Sodium-Glucose Co-Transporter 2 (SGLT-2) Inhibitors Drug Class Prior Authorization Protocol

Transcription

1 Sodium-Glucose Co-Transporter 2 (SGLT-2) Inhibitors Drug Class Prior Authorization Protocol Line of Business: Medicaid P&T Approval Date: February 21, 2018 Effective Date: April 1, 2018 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutics Subcommittee. Drug Requiring Prior Authorization Review: Farxiga (dapagliflozin), Jardiance (empagliflozin), Steglatro (ertugliflozin), Segluromet (ertugliflozin/metformin), Synjardy (empagliflozin/metformin), Xigduo XR (dapagliflozin/metformin ER) Formulary Alternative: Acarbose, alogliptin, alogliptin-metformin, glimepiride, glipizide, glipizide-metformin, glipizide ER, glyburide, glyburide-metformin, Invokamet (canagliflozin/metformin), Invokana (canagliflozin),janumet (sitagliptin-metformin), Janumet XR (sitagliptin/metformin), Januvia (sitagliptin), metformin, metformin ER, pioglitazone Criteria: A. Drug: Farxiga, Steglatro, Segluromet, Xigduo XR 1. Diagnosis: Diabetes Mellitus Type II Specialist: N/A Criteria: Must meet all of the following requirements: a. Failure or clinically significant adverse effects to all of the following requirements: i. Metformin. ii. 1 of the preferred SGLT-2 inhibitor products: Invokana or Invokamet. iii. 1 additional oral formulary alternatives (e.g. sulfonylurea, Januvia, pioglitazone, etc.). b. Documented HbA1c greater than 7 percent after 3 months (90 consecutive days) of optimal therapy with the tried alternatives.

2 Quantity Limit: a. Farxiga: 30 tablets per month (30 days) b. Steglatro: 30 tablets per month (30 days) c. Segluromet: 60 tablets per month (30 days) d. Xigduo XR: 60 tablets per month (30 days) Duration of Therapy: 1 year (365 days) Reauthorization Criteria: Must meet all of the following requirements: a. Recent pharmacy claim within 6 months (180 days) of request. b. Confirmed stability or no disease progression. Duration of Reauthorization: 1 year (365 days) B. Drugs: Jardiance, Synjardy 1. Diagnosis: Diabetes Mellitus Type II Specialist: N/A Criteria: Must meet all of the following requirements: a. Failure or clinically significant adverse effects to metformin. b. Documentation of 1 of the following: i. Established atherosclerotic cardiovascular disease. ii. Failure or clinically significant adverse effects to all of the following requirements: 1 of the preferred SGLT-2 inhibitor products: Invokana or Invokamet. 1 additional oral formulary alternatives (e.g. sulfonylurea, Januvia, pioglitazone, etc.). Documented HbA1c greater than 7 percent after 3 months (90 consecutive days) of optimal therapy with the tried alternatives. Quantity Limit: a. Jardiance: 30 tablets per month (30 days) b. Synjardy: 60 tablets per month (30 days) Duration of Therapy: 1 year (365 days) Reauthorization Criteria: Must meet all of the following requirements: a. Recent pharmacy claims within 6 months (180 days) of request. b. Confirmed stability or no disease progression. Duration of Reauthorization: 1 year (365 days)

3 Clinical Justification: 2018 American Diabetes Association: Standards of Medical Care in Diabetes

4 Pharmacologic Therapy for Type 2 Diabetes Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. Long-term use of metformin may be associated with biochemical vitamin B 12 deficiency, and periodic measurement of vitamin B 12 levels should be considered in metformintreated patients, especially in those with anemia or peripheral neuropathy. Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C 10% and/or blood glucose levels 300mg/dL. Consider initialing dual therapy in patients with newly diagnosed type 2 diabetes who have A1C 9%. In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors. A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, cost and patient preferences. In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors. (Level A level of evidence). Continuous re-evaluation of the medication regimen and adjustment as needed to incorporate patient factors and regimen complexity is recommended. In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors. (Level C level of evidence). For patients with type 2 diabetes who are not achieving glycemia goals, drug intensification, including consideration of insulin therapy, should not be delayed. Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. Sodium-Glucose Cotransporter 2 Inhibitors Sodium-glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2. These agents provide modest weight loss and blood pressure reduction. There are three FDA-approved agents for use in patients with type 2 diabetes, but there are insufficient data to recommend treatment in type 1 diabetes. The FDA recently issued a warning about the risk of ketoacidosis (euglycemic diabetic ketoacidosis) with SGLT2 inhibitors in individuals with type 1 or type 2 diabetes. Patients should stop taking their SGLT2 inhibitors immediately if they have symptoms of

