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Antiobesity Agents Formulary Exception Program Summary This program applies to FlexRx Closed and GenRx Closed formularies. FDA APPROVED INDICATIONS AND DOSAGE1,2,11,21,23-28,30,34,35 Available Agent Indication strengths Belviq™ 10 mg Adjunct to a reduced-calorie diet and (lorcaserin) increased physical activity for chronic weight management in adults with an tablets initial BMI of: ≥30 kg/m2 ≥27 kg/m2 in the presence of at least one weight-related comorbid condition Bontril PDM, 35 mg Short-term (a few weeks) adjunct in a Bontril Slow 105 mg regimen of weight reduction based on Release exercise, behavioral modification and (phendimetrazine) caloric restriction in the management of exogenous obesity for patients with an tablets, capsules ER initial body mass index ≥ 30 kg/m2 or higher and who have not responded to appropriate weight reducing regimen alone. Contrave® 8 mg / 90 (naltrexone/bupropio mg n) tablets ER Didrex, Regimex (benzphetamine) tablets 25 mg 50 mg Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: • 30 kg/m2 or greater (obese) • 27 kg/m2 or greater (overweight) in the presence of at least one weightrelated comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia) Short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index ≥ 30 kg/m2 or higher and who have not responded to appropriate weight reducing regimen alone. Dosage Twice daily Discontinue at 12 weeks if 5% weight loss is not achieved Immediate release (35 mg) 1 tablet twice or three times daily, 1 hour before meals; dosage should be individualized to lowest effective dosage; maximum dose is 2 tablets three times daily Slow release (105 mg) once daily in the morning, 30 – 60 minutes before morning meal Dose escalation schedule: Week 1 – 1 tablet in the morning Week 2 – 1 tablet in the morning and 1 tablet in the evening Week 3 – 2 tablets in the morning and 1 tablet in the evening Week 4 and Onward – 2 tablets in the morning and 2 tablets in the evening Discontinue at 12 weeks if 5% weight loss is not achieved 25 to 50 mg one to three times daily; dosage should be individualized according to patient response MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 1 of 12 Agent Diethylpropion Available strengths 25 mg 75 mg tablets, capsules ER Phentermine tablets, capsules Qsymia™ (phentermine/ topiramate) 15 mg 30 mg 37.5 mg capsules 3.75/23mg 7.5/46mg 11.25/69m g 15/92mg Saxenda® (liraglutide) 6 mg/ml, 3 ml/pens Suprenza (phentermine) 15 mg 30 mg 37.5 mg orally disintegrating tablets Indication Dosage Short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index ≥ 30 kg/m2 or higher and who have not responded to appropriate weight reducing regimen alone. Management of exogenous obesity as a short-term adjunct (a few weeks, up to 12 weeks based on agent) in a regimen of weight reduction based on caloric restriction in patients with an initial BMI of 30 kg/m2 or higher, or BMI greater than 27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes mellitus, or dyslipidemia), and who have not responded to appropriate weight reducing regimen (diet and/or exercise) alone Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of: ≥30 kg/m2 ≥27 kg/m2 in the presence of at least one weight-related comorbid condition Immediate release (25 mg) three times daily, 1 hour before meals Controlled release (75 mg) once daily in midmorning Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m2 or greater (obese) or 27 kg/m2 or greater (overweight) in the presence of at least one weightrelated comorbid condition (e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia) Short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index ≥ 30 kg/m2 or ≥27 kg/m2 in the presence of other risk Once or twice daily, depending on agent. 