To provide guidelines and criteria for the review and decision determination of requests for medications that requires prior authorization. Background Information: Medication Summary Femtara (Letrozole) • Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits
the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
• Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the
cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
• Indications: adjuvant treatment of early breast cancer, extended adjuvant treatment of early
breast cancer, first and second line treatment of advanced breast cancer.
• The recommended dose of Femara is one 2.5 mg tablet administered once a day, without
Arimidex (Anastrozole) • Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers
serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
• Arimidex is indicated for: adjuvant treatment of postmenopausal women with hormone
receptor-positive early breast cancer, first line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer, treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.
• The dose of arimidex is one 1 mg tablet taken once a day. For Members with advanced breast
cancer, arimidex should be continued until tumor progression. Arimidex can be taken with or without food.
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) Background Information, continued: Reference Statement • Guidelines are compiled from available US Food and Drug Administration (FDA) approved
indications, general practice guidelines, and/or evidence-based uses established through phase III clinical studies without published conflicting data. Only clinical studies published in their entirety in reputable peer-reviewed journals will be evaluated.
• Member must be eligible and have applicable benefit coverage (i.e., self-injectable rider)
within the specified date(s) of service.
• Prior authorization requests that do not meet clinical criteria in this Procedure will be
forwarded to a Clinical Pharmacist for review.
Request for initiation of therapy with Aromatase inhibitors for breast cancer requires documentation from the Member’s medical records maintained by the requesting independent practitioner:
Aromatase inhibitors are approvable for 12 months.
Request for initiation of therapy with Aromatase inhibitors for infertility/ovulation induction requires documentation from the Member’s medical records maintained by the requesting independent practitioner verifying the following:
Member has infertility benefits per BDS (Miami-Dade POS only at this time);
Documentation of recent negative pregnancy test AND normal liver function test;
If criteria are met, approve for six (6) months (5-10 tablets / 28 days).
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) Procedure, continued: 3.0
Request for initiation of therapy with Aromatase inhibitors for short stature requires documentation from the Member’s medical records maintained by the requesting independent practitioner verifying the following:
More than one (1) year since completion of successful malignancy treatment;
Member has not achieved a height consistent with mid-parental height (an average of mother’s and father’s heights);
Growth rate greater than 2.5cm/year on growth hormone therapy;
Member must be in puberty and meet ALL of the following criteria:
3.10.1 10 to 18 years of age; 3.10.2 Tanner stage two (2) to five (5) OR Testis volume greater than 4 ml;
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) Procedure, continued:
Request for initiation of therapy with Aromatase inhibitors for short stature requires documentation from the Member’s medical records maintained by the requesting independent practitioner verifying the following, continued:
Member must have one (1) of the following diagnoses:
3.11.1 Growth hormone deficiency (GHD) AND meets the following criteria:
184.108.40.206 Two (2) growth hormone provocation tests (with insulin,
propranolol, levodopa, arginine, clonidine, or glucagon) with post-stimulation peaks <10ng/ml (one (1) growth hormone provocation test if member has defined central nervous system pathology); AND
220.127.116.11 Height <3rd percentile; AND 18.104.22.168 Growth rate <4cm/year; AND 22.214.171.124 Bone age > 2 years behind actual age;
3.11.2 Small for gestational age (SGA) AND meets the following criteria:
126.96.36.199 Child’s birth weight, birth length, or both more than two (2) SD
below the mean normal values following adjustment for age and gender; AND
188.8.131.52 Age >2 years; AND 184.108.40.206 Current height ≥2SD adjusted mean normal values;
3.11.3 Prader-Willi Syndrome (PWS) or Noonan Syndrome (NS) or Short
stature homeobox-containing gene (SHOX) AND meets the following criteria:
220.127.116.11 Confirmed diagnosis by genetic testing; 18.104.22.168 Height <3rd percentile; AND 22.214.171.124 Growth rate <4cm/year; AND 126.96.36.199 Epiphyses confirmed open via wrist film;
If the above criteria are met, Aromatase Inhibitors are approvable for 12 months (30 tablets / 30 days).
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) Procedure, continued: 4.0
Request for continuation of therapy with Aromatase inhibitors for GHD, SGA, PWS, NS, SHOX requires documentation from the Member’s medical records maintained by the requesting independent practitioner verifying the following: 4.1 Prescriber is an endocrinologist; 4.2 Member is less than 18 years of age;
4.5 More than one (1) year since completion of successful malignancy treatment;
Member has not achieved a height consistent with mid-parental height (an average of mother’s and father’s heights);
4.7 Growth rate greater than 2.5cm/year on growth hormone therapy; 4.8 No hepatic impairment;
Member must be in puberty and meet ALL of the following criteria: 4.10.1 Ten (10) to eighteen (18) years of age; 4.10.2 Tanner stage two (2) to five (5) OR Testis volume greater than 4 ml; 4.10.3 Bone age greater than 14;
Member meets the following criteria: 4.11.1 Pre-treatment growth rate doubled; OR 4.11.2 Growth rate greater than 2.5cm/year; AND 4.11.3 Epiphyses confirmed open via wrist film;
Documentation has been submitted for lipid panel AND bone mineral density test;
If above criteria are met, Aromatase Inhibitor is approvable for 12 months (30 tablets / 30 days).
