Forteo (teriparatide) Prior Authorization Program Summary

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1 Forteo (teriparatide) Prior Authorization Program Summary FDA APPROVED INDICATIONS DOSAGE 1 FDA Indication 1 : Forteo (teriparatide) is indicated for: the treatment of postmenopausal women with osteoporosis who are at high risk for fracture; to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture; the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture. High risk for fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Dosing 1 : recommended dose is 20 mcg subcutaneously once daily CLINICAL RATIONALE Teriparatide Teriparatide is a recombinant form of human parathyroid hormone (PTH) used to treat severe osteoporosis, and stimulates bone formation, rather than reducing turnover. 1,3-4 Teriparatide s action is similar to that of endogenous PTH, the main function of which is the regulation of calcium and phosphate metabolism in the bone and kidney. Teriparatide has the same physiological actions as PTH on the bone and kidney to cause bone formation. 1,3-4 Treatment with parathyroid hormone or teriparatide results in increased bone mineral density, improved cancellous and cortical microarchitecture, and increased bone formation rate. With teriparatide therapy, there is significantly lower matrix mineralization compared with placebo and a shift towards less mature collagen cross-links. In addition, parathyroid hormone inhibits osteoblast apoptosis, resulting in an increase in bone formation, and with enhanced deposition of new bone matrix, the osteocyte pool is replenished. These changes account for the reported increase of bone strength and the significant reduction in vertebral and nonvertebral fracture risk. 3 Teriparatide in a dose of 20 mcg daily was shown to decrease the risk of vertebral fractures by 65% and nonvertebral fractures by 53% in patients with osteoporosis, after an average of 18 months of therapy. 8 Postmenopausal Osteoporosis The diagnosis of osteoporosis (OP) has been established by measurement of bone mineral density (BMD). BMD appears to be a predictor of fractures. BMD is expressed in absolute terms of grams of mineral per square centimeter scanned (g/cm 2 ) and as a relationship to two norms: compared to the expected BMD for the patient s age and sex (Z-score), or compared to young normal adults of the same sex (T-score). 8 The difference between the patient s score and the norm is expressed in standard deviations (SD) above or below the mean. Usually, 1 SD equals 10 to 15% of the BMD value in g/cm 2. The North American Menopause Society (NAMS) 5, World Health Organization (WHO) 7, International Society of Clinical Densitometry 6, and the National Osteoporosis Foundation (NOF) 8 define OP in postmenopausal women or a man 50 years old as a BMD T-score -2.5 at the total hip, femoral hip, or lumbar spine ( 2 vertebral levels measured in the posterior-anterior projection not the lateral projection). 6-8 In addition to diagnosis through densitometry, OP can be diagnosed clinically, regardless of the T- score. The presence of fragility fracture constitutes a clinical diagnosis of OP. 5 Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 1 of 8

2 BMD-based definitions of bone density 5,7-8 Normal T-score -1.0 Low bone mass T-score between -1.0 and -2.5 (osteopenia) Osteoporosis T-score -2.5 A management strategy focused on lifestyle approaches may be all that is needed in postmenopausal women who are at low risk of OP fracture. All postmenopausal women, regardless of their BMD or clinical risk factors for OP, should be encouraged to eat a balanced diet, obtain adequate calcium and vitamin D3, participate in appropriate exercise, avoid cigarette smoke and excessive alcohol consumption, and institute fall prevention measures. 5 The NAMS and NOF as well as the American Association of Clinical Endocrinologists (AACE) recommend adding OP drug therapy in the following populations: 5,8,13 All men and postmenopausal women who have had an osteoporotic vertebral or hip fracture All men and postmenopausal women who have BMD values consistent with OP (i.e., T- scores < -2.5) at the lumbar spine, femoral neck, or total hip region. All men age 50 and older, and postmenopausal women who have T-scores from -1.0 to -2.5 at the femoral neck, total hip, or spine and a 10-year probability of a hip fracture 3% or a 10-year probability of a major OP-related fracture 20%. Patients with a fragility fracture of the spine or hip are at very high risk for another fracture regardless of whether the T-score is below -2.5 or just in the osteopenia range. Although bone densitometry is useful for assessing disease severity and monitoring therapy in patients with fractures, densitometry is not essential for the diagnosis of osteoporosis in this setting. 