PHARMACY / UTILIZATION MANAGEMENT GUIDELINE
Medical Necessity Criteria for Pharmacy Edits
Revision Date(s) 03/10/15; 02/10/15; 01/13/15; 12/22/14; 12/08/14; 11/10/14; 10/13/14; 09/08/14; 08/11/14; 05/12/14; 04/14/14; 03/10/14; 11/11/13;10/14/13; 09/09/13; 08/12/13; 07/08/13; 05/13/13; 03/15/13; 03/11/13; 10/9/12; 07/10/12; 05/30/12; 04/10/12; 02/14/12; 09/07/11; 09/01/11; 08/01/11; 06/13/11; 02/08/11; 08/10/10; 06/08/10;04/13/10; 03/09/10; 02/09/10; 07/14/09; 02/10/09; 12/16/08; 04/08/08; 12/11/07; 06/12/07; 05/08/07; 08/08/06; 1/1/06
*This policy is managed through the Pharmacy benefit.
The medications in the following table are affected by the Company’s Pharmacy Prior Authorization program:
Brand non-stimulants for ADHD and other psychiatric conditions may be considered medically necessary when:
The use of two or more branded non-stimulant medications for ADHD or other psychiatric conditions is considered to be not medically necessary.
Brand stimulants for ADHD and other psychiatric conditions may be considered medically necessary when:
The simultaneous use of two or more stimulant medications for ADHD or other psychiatric conditions is considered to be not medically necessary except when a short-acting stimulant is used to provide coverage for an additional few hours after a long-acting stimulant wears off.
Vyvanse™(dextroamphetamine dimesylate) may be considered medically necessary for the treatment of Binge Disorder Eating (BED) without requiring a trial of or a contraindication to a generic stimulant when medical records show that all DSM-5 criteria for BED are met
Angiotensin II receptor blockers (ARBs)
Brand Angiotensin II receptor blockers that are not available generically may be considered medically necessary for the treatment of cardiovascular disease and diabetes when the patient has failed a trial of a generic ARB, due to intolerance or inadequate response.
Generic ARBs are:
Brand ARBs are:
Brand second generation antipsychotics (SGAs, formerly known as "atypicals") may be considered medically necessary when the patient has failed a trial of one generic SGA for the treatment of disorders or symptoms for which there is established evidence of the effectiveness of SGAs, including:
Brand second generation antipsychotics (SGAs, formerly known as "atypicals") may also be considered medically necessary when used in addition to a generic SGA when there has been an inadequate response to the generic SGA alone, for the treatment of the following disorders:
Abilify® (aripiprazole) may be considered medically necessary for the treatment of any psychotic disorder or psychotic symptoms, Schizoaffective Disorder, Bipolar Disorders, disorders with subtle psychotic thinking (eating disorders, Post Traumatic Stress Disorder, personality disorders), severe agitation, or Autism or Autism Spectrum Disorders, without trial and failure of at least one generic SGA.
Abilify® (aripiprazole) or Seroquel XR® (quetiapine fumarate) may be considered medically necessary for the augmentation of antidepressant medication for depressive disorders (without trial and failure of at least one generic SGA) when there have been trials and failure of at least two antidepressant medications, and Abilify® or Seroquel XR® is being used to augment an antidepressant (either one that the member is currently taking, or a new one).
Abilify® (aripiprazole) or Seroquel XR® (quetiapine fumarate) may be considered medically necessary for the augmentation of medication for Generalized Anxiety Disorder (without trial and failure of at least one generic SGA) when there have been trials and failure of at least two anxiolytic medications*, at least one of which is or was an SSRI, and Abilify® or Seroquel XR® is being used to augment an anxiolytic (either one that the member is currently taking, or a new one).
*SSRIs, benzodiazipines, hydroxyzine
Abilify® (aripiprazole) may be considered medically necessary for the augmentation of medication for OCD (without trial and failure of at least one generic SGA) when there have been trials and failure of at least two established medications for OCD (SSRIs, clomipramine), and Abilify® is being used to augment an OCD medication (either one that the member is currently taking, or a new one).
Latuda® (lurasidone HCL) or Seroquel XR® (quetiapine fumarate) may be considered medically necessary for the treatment of bipolar depression without trial and failure of a generic second generation antipsychotic.