18.75 mg twice daily, onehalf hour before meals; 15-37.5 mg once daily before or after breakfast or at least 10-14 hours before bedtime Once daily Titration schedule: 3.75mg/23mg once daily for 14 days, then increase to 7.5mg/46mg daily Discontinue or escalate the dose if 3% weight loss is not achieved after 12 weeks on 7.5mg/46mg daily Discontinue if 5% weight loss is not achieved after 12 weeks on maximum daily dose of 15mg/92mg Initiate at 0.6 mg per day for one week. In weekly intervals, increase the dose until a dose of 3 mg per day is reached Once daily Dosage should be individualized to obtain an adequate response with the lowest effective dose. MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 2 of 12 Agent Xenical (orlistat) capsules Available strengths 120 mg Indication factors (e.g., controlled hypertension, diabetes, hyperlipidemia) Not for use in pediatric patients < 16 years of age Obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet and to reduce the risk for weight regain after prior weight loss. It is indicated for obese patients with an initial body mass index (BMI) ≥30 kg/m2 or >27 kg/m2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia) Safety/effectiveness in patients <12 years of age not established Dosage 120 mg three times daily with each main meal containing fat (during or up to 1 hour after the meal) CLINICAL RATIONALE: Disease state Obesity, a complex, multi-factorial condition and is a fast growing epidemic among adults, adolescents and children. It increases the risk of morbidity and mortality from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems. 3 Adults with body mass index (BMI) 25-29.9 kg/m2 are considered overweight; those with BMI ≥30 kg/m2 are considered obese. Losing even a small amount of weight and increasing physical activity can prevent some complications of obesity, particularly type 2 diabetes. Diet and exercise are the preferred methods for losing weight, but long-term failure rates are high. Pharmacologic treatment of obesity has been limited by modest efficacy, adverse effects, low adherence rates, and regain of weight with drug cessation. 33 The Canadian Task Force on Preventive Health Care (2015) states lifestyle interventions (e.g., behavioral therapies, dietary and physical activity programming and support) are the first line of treatment for most patients with overweight or obesity as the benefit-to-harm ratio appears more favorable than for pharmacologic interventions. Pharmacotherapy and surgery are options for more severe cases of obesity. 20 The Endocrine Society (U.S., 2015) suggests medications approved for chronic weight management can be useful adjuncts to lifestyle change for patients who have been unsuccessful with diet and exercise alone. They recommend adherence to American Heart Association Guidelines (2013) [see below] which include advice for assessment and treatment with diet and exercise, as well as bariatric surgery for appropriate candidates. 32 Diet, exercise, and behavioral modification should be included in all overweight and obesity management approaches for BMI >25 kg/m2 and other tools [e.g., pharmacotherapy (if BMI >27 kg/m2 with comorbidity or BMI >30 kg/m2) and bariatric surgery (BMI >35 kg/m2 with comorbidity or BMI >40 kg/m2)] should be used as adjuncts to behavioral modification to reduce food intake and increase physical activity when possible. Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially. MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 3 of 12 Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications. Given the wide clinical prescribing of phentermine for >20 years and lack of evidence of serious side effects, even in the absence of long-term controlled safety and efficacy data, it seems reasonable for clinicians to prescribe phentermine long term as long as the patient: 1) has no evidence of serious cardiovascular disease; 2) does not have serious psychiatric disease or a history of substance abuse; 3) has been informed about weight loss medications that are FDA approved for long-term use and told that these have been documented to be safe and effective whereas phentermine has not; 4) does not demonstrate a clinically significant increase in pulse or BP when taking phentermine; and 5) demonstrates a significant weight loss while using the medication. These aspects of care should be documented in the patient’s medical record, and the off-label nature of the prescribing should be documented at each visit. Medication should be started at 7.5 or 15 mg/day initially and only increased if the patient is not achieving clinically significant weight loss. Patients should be followed at least monthly during dose escalation and then at least every 3 months when on a stable dose. The Department of Veteran’s Affairs (U.S., 2014) states controversy exists around optimal timing of introducing pharmacotherapy into a weight loss program. Some favor prescribing these agents only after Comprehensive Lifestyle Intervention (CLI) has failed to produce weight loss consistent with goals. Others offer these agents earlier in treatment to assist in the initiation of weight loss, boost patient self-confidence, and expedite reduction in risk for obesity-associated conditions. Regardless of when pharmacotherapy is introduced, it should always be in combination with a reduced calorie diet and other lifestyle changes. 