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) References: 1. Femara Prescribing Information. Novartis Pharmaceuticals Corp. East Hanover, NJ. June
2. Arimidex Prescribing Information. AstraZeneca Pharmaceuticals LP. Wilmington, DE.
3. Badawy, A, Elnashar, A, Totongy, M. Clomiphene citrate or aromatase inhibitors for
superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fertil Steril 2009 Oct; 92(4): 1355-9.
4. Bedaiwy, MA, Forman, R, Mousa, NA, Al Inany, HG, Casper, RF. Cost-effectiveness of
aromatase inhibitor co-treatment for controlled ovarian stimulation. Hum Reprod 2006 Nov; 21(11): 2838-44.
5. Casper, RF, Mitwally, MFM. Review: Aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006 Mar; 91(3): 760-771.
6. Czajka-Oraniec, I, Simpson, E. Aromatase research and its clinical significance.
Endokrynologia Polska 2010 Jan-Feb; 61(1): 126-34.
7. Faglia, G, Arosio, M, Porretti, S. Delayed closure of epiphyseal cartilages induced by the
aromatase inhibitor anastrozole. Would it help short children grow up? J Endocrinol Invest 2000 Dec; 23(11): 721-3.
8. Ganesh, A, Goswami, SK, Chattopahyay, K, et al. Comparison of letrozole with continuous
gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1837 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. Journal of Assisted Reproduction and Genetics 2009; 26(1): 19-24.
9. Hero, M, Norjavaara, E, Dunkel, L. Inhibition of estrogen biosynthesis with a potent
aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005 Dec; 90(12): 6396-402.
10. Hero, M, Wickman, S, Dunkel, L. Treatment with the aromatase inhibitor letrozole during
adolescence increases near-final height in boys with constitutional delay of puberty. Clin Endocrinol (Oxf) 2006 May; 64(5): 510-513.
11. Karmazin, A, Moore, WV, Popovic, J, Jacobson, JD. The effect of letrozole on bone age
progression, predicted adult height, and adrenal gland function. J Pediatr Endocrinol Metab. 2005 Mar; 18(3): 285-93.
12. Mauras, N. Strategies for maximizing growth in puberty in children with short stature.
Endocrinol Metab Clin N Am 2009; 38: 613-24.
13. Mauras, N, Gonzalez de Pijem, L, Hsiang, HY, Desrosiers, P, Rapaport, R, Schwartz, ID,
Klein, KO, Singh, RJ, Miyamoto, A, Bishop, K. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 2008 Mar; 93(3): 823-31.
14. Mauras, N, Welch, S, Rini, A, Klein, KO. An open label 12-month pilot trial on the effects of
the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys. J Pediatr Endocrinol Metab 2004 Dec; 17(12): 1597-606.
Title: Aromatase Inhibitors (Femara [letrozole] & Arimidex [anastrozole]) References, continued: 15. Requena, A, Herrero, J, Landeras, J, et al. Use of letrozole in assisted reproduction: a
systematic review and meta-analysis. Hum Reprod Update 2008 Nov-Dec; 14(6): 571-82.
16. Shulman, DI, Francis, GL, Palmert, MR, Eugster, EA. Use of aromatase inhibitors in
children and adolescents with disorders of growth and adolescent development. Pediatric 2008 Apr; 121(4): e975-83.
17. Hero, Matti et al. Vertebral morphology in aromatase inhibitor treated males with idiopathic
short stature or constitutional delay or puberty. Journal of Bone and Mineral Research 2010 Feb; Epub ahead of print.
18. Wickman, S, Sipilä, I, Ankarberg-Lindgren, C, Norjavaara, E, Dunkel, L. A specific
aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial. Lancet 2001 Jun 2; 357(9270): 1743-8.
19. Yang, MQ, Quan, S, Li, H, Song, YL, Xing, FQ. [Effect of two different doses of letrozole in
promoting ovulation in infertile women with polycystic ovarian syndrome]. Nan Fang Yi Ke Da Xue Xue Bao 2008 Nov; 28(11): 2060-1. Chinese Article.
Disclaimer Information: Prior Authorization criteria are developed to determine coverage for AvMed Health Plans’ benefits, and are published to provide a better understanding of the basis upon which coverage decisions are made. AvMed Health Plans makes coverage decisions based on the Member’s benefit plan contract and these criteria. This guideline sets forth concise clinical coverage criteria which have been developed from a review of current literature, policies of the FDA and other government agencies, and other appropriate references, in consultation and with approval from practicing physicians who are members of AvMed’s Pharmacy and Therapeutic committee. Treating providers are solely responsible for the medical advice and treatment of Members. This guideline may be updated and therefore is subject to change. The use of these criteria is neither a guarantee of payment nor a final prediction of how specific claim(s) will be adjudicated.
United Nations Convention against Illicit Traffic In Narcotic Drugs and Psychotropic Substances of 1988 ANNUAL INFORMATION ON SUBSTANCES FREQUENTLY USED IN THE ILLICIT MANUFACTURE OF NARCOTIC DRUGS AND PSYCHOTROPIC SUBSTANCES United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988: article 12, paragraph 12 Economic and Social Co
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