Versacloz™ (clozapine) Oral solution may be considered medically necessary for Schizophrenia when the patient has experienced failure or intolerance to at least two second generation antipsychotics (brand or generic).
Versacloz™ (clozapine) Oral solution may be considered medically necessary for Schizoaffective Disorder when the patient has experienced failure or intolerance to at least one mood stabilizer and at least one second generation antipsychotic, or, to at least two second generation antipsychotics (brand or generic).
Versacloz™ (clozapine) Oral solution may be considered medically necessary for Bipolar Disorder when the patient has experienced failure or intolerance to at least one mood stabilizer and at least one second generation antipsychotic (brand or generic).
Versacloz™ (clozapine) Oral solution may be considered medically necessary for patients who require a liquid formulation instead of a pill (e.g. swallowing difficulties, a pattern of cheeking or spitting out pills, child or young adolescent who has not been able to swallow pills).
Linaclotide (Linzess™) may be considered medically necessary for the following labeled indications:
All other uses of linaclotide are considered investigational.
Lubiprostone (Amitiza®) may be considered medically necessary for the following labeled indications:
All other uses of lubiprostone are considered investigational.
Crofelemer (Fulyzaq™) may be considered medically necessary for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS when ALL of the following conditions are met:
All other uses of crofelemer are considered investigational.
Homozygous Familial Hypercholesterolemia Agents
Mipomersen (Kynamro™) and lomitapide (Juxtapid®), may be considered medically necessary as adjunctive therapy to lower low-density cholesterol (LDL), apolipoprotein B, total cholesterol and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia (HoFH).
All other uses of mipomersen and lomitapide are considered investigational.
Non-benzodiazepine hypnotic agents (branded single source), may be considered medically necessary for treatment of insomnia when the patient has failed a trial of a generic agent (e.g., eszopiclone, zolpidem or zaleplon) unless such therapy would be inappropriate.
Nonpreferred Combination Beta-2 Agonist / Corticosteroid Inhalers; Advair Diskus® (fluticasone propionate / salmeterol), Advair HFA® (fluticasone propionate / salmeterol) and Breo Ellipta™ (fluticasone furoate/ vilanterol) may be considered medically necessary after the trial and failure of at least one Preferred Combination Beta-2 Agonist/Corticosteroid Inhalers.
Preferred Combination Beta-2 Agonist/Corticosteroid Inhalers include Dulera® (mometasone furoate / formoterol fumarate) and Symbicort® (budesonide / formoterol fumarate)
Intranasal brand corticosteroid products (e.g., Beconase AQ®, Qnasl®, Nasonex®, Omnaris®, Veramyst®) may be considered medically necessary for the treatment of allergic rhinitis when the patient has failed a trial of at least one generic intranasal corticosteroid.
Ravicti™ (glycerol phenylbutyrate) may be considered medically necessary for the treatment of Urea Cycle Disorder when the patient has failed a trial of Buphenyl® (sodium phenylbutyrate) that was ineffective or not tolerated.
All brand non-insulin agents for the treatment of type 2 diabetes may be considered medically necessary for treatment of type 2 diabetes in patients who are concurrently taking or have failed metformin, AND EITHER another generic antidiabetic agent OR an insulin.
Combination products consisting of an incretin mimetic or DPP4 inhibitor and metformin may be considered medically necessary for treatment of type 2 diabetes in patients who are concurrently taking or have failed EITHER another generic antidiabetic agent OR an insulin.
Combination products consisting of an incretin mimetic or DPP4 inhibitor and a generic antidiabetic agent other than metformin may be considered medically necessary for treatment of type 2 diabetes in patients who are concurrently taking or have failed metformin.
For patients with contraindications to metformin use, another generic antidiabetic agent may be substituted in its place in the above requirements.
Brand Ophthalmic Prostaglandin Analogs (e.g., Lumigan®, Travatan Z®, Xalatan®, and Zioptan®) may be considered medically necessary to reduce intraocular pressure in patients with glaucoma when the patient has failed trial of generic latanoprost or travoprost.