4 Note: In clinical trials, pharmacotherapy was started simultaneously with CLI. Introduction of drugs very early in treatment is not suggested in clinical practice. Hence, the initial weight loss may be less than demonstrated in studies when pharmacotherapy is started after CLI. 4 VA algorithm recommendations include the following. For obese patients (BMI >30 kg/m2), or overweight patients (BMI >25 kg/m2) with >1 obesity associated condition, they recommend patients participate in CLI (i.e., combination dietary, physicial activity, and behavioral components, including >12 intervention sessions over a 12 month period). If patients do not meet goals with CLI, and meet appropriate criteria, then consider pharmacotherapy and/or bariatric surgery as adjunct therapies. For overweight patients (not obese) without obesity associated conditions, they recommend providing information and behavioral counseling on healthy diet, physical activity, and behavior in order to pursue and maintain a healthy weight. 4 The American Heart Association/American College of Cardiology/Obesity Society Guideline (2013) suggests if history indicates the patient has never participated in a comprehensive lifestyle intervention program as defined in the guidelines (i.e., trained interventionist or nutritional professional supervision of diet, exercise, and behavior therapy), it is recommended that the patient undertake such a program before addition of adjunctive therapies (e.g., pharmacotherapy), since a substantial proportion of patients will lose sufficient weight to improve health with comprehensive lifestyle management alone. If a patient has been unable to lose weight or sustain weight loss with comprehensive lifestyle intervention and has BMI >30 kg/m2 or >27 kg/m2 with comorbidity, adjunctive therapy may be considered. The expert panel did not review comprehensive evidence on pharmacotherapy for weight loss. Medications should be FDA approved and clinicians should be knowledgeable about the product label. The provider should weigh potential risks of the medication vs. potential benefits of successful weight loss for the individual patient. 13 A review (2015) suggests that although these agents have all shown efficacy in weight loss, some may regard the amount of loss insufficient. It is important to recognize that clinical MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 4 of 12 trials report means derived from intention-to-treat populations, whereas in clinical practice it is “responder” populations that better reflect the target population. Significant metabolic, and in the main cardiovascular, risk factors are improved, which may be related to weight loss rather than independent effects of the drugs. Substantial barriers remain in successfully integrating these agents into weight management practice, largely related to cost, patient acceptability, and clinician willingness to be engaged in adjunctive lifestyle management. Hard clinical outcome benefit has not yet been established. 36 Efficacy Sympathomimetic Drugs A 36 week trial compared placebo vs continuous phentermine or intermittent phentermine. Both continuous and intermittent phentermine produced more weight loss vs placebo. In a survey of bariatric physicians, use of these sympathomimetics was found to be more frequent than sibutramine or orlistat, and they were often used for longer than approved by the FDA. Despite the risk of adverse effects and the FDA recommendation for only short term use, data suggest phentermine has been widely prescribed for weight loss in the United States, often for durations longer than recommended. Published studies have provided longer term safety and efficacy data on phentermine (used in combination with topiramate) in recent weight loss trials.29 In a randomized trial, diethylpropion was compared with phentermine over 12 weeks in patients on 1,500 calories/day (n = 99). Patients had to be >20% above an undefined desirable weight, and were excluded if anorectic agents were used within one month of the study. After 12 weeks of treatment, phentermine 30 mg/day resulted in a mean weight loss of 1.96 kg