hyperplasia, testotoxicosis, testicular tumors and/or other autonomous feminizing or masculinizing disorders must be excluded by proper clinical hormonal and diagnostic imaging examinations.

Synarel is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. Experience with Synarel for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.

Recommended Dosing

FDA Recommended Dosing For the management of endometriosis, the recommended daily dose of Synarel is 400 μg. This is achieved by one spray (200 μg) into one nostril in the morning and one spray into the other nostril in the evening. Treatment should be started between days 2 and 4 of the menstrual cycle.

In an occasional patient, the 400 μg daily dose may not produce amenorrhea. For these patients with persistent regular menstruation after 2 months of treatment, the dose of SYNAREL may be increased to 800 μg daily. The 800 μg dose is administered as one spray into each nostril in the morning (a total of two sprays) and again in the evening.

The recommended duration of administration is six months. Retreatment cannot be recommended since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with Synarel is contemplated, it is recommended that bone density be assessed before retreatment begins to ensure that values are within normal limits.

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There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of Synarel; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with Synarel, the decongestant should not be used until at least 2 hours following dosing with Synarel.

At 400 μg/day, a bottle of Synarel provides a 30-day (about 60 sprays) supply. If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the recommended duration of therapy. For the treatment of central precocious puberty (CPP), the recommended daily dose of Synarel is 1600 μg. The dose can be increased to 1800 μg daily if adequate suppression cannot be achieved at 1600 μg/day.

The 1600 μg dose is achieved by two sprays (400 μg) into each nostril in the morning (4 sprays) and two sprays into each nostril in the evening (4 sprays), a total of 8 sprays per day. The 1800 μg dose is achieved by 3 sprays (600 μg) into alternating nostrils three times a day, a total of 9 sprays per day. The patient’s head should be tilted back slightly, and 30 seconds should elapse between sprays.

If the prescribed therapy has been well tolerated by the patient, treatment of CPP with Synarel should continue until resumption of puberty is desired.

At 1600 μg/day, a bottle of Synarel provides about a 7-day supply (about 56 sprays). If the daily dose is increased, increase the supply to the patient to ensure uninterrupted treatment for the duration of therapy.

Sneezing during or immediately after dosing with Synarel should be avoided, if possible, since this may impair drug absorption.

Drug Availability Each 0.5 ounce bottle contains 8 mL Synarel (nafarelin acetate) Nasal Solution 2 mg/mL (as nafarelin base), and is supplied with a metered spray pump that delivers 200 μg of nafarelin per spray.

Background

Professional Societies/Organizations American Academy of Pediatrics American Academy of Pediatrics (AAP) guidelines on the evaluation and referral of children with signs of early puberty recommends treatment with Gonadotropin Releasing Hormones (GnRH) agonists, such as leuprolide, may be administered either with an injection at monthly or 3-month intervals or with an annual subcutaneous histrelin implant. AAP recommends that therapy should be continued until the physician determines that continued pubertal suppression is no longer a benefit to the child. (Kaplowitz, 2016)

For suspected central precocious puberty, the diagnostic evaluation will normally include a bone age determination. Baseline laboratory testing may include the following: FSH, LH, and either estradiol or testosterone. An LH of greater than 0.3 IU/L is the most reliable screening test on a random sample of blood, however if it is less than 0.3 and CPP is suspected, a GnRH analog stimulation test may be necessary. (Kaplowitz, 2016)

American College of Obstetrics and Gynecologists American College of Obstetrics and Gynecologists (ACOG) guidelines state that medical suppressive therapies (such as combined oral contraceptives, progestins, GnRH agonists, androgens) may help alleviate pain symptoms; however, the rate of symptom recurrence is high after discontinuing the medication. Oral contraceptives and NSAIDs are used as initial treatment of endometriosis. If a patient experiences treatment failure with these agents then a trial with a GnRH agonist may be appropriate. The FDA has approved the use of a 12-month course of GnRH agonist therapy, however, guidelines state that in patients who responded well to

Page 3 of 4 Pharmacy Benefit Clinical Criteria: P0082 previous GnRH agonist therapy, long-term treatment with add-back therapy (progestins alone, progestins and bisphosphonates, low dose progestins, and estrogens) has been reported. (ACOG 2010, Armstrong 2010)

American Society for Reproductive Medicine American Society for Reproductive Medicine (ASRM) committee opinion for the treatment of pelvic pain associated with endometriosis recommends that endometriosis be viewed as a chronic disease that requires a lifelong plan to manage with the goal to maximize use of medical treatment and avoid repeated procedures which are surgical in nature. ASRM recommends definitive diagnosis using laparoscopic surgery with the option of treating visible endometriosis at that same time. Pharmacologic therapies (such as NSAIDs, combined hormonal contraceptives, progestins, danazol, GnRH agonists) are recommended for endometriosis treatment. (ASRM, 2014)

Off label uses: AHFS Drug Information 2020 Edition does not support any off-label uses of nafarelin.

References

1. American College of Obstetricians and Gynecologists. ACOG practice bulletin: Alternatives to hysterectomy in the management of leiomyomas. Obstet Gyneco.l 2008;112:387-400. 2. AHFS Drug Information 2019 Edition 3. Armstrong C. ACOG updates guideline on diagnosis and treatment of endometriosis. Am Fam Physician. 2011;83(1):84-85. 4. Kaplowitz P, Bloch C. Evaluation and referral of children with signs of early puberty. Pediatrics. 2016;137(1):e20153732. 5. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2018. 6. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: A committee opinion. Fertil Steril. 2014;101(4):927-935. 7. Synarel (nafarelin acetate) nasal solution Prescribing Information, New York, NY: Pfizer; December 2017.

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