Nonpreferred Proton Pump Inhibitors may be considered medically necessary for acid peptic diseases such as GERD, esophagitis or ulcer in cases when:
Preferred Proton Pump inhibitors:
Nonpreferred Proton Pump Inhibitors:
• Aciphex Sprinkles
Solodyn® (extended-release minocycline) may be considered medically necessary for the treatment of inflammatory lesions of acne in patients that have failed a trial of any generic tetracycline product, e.g., doxycycline or minocycline.
Nonpreferred Testosterone Replacement agents may be considered medically necessary when the patient has failed a trial of the preferred agent, Androgel® (testosterone gel).
Nonpreferred Testosterone Replacement agents include:
Modafinil (Provigil®) or armodafinil (Nuvigil®) may be considered medically necessary for the treatment of sleep apnea, narcolepsy or idiopathic hypersomnia when documented by a sleep study.
Modafinil (Provigil®) or armodafinil (Nuvigil®) may also be considered medically necessary for the treatment of depression when ALL of the following are present:
Modafinil (Provigil®) or armodafinil (Nuvigil®) may also be considered medically necessary for the treatment of bipolar depression when ALL of the following are present:
Use of modafinil (Provigil®) or armodafinil (Nuvigil®) for shift work sleep disorder is considered not medically necessary.
Modafinil (Provigil®) or armodafinil (Nuvigil®) may be covered with the following limits:
Xyrem® (sodium oxybate) may be considered medically necessary for the following labeled indications:
Quantity dispensed is not more than 9 grams per day.
All other uses of Xyrem® (sodium oxybate) are considered investigational.
Note: An adequate trial of a medication means:
A therapeutic dose of the medication, (i.e. a dose that usually works) is taken for a period that is long enough to get a positive response. A trial that was stopped because medication was not tolerated due to a severe adverse response is considered adequate, regardless of whether or not the medicine was taken for the recommended length of time to get a positive response.
Medication dosage and duration to achieve a therapeutic response while taking a trial of medication will vary based on the specific medication, the condition being treated and the age and/or size of the patient in some cases.
Medical Necessity Criteria and Dispensing Quantity Limits for Exchange Formulary Benefits
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
This policy applies to all pharmacy benefit contracts that include Pharmacy Prior Authorization Edits.
The Company’s Pharmacy Prior Authorization program is a set of electronic “smart edits” designed to improve the quality of pharmacy care for our members and promote appropriate and cost-effective drug therapies.
The goals of this program are:
This policy briefly describes each edit and sets forth the clinical criteria upon which the computerized edit logic is based. The medications included in the Pharmacy Prior Authorization are listed within the table located in the Coverage Guidelines section. Additional Prior Authorization drugs are contained in other medical policies. (See Related Policies/Guidelines)
Brand ADHD Agents
Stimulant drugs for ADHD fall into two categories: methylphenidate-based products and amphetamines. Within each category, pharmacokinetic profile is the primary differentiating characteristic. A wide variety of generic medications are currently available to meet the needs of most patients.
Strattera® (atomoxetine) is an ADHD drug with novel pharmacology, longer effect duration and a favorable side effect profile as compared to placebo in short term (10 weeks or less) clinical trials. It appears to be equally effective in pediatric and adult patients with ADHD. One longer-term open label study showed it to be comparable in effect to methylphenidate in children age 7-15. Other agents are appropriate for first-line use. Exceptions should be made when there are patient-specific concerns about abuse or diversion of controlled substances or contraindications to stimulant medication.
Intuniv® (guanfacine) and Kapvay® (clonidine hydrochloride) are indicated as adjuncts to stimulant medication when a stimulant has been ineffective or only partially effective. As such, Intuniv and Kapvay are not first-line agents unless stimulants are contraindicated for specific patients or when there are patient-specific concerns about abuse or diversion of controlled substances
Angiotensin II Receptor Blockers
All ARBs are indicated for treatment of hypertension (HTN) as monotherapy or in combination with other anti-HTN agents. These agents have demonstrated efficacy comparable to angiotensin-converting enzyme inhibitors (ACEIs) in lowering diastolic (DBP) and systolic blood pressure (SBP) in randomized clinical trials. Studies comparing various ARBs to beta-blockers, diuretics and calcium channel blockers (CCBs) demonstrated comparable efficacy in lowering SBP and DBP. ARBs have favorable drug interaction and adverse reaction profiles compared to ACEIs. In general, there is no a priori reason to prefer one ARB over another.