more vs diethylpropion 75 mg/day (p <0.01). Patients taking diethylpropion trended toward a lower baseline weight. Diethylpropion caused more dizziness/giddiness (number needed to harm [NNH] = 25) and dry mouth (NNH = 17) vs phentermine; phentermine caused more drowsiness (NNH = 25) and constipation (NNH = 25).14 A meta-analysis found a modest degree of weight loss in patients taking sibutramine (off market), phentermine, or diethylpropion. A mean difference in weight loss of 4.45 kg (95% CI 3.62 to 5.29) was found at 12 months with sibutramine. In patients taking phentermine or diethylpropion, there was a reported pooled mean difference in weight loss at six months of 3.6 kg (95%CI 0.6 to 6.0) and 3.0 kg (95% CI –1.6 to 11.5), respectively.14 Lorcaserin The efficacy of lorcaserin was evaluated in three phase III trials (BLOOM5, BLOSSOM6 and BLOOM-DM7) in overweight adult patients with one co-existing condition or obese patients. The efficacy and safety of phentermine/topiramate was evaluated in two phase III trials (EQUIP8 and CONQUER9) and one long-term extension study (SEQUEL10) in uncomplicated, severely obese patients and overweight and obese patients with two or more comorbidities. Sustained weight loss and discontinuation effects of lorcaserin were evaluated in the BLOOM study in patients who were randomized to continue on therapy or receive placebo for an additional year. Of the patients who received lorcaserin for one year and continued on therapy for a second, 67.9 percent of the patients maintained a weight loss of 5 percent or more of their body weight compared to 50.3 percent of patients who received lorcaserin for one year and placebo for the second year.5 Sustained effects of phentermine/topiramate were also evaluated in an extension study (SEQUEL) and showed continued weight loss in patients on therapy up to a 108 week period.10 MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 5 of 12 Lorcaserin should be discontinued if the patient has not lost at least 5% of baseline body weight at week 12, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.1 Phentermine/topiramate should be discontinued if the patient has not lost at least 5% of baseline body weight at week 12 on maximum doses, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.2 Naltrexone/bupropion (NB) Four 56-week multicenter, double-blind, placebo-controlled obesity trials (Contrave Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of NB in conjunction with lifestyle modification in 4,536 patients randomized to NB or placebo. The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI >30 kg/m2) or overweight (BMI >27 kg/m2) and >1 comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI >27 kg/m 2 with type 2 diabetes with or without hypertension and/or dyslipidemia. 21 FDA guidance stipulates that a drug will be considered effective if >1 of the following criteria is satisfied after one year of treatment: 1) The difference in mean weight loss between the active-product and placebo-treated groups is >5% and the difference is statistically significant or, 2) The proportion of patients who lose >5% of baseline body weight in the active-product group is >35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant. 1) Mean placebo subtracted weight changes with NB from baseline in the four trials were: -4.8%, -4.2%, 4.6%, -3.3% (all p<0.001 vs placebo). Therefore NB did not satisfy the first FDA criterion for efficacy. 2) In the four NB trials, proportions of patients who lost >5% of baseline body weight (NB vs placebo) were: Trial 301 [COR-I] 48% vs 16%; 302 [COR-BMOD] 66% vs 43%; 303 [COR-II] 56% vs 18%; 304{COR-Diabetic] 45% vs 19%. All NB32 vs placebo comparisons were considered of nominal statistical significance. Two of these trials (301 [COR-I] and 304 [COR-Diabetes]) did satisfy the second criterion for efficacy. 22 Naltrexone/buproprion should be discontinued if the patient has not lost at least 5% of baseline body weight at week 12, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.21 Phentermine/topiramate The effect of phentermine/topiramate on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in 2 randomized, double-blind, placebocontrolled studies in obese patients (Study 1) and in obese and overweight patients with two or more significant co-morbidities (Study 2). Both studies had a 4-week titration period, followed by 52 weeks of treatment. Study 1 showed a -1.6%, -5.1%, and -10.9% least squares mean change from baseline body weight in placebo, 3.75 mg/23 mg phentermine/topiramate, and 15 mg/92 mg phentermine/topiramate respectively. Study 2 showed a -1.2%, -7.8%, and -9.8% least squares mean change from baseline body weight in placebo, 7.5 mg/46 mg phentermine/topiramate, and 15 mg/92 mg phentermine/topiramate respectively. The differences in least square mean body weight for all strengths of phentermine/topiramate compared to placebo were statistically significant. 