14 The risk for a second fragility fracture decreases as time passes from the first fracture. 15,16 The study by Johnell et al. found that for all fractures, more fractures occurred in the first year after initial fracture than in subsequent years. The number of fractures decreased progressively thereafter with time. 15 Schousboe et al. found that prior non-spine non-hip fracture confers a modest excess risk for incident hip fracture independent of BMD after 10 years; that excess risk, however, was only about one third the excess risk during the first 5 years of follow-up. 16 The NAMS recommends bisphosphonates as first line therapy in the treatment of postmenopausal OP. They also recommend teriparatide offered to women with OP who are at high risk for fracture. Teriparatide therapy is not indicated for 24 months. 5 Guidelines from the American Association of Clinical Endocrinologists (AACE) 13 and the American College of Obstetricians and Gynecologists (ACOG) 18 state that although evidence for the efficacy in reducing the risk of new vertebral fractures is available for all of the agents approved for the treatment of osteoporosis (alendronate, ibandronate, risedronate, zoledronic acid (5 mg/100 ml), calcitonin, denosumab (60mg/mL), raloxifene, and teriparatide), only alendronate, risedronate, zoledronic acid, denosumab, and teriparatide reduce the risk of nonvertebral fractures. Alendronate, risedronate, zoledronic acid, and denosumab have demonstrated reduction of the risk of hip fractures in prospective controlled osteoporosis trials 13,18 Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 2 of 8

3 The AACE recommends alendronate, risedronate, zoledronic acid, or denosumab as first line agents, ibandronate as a second line agent, raloxifene as a second or third line agent, and calcitonin as the last line agent. Teriparatide is best used in treating women with osteoporosis who are at high risk for fracture. 13 Medical Letter treatment guidelines (2014) state that although teriparatide has been shown to reduce the risk of vertebral and nonvertebral fractures, it must be injected daily and is expensive. 19 Teriparatide in Postmenopausal Osteoporosis A multicenter double blind placebo control study of once daily subcutaneous injection of teriparatide included 1637 postmenopausal women with OP. New vertebral fractures occurred in 14% of the women in the placebo group and in 5 % and 4 % respectively, of the women in the 20 mcg and 40 mcg parathyroid hormone groups; the respective relative risks of fracture in the 20 mcg and 40 mcg groups, as compared with the placebo group, were 0.35 and 0.31 (95% confidence intervals [CI], 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6% of the women in the placebo group and in 3% of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95% CI, 0.25 to 0.88 and 0.25 to 0.86]). As compared with placebo, the 20 mcg and 40 mcg doses of parathyroid hormone increased BMD by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40 mcg dose decreased BMD at the shaft of the radius by 2 more percentage points. Both doses increased total body bone mineral by 2 to 4 more percentage points than did placebo. 2 The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin: Osteoporosis (2012) states that teriparatide is usually reserved for cases of severe osteoporosis and for patients who have experienced fractures. Teriparatide therapy should be limited to 24 months. 18 The efficacy and safety of teriparatide in combination with alendronate or raloxifene was assessed in an open label, randomized trial. Postmenopausal women with OP on alendronate or raloxifene for at least 18 months (n=198) were enrolled. Patients were randomized to either add on teriparatide to existing therapy (add group) or discontinue previous therapy and switch to teriparatide (switch group). The primary outcome measure was the change in bone mineral density (BMD) at 18 months. BMD in the lumbar spine increased 8.4% in the add group compared to 4.8% in the switch group at 18 months (p=0.003). Total hip BMD was increased 3.2% in the add group compared to 0.9% in the switch group at 18 months (p=0.02). Increases in femoral neck BMD were not significantly different between groups at 18 months. PINP (a marker of bone turnover) increases were smaller in the add group compared to the switch group (64% vs. 401%; p<0.001) at six months. 