5 ketoacidosis. Urinary tract infections leading to urosepsis and pyelonephritis may also occur with SGLT2 inhibitors. Cardiovascular Outcomes Trials There are now three large randomized controlled trials reporting statistically significant reductions in cardiovascular events for two SGLT2 inhibitors (empagliflozin and canagliflozin) and one GLP-1 receptor agonist (liraglutide) where the majority, if not all patients, in the trial had ASCVD. The empagliflozin and liraglutide trials demonstrated significant reductions in cardiovascular death. For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction especially those with proven benefits on both major adverse cardiovascular events and cardiovascular death after consideration of drug-specific patient factors. EMPA-REG OUTCOME: A randomized, double-blind trial was conducted to assess the effect of empagliflozin versus placebo on cardiovascular outcomes in 7020 patients with type 2 diabetes and existing cardiovascular disease. The primary outcome event (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke) was significantly lower in the empagliflozin group then placebo (10.5% vs. 12.1%; hazard ratio pooled analysis 0.86, 95% CI ). This outcome was primarily driven by a reduction in CV mortality, as there was insignificant difference for non-fatal myocardial infarction and stroke. CANVAS Program integrated data from two trials, including the CANVAS trial that started in 2009 before the approval of canagliflozin and CANVAS-R trial that started in 2014 after the approval of canagliflozin. The combined analysis of the two trials found that canagliflozin significantly reduced the composite outcome of cardiovascular death, MI or stroke versus placebo (occurring in 26.9 vs participants per 1000 patientyears; HR 0.86 [95% CI ]; p<0.001 for non-inferiority; p=0.02 for superiority). The specific estimates for canagliflozin versus placebo on the primary composite cardiovascular outcome were HR 0.88 ( ) for the CANVAS trial, and 0.82 ( ) for the CANVAS-R with no heterogeneity found between trials. In the combined analysis, there was not a statistically significant difference in cardiovascular death (HR 0.87 [95% CI ]). The initial CANVAS trial was partially unblinded prior to completion because of the need to file interim cardiovascular outcome data for regulatory approval of the drug. Of note, there was an increased risk of amputation with canagliflozin (6.3 vs. 3.4 participants per 1000 patient-years; HR 1.97 [95% CI ]).

6 2018 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm Sodium glucose cotransporter 2 (SGLT-2) inhibitors have a glucosuric effect that results in decreased A1C, weight, and systolic BP. Empagliflozin was associated with significantly lower rates of all-cause and cardiovascular death and lower risk of hospitalization for heart failure in the EMPA-REG OUTCOME trial. Treatment with canagliflozin significantly reduced the risk of the combined cardiovascular outcomes of cardiovascular death, myocardial infraction or nonfatal stroke, but increased the risk of amputation in the CANVAS, and hospitalization for heart failure was also reduced in CANVAS. Both empagliflozin and canagliflozin reduced secondary renal endpoints. Heart failure-related endpoints appeared to account for most of the observed benefits in this study. SGLT-2 inhibitors are associated with increased risk of mycotic genital infections and slightly increased LDL-C levels, and because of their mechanism of action, they have limited efficacy in patients with an egfr <45mL/min/1.73 m 2. Dehydration due to increased diuresis may lead to hypotension. The incidence of bone fractures in patients taking canagliflozin and dapagliflozin increased in clinical trials. Investigations into postmarketing reports of SGLT-2 inhibitor-associated diabetic ketoacidosis (DKA), which has been reported to occur in type 1 diabetes and T2D patients with less than expected hyperglycemia (euglycemic DKA) are ongoing. After a thorough review of the evidence during October 2015 meeting, an AACE/ACE Scientific and Clinical Review expert consensus group recommended stopping SGLT2 inhibitors 24 hours prior to scheduled surgeries and anticipated metabolically stressful activities and that patients taking SGLT2 inhibitors with insulin should avoid very low carbohydrate meal plans and excess alcohol intake.