2 Liraglutide 30 The efficacy of liraglutide for chronic weight management in conjunction with reduced caloric intake and increased physical activity were studied in three 56-week, randomized, doubleblind, placebo-controlled trials. In all studies, Saxenda was titrated to 3 mg daily during a 4week period. All patients received instruction for a reduced calorie diet (approximately 500 kcal/day deficit) and exercise counseling (recommended increase in physical activity of MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 6 of 12 minimum 150 mins/week) that began with the first dose of study medication or placebo and continued throughout the trial. Liraglutide is not indicated for the treatment of type 2 diabetes. Liraglutide should not be used in combination with any GLP-1 receptor agonist or insulin. The effects of liraglutide on cardiovascular morbidity and mortality have not been established. The safety and efficacy of liraglutide co-administered with other products for weight loss have not been established. Liraglutide has not been studied in patients with a history of pancreatitis. Safety Phentermine, benzphetamine, phendimetrazine, diethylpropion These drugs should not be used in advanced arteriosclerosis; symptomatic cardiovascular disease; moderate-to-severe hypertension; hyperthyroidism; known hypersensitivity or idiosyncrasy to sympathomimetic amines; glaucoma; highly nervous or agitated states; history of drug abuse; during or within 14 days following the administration of MAO inhibitors (hypertensive crises may result); or for co-administration with other CNS stimulants. Tolerance to the anorectic effects may develop within a few weeks. The recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.11 Abrupt discontinuation may result in depression or extreme fatigue; sleep EEG changes have been noted. Gradual withdrawal of therapy is recommended. These drugs are related to amphetamines, and have abuse potential. Psychological dependence may occur. Phentermine is Drug Enforcement Agency (DEA) Schedule IV. Benzphetamine and phendimetrazine are DEA schedule III; diethylpropion is DEA schedule IV.11 To what degree phentermine used longer term for weight loss actually increases risk of abuse or results in significant cardiovascular adverse effects has been debated in clinical practice.15,16 Although phentermine is only approved for short-term use (usually interpreted as 12 weeks), some clinicians use the drug on a long-term basis. A well conducted observational study did not show significant increases in blood pressure or pulse among patients receiving phentermine for 1 year vs control group with similar weight loss.18 These agents should not be used in combination with other anorectic agents, including prescribed drugs, OTC preparations, and herbal products. There are additional potential adverse interactions with alcohol. Convulsions may be increased in some epileptics receiving diethylpropion. Dose titration or drug discontinuance may be necessary. 11 Data on adverse events in weight-loss trials that used sympathomimetic amines are limited, but include increased heart rate and blood pressure, dry mouth, nervousness, insomnia and constipation.17 Lorcaserin In the lorcaserin placebo-controlled trials, 3451 patients aged 18 to 66 years were exposed to the drug for a minimum duration of one year. The most commonly reported adverse reactions were headache, dizziness, fatigue, nausea, dry mouth, and constipation. Other clinically important adverse reactions reported included hypoglycemia in patients with type 2 diabetes mellitus (1.6% vs. 0.4%), cognitive impairment (2.3% vs. 0.7%), psychiatric disorders leading to hospitalization or drug withdrawal (2.2% vs. 1.1%), euphoria (0.17% vs. 0.03%), depression (2.6% vs. 2.4%), and suicidal ideation (0.6% vs. 0.4%), eye disorders (without diabetes: 4.5% vs. 3.0%, with type 2 diabetes: 6.3% vs. 1.6%), and possible occurrence of regurgitant