12 Regarding combination therapy, the AACE guidelines state: There are no studies showing that combination treatment with 2 or more osteoporosis drugs has a greater effect on fracture reduction than treatment with a single agent. Modest additive effects on BMD and bone turnover have been observed with combinations of 2 antiresorptive agents. The combined use of an antiresorptive drug and teriparatide or parathyroid hormone (PTH) may alter the BMD and bone turnover response, depending on which antiresorptive agent is used. Combination therapy substantially increases the cost and probably increases the potential for side effects. Until the effect of combination therapy on fracture risk is better understood, however, AACE does not recommend concomitant use of these agents for prevention or treatment of postmenopausal osteoporosis. 13 Osteoporosis in Men OP in men can be classified as primary or secondary, with primary osteoporosis often divided Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 3 of 8

4 into idiopathic and age-related based on the age of diagnosis. Secondary osteoporosis in men is caused by glucocorticoid use, hypogonadism, or excessive alcohol intake. These factors are present in the majority of men 65 years old with OP. 4 Bisphosphonate therapy halts bone loss but does not add new bone, nor do they restore disrupted microarchitecture. In severe cases of osteoporosis, putting a stop to further bone loss may not be enough to prevent further fractures. In these cases, treatments that stimulates bone formation and reverse skeletal deterioration may be necessary. 4 In men, where decreased bone formation is an important etiological factor, an anabolic treatment is the treatment of choice. 3-4 Teriparatide is the only anabolic agent currently approved for treatment of OP in men. 3 The Endocrine Society 2012 Clinical Practice Guideline: Osteoporosis in Men recommends the following: Men at high risk of fracture be treated with medication approved by regulatory agencies such as the U.S. FDA or the European Medicines Agency (EMA) (alendronate, risedronate, zoledronic acid, and teriparatide; also denosumab for men receiving ADT [androgen deprivation therapy] for prostate cancer) and that the selection of therapeutic agent be individualized based on factors including fracture history, severity of osteoporosis (Tscores), the risk for hip fracture. 17 Teriparatide in Osteoporosis in Men Orwoll, et al. 10 studied the effects of teriparatide on bone density in men with OP. Four hundred thirty seven men with spine or hip BMD more than 2 standard deviations below the young adult male mean were randomized to three groups: (i) daily injections of placebo, (ii) teriparatide 20 mcg, or (iii) teriparatide 40 mcg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine BMD was significantly greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 mcg) and 9.0% (40 mcg) above baseline. Femoral neck BMD increased 1.5% (20 mcg) and 2.9% (40 mcg), and whole body bone mineral content increased 0.6% (20 mcg) and 0.9% (40 mcg) above baseline in the teriparatide-treated subjects. There was no change in radial BMD in the teriparatide-treated groups. BMD responses to teriparatide were similar regardless of gonadal status, age, baseline BMD, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20 mcg groups, but more frequent in the 40 mcg group. This study shows that teriparatide treatment results in an increase in BMD and is a potentially useful therapy for OP in men. Glucocorticoid Induced Osteoporosis Glucocorticoids decrease bone formation by reducing the lifespan of osteoblasts and osteocytes. Bisphosphonates are effective in preventing and treating glucocorticoid induced OP (GIO) at the lumbar spine and femoral neck. 9 The American College of Rheumatology 2010 recommendations for the prevention and treatment of Glucocorticoid-induced Osteoporosis (GIOP): 9 For postmenopausal women and men over the age of 50 starting on a glucocorticoid, a stepwise management begins with counseling and risk factor assessment, then determination of the fracture risk category. If the risk is high, for example, and glucocorticoid dosage is <5 mg/d and expected to last less than a month, treatment with alendronate, risedronate, or zoledronic acid is recommended. If risk is high and glucocorticoid dosage is >5 mg/d and expected to last less than a month, or any glucocorticoid dose for greater than one month, treatment with alendronate, risedronate, zoledronic acid, or teriparatide is recommended. Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 4 of 8