7 2018 American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm

8 U.S. Food and Drug Administration Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin(invokana, Invokamet, Invokamet XR), May 16, 2017 Based on new data from two large clinical trials (CANVAS & Canvas-R), the FDA has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations Before starting canagliflozin, health care professionals should consider factors that may predispose patients to the need for amputations. These factors include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur. Final results from two clinical trials the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo. The most common amputations were of the toe and middle of the foot; however, amputations involving the leg, below and above the knee, also occurred. Some patients had more than one amputation, and some involving both limbs. U.S. Food and Drug Administration Drug Safety Communication: FDA Strengthens Kidney Warnings for Diabetes Medicines Canagliflozin and Dapagliflozin, June 14, 2016 Health care professionals should consider factors that may predispose patients to acute kidney injury prior to starting them on canagliflozin or dapagliflozin. These include decreased blood volume, chronic kidney insufficiency, congestive heart failure, and taking other medications such as diuretics, blood pressure medicines (ACEi, ARBs), and NSAIDs. Assess kidney function prior to starting canagliflozin or dapagliflozin and monitor periodically thereafter. If acute kidney injury occurs, promptly discontinue the drug and treat the kidney impairment. From March 2013, when canagliflozin was approved to October 2015, FDA received reports of 101 confirmable cases of acute kidney injury, some requiring hospitalization and dialysis, with canagliflozin or dapagliflozin use. In approximately half of the cases, the events of acute kidney injury occurred within 1 month of starting the drug, and most patients improved after stopping it.

9 U.S. Food and Drug Administration Drug Safety Communication: FDA Revises Labels of SGLT2 Inhibitors for Diabetes, December 4, 2015 Health care professionals should access for ketoacidosis and urinary tract infections in patients taking SGLT2 inhibitors who present with suggestive symptoms. Ketoacidosis associated with the use of SGLT2 inhibitors can occur even if the blood sugar level is not very high. If ketoacidosis is suspected, the SGLT2 inhibitor should be discontinued and treatment instituted promptly. Our review of the FDA Adverse Event Reporting System (FAERS) database from March 2013 to May 2015 identified 73 cases of ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors. All patients required hospitalization or treatment in an emergency department. In many cases, ketoacidosis was not immediately recognized because the blood glucose levels were below those typically expected for diabetic ketoacidosis. 19 cases of life-threatening blood infections (urosepsis) and kidney infections (pyelonephritis) that started as urinary tract infection with the SGLT2 inhibitors reported to FAERS from March 2013 through October New Warnings and Precautions to the labels of all SGLT2 inhibitors were added to describe these two safety issues. U.S. Food and Drug Administration Drug Safety Communication: FDA Revises Label of Diabetes Drug Canagliflozin (Invokana, Invokamet), September 10, 2015 Health care professionals should consider factors that contribute to fracture risk prior to starting patients on canagliflozin. Information about the risk of bone fractures was already in the Adverse Reactions section of the drug label at the time of canagliflozin s approval. Based on updated information about bone fractures from several clinical trials, we revised the drug label and added a new Warning and Precaution. The additional data confirm the finding that fractures occur more frequently with canagliflozin than placebo. Fracture can occur as early as 12 weeks after starting the drug. In addition, FDA has added new information about the risk of decreased bone mineral density to the canagliflozin label. Canagliflozin was shown to cause greater loss of bone mineral density at the hip and lower spine than a placebo. This new safety information has been added to the Adverse Reactions section of the drug label.

10 References: 1. Blevins T, Pullman J, Malloy J et al. J Clin Endocrinol Metab 2011 May; 96(5): FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. September 10, Available at: Accessed December 9, FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR); May 16, Available at: Accessed October 9, FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). June 14, Available at: Accessed December 9, FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. December 4, Available at: Accessed December 9, Zinman B, Wanner C, et al. N Engl J Med 2015;373(22): Garber, AJ, Abrahamson MJ, et al. Endocrine Practice, Vol 24(1), January American Diabetes Association. Standards of Medical Care in Diabetes Diabetes Care, January 2018, Volume 41, Supplement 1. Change Control Date Change 02/21/2018 Updated 2018 ADA and AACE Guidance