cardiac valve disease (2.4% vs. 2.0%) and serotonin associated adverse reactions. Lorcaserin carries warnings for serotonin syndrome or neuroleptic malignant syndrome like reactions, valvular heart disease, cognitive impairment, psychiatric disorders, depression and suicidal thoughts, use of antidiabetic medications, and priaprism. Lab abnormalities reported included lymphocyte counts below lower limit of normal (LLN) was MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 7 of 12 seen in 12.2% vs. 9.0%, low neutrophil counts (5.6% vs. 4.3%), hemoglobin below LLN (10.4% vs. 9.3%), prolactin levels greater than the upper limit of normal (ULN).1 Phentermine/topiramate The safety of phentermine/topiramate was evaluated in 2 phase III trials and 2 phase II supportive trials in 2318 patients. The most commonly reported adverse reactions were paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Other clinically important adverse reactions reported included paresthesias (4.2% to 19.9% depending on the dose vs. 1.9%), dysgeusia (1.3% to 9.4% depending on dose vs. 1.1%), mood and sleep disorders (14.5% to 20.6% depending on dose vs. 10.3%), cognitive disorders (2.1% to 7.6% depending on dose vs. 1.5%), and nephrolithiasis (0.4% to 1.2% depending on dose vs. 0.3%). Phentermine/topiramate carries warnings for fetal toxicity, increased heart rate, suicidal behavior and ideation, acute myopia and secondary angle closure glaucoma, mood and sleep disorders, cognitive impairment, metabolic acidosis, elevated creatinine, and use of antidiabetic medications. Lab abnormalities reported included minor decreases in serum bicarbonate levels, hypokalemia, dose related increases of serum creatinine from baseline. 2 Naltrexone/bupropion (NB) Prescribing information for NB contains contraindications and precautions/warnings similar with those for bupropion and naltrexone products. There is a boxed warning on suicidal thoughts and behavior and neuropsychiatric reactions, and a dose related seizure risk. NB should not be administered to patients receiving chronic opioids, due to the naltrexone component. If chronic opiate therapy is required, NB treatment should be stopped. Patients may be more sensitive to opioids, even at lower doses, after NB treatment is discontinued. Patients should be opioid-free before starting NB treatment. Other safety precautions include risk of increased blood pressure and heart rate, allergic reactions, hepatotoxicity, mania, angle closure glaucoma, and drug interactions with drugs metabolized by CYP2D6 or CYP2B6, drugs that lower seizure threshold, dopaminergic drugs or alcohol. 21 Liraglutide The safety of liraglutide for chronic weight management in conjunction with reduced caloric intake and increased physical activity were studied in three 56-week, randomized, doubleblind, placebo-controlled trials. Liraglutide is contraindicated in those with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2; hypersensitivity to liraglutide or any product components; and in pregnancy. Liraglutide is not indicated for the treatment of type 2 diabetes. Liraglutide should not be used with another GLP-1 receptor agonist agent, including another liraglutide agent. Saxenda should not be used with insulin. Liraglutide should be discontinued if the patient has not lost at least 4% of baseline body weight at week 16, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment. 30 Co-Administration None of the FDA approved weight loss agents have approval for co-administration with another weight loss agent. New guidelines do not support the use of co-administration of weight loss pharmacological agents.32,33 The prescribing information for benzphetamine, lorcaserin, naltrexone/bupropion, and phentermine/ topiramate states that the safety and efficacy of co-administration with other products for weight loss have not been established.1,2,21 Diethylpropion lists co-administration with other anorectic agents as a contraindication.34 Use of non-approved drug combinations for obesity treatment should be limited to clinical trials, and patients should be informed when drugs are being used off label alone or in combination.31 For additional clinical information see Prime Therapeutics Formulary Chapter 9.5B: Weight Loss Agents. MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 8 of 12 REFERENCES: 1. Belviq (lorcaserin) Prescribing Information. Arena. December 2014. 