5 For postmenopausal women and men over the age of 50, premenopausal women not of child bearing potential and men under the age of 50 with a history of fragility fracture, zoledronic acid, teriparatide, alendronate, and risedronate are recommended for the treatment of GIOP. Teriparatide in Glucocorticoid Induced Osteoporosis In 2009 the FDA expanded the indications for teriparatide to include adults with a high risk for fracture related to GIO. The FDA's decision was based on data from an 18-month randomized, double-blind, controlled clinical trial that compared teriparatide with alendronate in 428 women and men with osteoporosis (aged 22 to 89 years) who had received sustained glucocorticoid therapy. Sustained glucocorticoid therapy was defined as a mean daily dose of 5 mg or more of prednisone or its equivalent for at least 3 months. A total of 214 patients received 20 mcg of teriparatide once-daily, and 214 received 10 mg of alendronate once-daily. The primary outcome was the change in BMD at the lumbar spine. Secondary outcomes included changes in BMD at the total hip and in markers of bone turnover, the time to changes in BMD, the incidence of fractures, and safety. At the last measurement, the mean (+/- SE) BMD at the lumbar spine had increased more in the teriparatide group than in the alendronate group (7.2 +/- 0.7 % versus 3.4 +/- 0.7 %, p < 0.001). A significant difference between the groups was reached by 6 months (p < 0.001). At 12 months, BMD at the total hip had increased more in the teriparatide group. Fewer new vertebral fractures occurred in the teriparatide group than in the alendronate group (0.6 % versus 6.1%, p = 0.004); the incidence of non-vertebral fractures was similar in the two groups (5.6% versus 3.7%, p = 0.36). 11 Teriparatide Safety 1 In clinical trials, the frequency of 1 episode of transient hypercalcemia in the 4 to 6 hours after teriparatide administration was 11% of women and 6% of men. Antibodies to teriparatide have been noted in about 3% of women with long-term treatment; however hypersensitivity reactions or decreased efficacy has not been seen. Teriparatide should not be used in patients at increased risk of bone cancers, such as those with: Paget s disease Hyperparathyroidism Open epiphyses A history of skeletal radiation therapy Unexplained increases in serum alkaline phosphatase concentration Pre-existing hypercalcemia or urolithiasis Forteo's (teriparatide) product labeling carries a Boxed Warning, which highlights the concern over the association between the drug and osteosarcomas in laboratory rats. 1 Because individuals with growing bones (namely children and adolescents with open epiphyses), persons with unexplained elevations in alkaline phosphatase, patients with prior external beam or implant irradiation of the skeleton, and patients with Paget's disease of the bone have a higher risk for developing osteosarcoma, the Boxed Warning states that it is important that teriparatide not be used in these groups. Furthermore, the product labeling states that individuals with hypercalcemia, women who are pregnant or nursing, or those who have ever been diagnosed with bone cancer or other cancers that have metastasized to the bones, should not use teriparatide. According to the product labeling, because the long-term effectiveness and safety of teriparatide treatment are not known at this time, therapy for more than 2 years is not recommended. For additional clinical information see the Prime Therapeutics Formulary Chapter 4.9A Calcium Regulators/Osteoporosis Agents. Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 5 of 8

6 REFERENCES 1. Forteo Prescribing Information. Eli Lilly & Co. Indianapolis, IN. March Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;19(344): National Cancer Institute Surveillance Research Program (SEER). Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: Gagnon C, Li V, Ebeling PR. Osteoporosis in men: its pathophysiology and the role of teriparatide in its treatment. Clin Interventions Aging. 2008;3(4): North American Menopause Society. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause. 2010;17(1):25-54 or at Accessed August The International Society of Clinical Densitometry. Bone mineral density definition and position statement Available at: AdultandPediatric.pdf. Accessed August Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis synopsis of a WHO report. WHO study Group. Osteoporosis Int. 1994;4: National Osteoporosis Foundation (NOF) Clinician s Guide to Prevention and Treatment of Osteoporosis Accessed 9. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoidinduced osteoporosis: 2010 update. Arthritis Care & Research 2010;62(11): Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res. 2003;18(1): Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoidinduced osteoporosis. N Engl J Med. 2007;357(20): Cosman F, Wermers RA, Recknor C, et al. Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive agent. J Clin Endocrinol Metab. 2009;94: Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for postmenopausal osteoporosis. Endocrin Pract 2010;16(suppl3): World Health Organization (WHO) Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level. May Available at: Accessed September Johnell O, Kanis JA, Oden, et al. Fracture risk following an osteoporotic fracture. Osteoporosis Int. 2004;15: Schousboe JT, Fink HA, Lui LY, et al. Association between prior non-spine non-hip fractures or prevalent radiographic vertebral deformities known to be at least 10 years old and incident hip fracture. J Bone Miner Res. 2006;21: Watts NB, Adler RA, Bilezikian MT,et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97: ACOG. Practice bulletin 129: Osteoporosis. Ob Gynecol. 2012:120: Drugs for postmenopausal osteoporosis. Medical Letter Treatment Guidelines. 2014;56(1452): Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 6 of 8

7 Forteo (teriparatide) Prior Authorization OBJECTIVE The intent of the Forteo (teriparatide) Prior Authorization (PA) program is to ensure appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or guidelines and according to dosing recommended in product labeling. Patients considered candidates for therapy with Forteo include: 1) patients with prior vertebral or low-trauma or fragility fractures in the past five years; 2) patients with a diagnosis of osteoporosis (T-score -2.5 standard deviations (SDs) per World Health Organization (WHO) classification system) who have already tried a bisphosphonate, or a selective estrogen receptor modulator (SERM) for those whom it is appropriate, or cannot take those medications; Forteo will not be approved for patients in whom it would be contraindicated or for patients who are at an increased baseline risk for osteosarcoma. Because the safety and efficacy of Forteo beyond two years of treatment have not been evaluated, the PA criteria for Forteo will approve use initially for 2 years with no renewal. Because concomitant use of Forteo and other osteoporosis agents including bisphosphonates, SERMs, and Prolia (denosumab) is not supported by current guidelines, these combinations will not be approved. TARGET DRUG Forteo (teriparatide) PRI AUTHIZATION CRITERIA F APPROVAL Forteo will be approved when ALL of the following are met: 1. The patient has a diagnosis of osteoporosis defined as ONE of the following: a. The patient has a history of vertebral fracture(s), or low trauma or fragility fracture(s) [e.g., prior fracture from minor trauma such as falling from standing height or less] within the past 5 years b. The patient has a T-score that is 2.5 or lower ONE of the following: i. The patient has failed a bisphosphonate ii. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to bisphosphonate iii. BOTH of the following: 1. ONE of the following: a. The patient is female b. The prescriber has provided documentation that SERMS is medically appropriate for the patient s gender 2. ONE of the following: a. The patient has failed a SERM b. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to a SERM 2. The patient does NOT have any FDA labeled contraindication(s) to the requested agent 3. The patient does NOT have an increased baseline risk for osteosarcoma 4. ONE of the following: Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 7 of 8

8 a. The patient is not receiving concomitant bisphosphonate, SERM, Xgeva (denosumab), or Prolia (denosumab) therapy in the past 90 days b. The prescriber indicates that the patient will discontinue the current, bisphosphonate, SERM, Xgeva, or Prolia therapy before starting the requested agent 5. The dose requested is within the FDA approved labeling (20 mcg subcutaneously once daily) 6. The total duration of treatment with Forteo has not exceeded 2 years Length of approval: up to a total of 2 years of treatment NOTE: If Quantity Limit ONLY program applies, please refer to Quantity Limit documents. Choice_PS_Forteo_PA_ProgSum_0117_r0517_v2 Page 8 of 8