2. Qsymia (phentermine/topiramate) Prescribing Information. Vivus. September 2014. 3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009–2010. NCHS data brief, no 82. Hyattsville, MD: National Center for Health Statistics. January 2012. Accessed on July 13, 2012 @ http://www.cdc.gov/nchs/data/databriefs/db82.pdf 4. Department of Veteran’s Affairs. Department of Defense. Management of overweight and obesity. 2014. Accessed 10.9.2015 at: http://www.healthquality.va.gov/guidelines/CD/obesity/CPGManagementOfOverweight AndObesityFINAL041315.pdf. 5. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management. NEJM. 2010;363:245-56. [BLOOM] 6. Fiddler MC, Sanchez M, Raether B, et al. A One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults: The BLOSSOM Trial. J Clin Endocrinol Metab. 2011:96(10):3067-3077. 7. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study. Obesity Journal. 2012:20(7):1426-1436. 8. Allison DB, Gadde KM, Garvey WT, et al. Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP). Obesity Journal. 2012:20(2):330-342. 9. Gadde KM, Allison DB, Ryan DH, et al. Effect of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. The Lancet. 2011;377:1341-1352. 10. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012;95:297-308. 11. Clinical Pharmacology Online. www.clinicalpharmacology-ip.com. Accessed November 2014. 12. Plourde G, Prud’homme D. Managing obesity in adults in primary care. CMAJ 2012. DOI:10.1503/cmaj.111640. 13. American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Management of Overweight and Obesity in Adults (2013). JACC 2014;63(25): 2985–3023 14. Wilbert B, Labruzzo-Mohundro B, Shaw V, et al. Appetite suppressants as adjuncts for weight loss. Medical Letter. April 2011;83(7):1-2. 15. Hendricks E, Greenway F. A study of abrupt phentermine cessation in patients in a weight management program. Am J Therapeutics. 2011;18: 292-299. 16. Hendricks E, Greenway F, Westman E, Gupta A. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity. 2011;19: 2351–2360. 17. Anon. Diet, Drugs, and Surgery for Weight Loss. Medical Letter Treatment Guidelines. 2011;9(104):17-22. 18. Tsai A, Wadden T, Cotton D, et al In the clinic: Obesity. Ann Intern Med. September 2013;INT3:1-15. 19. Derbyshire M, Shek A, Szkotak J. Review of the pharmacologic arsenal for the war on obesity. Formulary. 2013; 48:136-143. 20. Canadian Task Force on Preventive Health Care. Recommendations for prevention of weight gain and use of behavioral and pharmacologic interventions to manage overweight and obesity in adults in primary care. CMAJ 2015. DOI:10.1503 MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 9 of 12 21. 22. 23. 24. 25. 26. 27. 28. 29. 29. 30. 31. 32. 33. 34. 35. /cmaj.140887. Contrave prescribing information. Takeda Pharmaceuticals America, Inc. September 2014. Contrave prescribing information. Takeda Pharmaceuticals America, Inc. September 2014. Food and Drug Administration (FDA). Briefing Document. NDA 200063. Contrave (Naltrexone 4mg, 8mg/Bupropion 90mg ER). December 7, 2010. Accessed November 7, 2014 at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dru gs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM235671.pdf. Xenical prescribing information. Roche Laboratories, Inc. August 2015. Adipex-P prescribing information. Teva Pharmaceuticals. January 2012. Suprenza prescribing information. Akrimax Pharmaceuticals, LLC. June 2013. Tenuate prescribing information. Patheon Pharmaceuticals Inc. November 2003. Didrex prescribing information. Mova Pharmaceuticals. August 2009. Phendimetrazine prescribing information. Epic Pharma, LLC. October 2011. Bray G, Ryan D. Drug treatment of obesity. Psychiatr Clin N Am. 2011;34: 871–880. Saxenda prescribing information. Novo Nordisk Inc. January 2015. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 January 1; 311(1) Apovian CM, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab, February 2015, 100(2):342–362. Diet, drugs, and surgery for weight loss. The Medical Letter on Drugs and Therapeutics. February 16, 2015. 57;1462. Diethylpropion prescribing information. Actavis Pharma, Inc. July 2014. Bontril prescribing information. Valeant Pharmaceuticals International. July 2013. Pucci A, Finer N. New medications for treatment of obesity: metabolic and cardiovascular effects. Can J Cardiol 2015;31: 142-152. MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 10 of 12 Antiobesity Agents Formulary Exception Criteria OBJECTIVE The criteria defined in the Antiobesity Formulary Exception Criteria will be applied when the included medications are prescribed for any patient. The intent of the criteria is to limit prescribing to those patients whose initial body mass index (BMI) is > 30 kg/m2 or > 27 kg/m2 in the presence of other risk factors (e.g., hypertension, coronary heart disease, type 2 diabetes, dyslipidemia, sleep apnea). Initial criteria also include medical evaluation ruling out organic causes of obesity, determination of obesity-related risk factors, and involvement in a weight loss program including a reduced-calorie diet and/or exercise, and/or behavioral modification. These medications will not be approved for patients receiving monoamine oxidase inhibitors. In addition, the criteria will require use of an orlistat product (prescription Xenical or nonprescription Alli) prior to a stimulant. If the initial criteria are met, Xenical will be approved for 12 months; stimulant medications for 3 months. Clinical literature supports a reasonable and medically significant outcome for many patients is to lose 10% of body weight in the first 6 months of treatment.3 If the patient loses 5% or more of his/her initial BMI or body weight, the patient will receive an approval for 12 months for Xenical or for 3 months for the stimulants. TARGET DRUG Adipex-P (phentermine)a Belviq (lorcaserin) Bontril Slow Release (phendimetrazine)a Bontril PDM (phendimetrazine)a Contrave® (naltrexone/bupropion) Didrex (benzphetamine)a Diethylpropion Qsymia™ (phentermine/topiramate) Regimex™ (benzphetamine) Saxenda® (liraglutide) Suprenza™ (phentermine) Xenical (orlistat) a - Indicates generic availability b – brand name product no longer available in U.S. market FORMULARY EXCEPTION CRITERIA FOR APPROVAL Initial Evaluation - FlexRX formulary Antiobesity Agents will be approved when ALL of the following are met: 1. Requested medication is not excluded under the patient’s current benefit plan AND 2. The patient has received a complete medication evaluation ruling out organic causes of obesity (e.g., hypothyroidism) and including a determination of BMI and other obesity-related risk factors (e.g., hypertension, coronary heart disease, type 2 diabetes, dyslipidemia, sleep apnea) AND 3. The patient has a BMI > 30 kg/m2 OR BMI > 27 kg/m2 (or high waist circumference) and the presence of at least one obesity-related risk factor listed above AND 4. The patient will be concurrently involved in a weight loss program including a reducedcalorie diet and/or exercise, and/or behavioral modification AND 5. The patient is not currently taking a monoamine oxidase inhibitor or hasn’t taken one in the past 14 days AND 6. ONE of the following: a. The patient has tried and failed both Xenical AND generic phentermine MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 11 of 12 OR b. Patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to both Xenical and phentermine Length of approval: 3 months Initial Evaluation - GenRx Formulary Antiobesity Agents will be approved when ALL of the following are met: 1. Requested medication is not excluded under the patient’s current benefit plan AND 2. The patient has received a complete medication evaluation ruling out organic causes of obesity (e.g., hypothyroidism) and including a determination of BMI and other obesity-related risk factors (e.g., hypertension, coronary heart disease, type 2 diabetes, dyslipidemia, sleep apnea) AND 3. The patient has a BMI > 30 kg/m2 OR BMI > 27 kg/m2 (or high waist circumference) and the presence of at least one obesity-related risk factor listed above AND 4. The patient will be concurrently involved in a weight loss program including a reducedcalorie diet and/or exercise, and/or behavioral modification AND 5. The patient is not currently taking a monoamine oxidase inhibitor or hasn’t taken one in the past 14 days AND 6. ONE of the following: a. The patient has tried and failed generic phentermine OR b. Patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to phentermine Length of approval: 3 months Renewal Evaluation – GenRx Formulary and FlexRx Formulary Antiobesity Agents will be approved when the following is met: 1. The patient has lost 5% or more of his/her initial BMI or weight Length of approval: 3 months for stimulants 12 months for non-stimulants MN_CS_Antiobesity_FE_ProgSum_AR0716 © Copyright Prime Therapeutics LLC. 07/2016 All Rights Reserved Page 12 of 12