Second Generation Antipsychotics (SGA)
Head-to-head comparative effectiveness evidence for these agents in the treatment of psychotic disorders, psychotic symptoms, and manic symptoms is minimal. A series of Cochrane meta-analyses, each focusing on comparison of one agent with others for which direct comparative trials exist, supports the current standard of care, which is empiric drug selection based on patient characteristics, balancing the potential risk/benefit in each individual. Adverse effects and poor patient adherence continue to be major limitations in the use of these drugs. So far, the ideal antipsychotic agent does not exist. Clearly, this class is a fertile field for future comparative effectiveness research. SGAs are potent drugs with serious adverse effects. No clear evidence supports initial drug selection of any of the newer agents over the older alternatives in this class.
A total of two large meta-analysis and a systematic reviews of randomized controlled trials using fracture as an outcome in the treatment of osteoporosis have been published since the last review. All analyses have found good evidence to support vertebral fracture risk reduction with all three oral bisphosphonates, alendronate, risedronate and ibandronate. Good evidence was also found for nonvertebral and hip fracture risk reduction with alendronate and risedronate. However, the data with ibandronate was less consistent. Good evidence was found supporting no reduction in risk of nonvertebral fractures and insufficient evidence was found for evaluation of hip fracture with ibandronate. Of note, all included trials used daily dosing regimens; no fracture data is available for weekly or monthly dosing regimens.
Additional trials published since the last review support the efficacy of alendronate in patients with mildly reduced renal function; risedronate with monthly dosing regimens, men with osteoporosis and elderly women; and monthly dosing regimens with ibandronate. A meta-analysis found treatment of osteoporosis decreases mortality by 11% with an absolute benefit of 0.4 to 7 deaths per 1,000 patients-years of treatment. Delayed release (DR) risedronate was approved in October 2010 for the treatment of osteoporosis in postmenopausal women. DR risedronate contains a pH sensitive enteric coating and a chelating agent which allows for administration immediately following breakfast. In contrast, other bisphosphonates must be taken 30 minutes before breakfast. A single, unpublished, noninferiority trial is available which found DR risedronate noninferior to immediate release risedronate based on lumbar spine BMD over two years. The trial was not designed to assess differences in fracture. Two large, double-blind, randomized head-to-head trials with oral bisphosphonates have been published since the last review. Neither trial was designed to compare differences in fracture prevention. The FACTS-INT trial found alendronate significantly increased BMD compared to risedronate at all sites. The MOTION trial found ibandronate monthly noninferior to alendronate weekly based on BMD.
Osteoporosis guidelines have been published by four agencies since 2008. The National Osteoporosis Foundation (NOF), the American College of Physicians (ACP) and the North American Menopause Society (NAMS) include all bisphosphonates as first line agents. The American Association of Clinical Endocrinologists (AACE), however, recommends agents with fracture data for vertebral and hip fractures as first line. Based on these criteria, alendronate and risedronate are considered first line agents while ibandronate is considered second line due to a lack of efficacy with nonvertebral fractures and insufficient data with hip fractures, as described above.
The bulk of recent research with bisphosphonates has focused on safety data. Osteonecrosis of the jaw (ONJ): Case reports and retrospective studies indicate the majority of ONJ occurs in patients with malignancies receiving IV therapy, most commonly with zoledronic acid. Cases of ONJ in patients treated for osteoporosis are quite rare (0.00038% to 0.01%). There is not sufficient data to determine differences in risk between agents. Currently, the American Society for Bone and Mineral Research (ABSMR) estimates 0.85% to 2.9% of hip fractures are atypical fractures. The ABSMR estimates the number of fractures prevented by bisphosphonates is 13-29 times greater than the number of atypical fractures. Data is not available currently to compare the risk of atypical fractures between bisphosphonates.
Two conflicting studies have been published since the last review. The larger study indicates the risk of esophageal cancer appears elevated with long term bisphosphonate use. The studies did not evaluate differences in risk between agents.
Although data is conflicting, there does not appear to be an increased risk of atrial fibrillation with oral bisphosphonates. No data supports an increased risk with any particular oral agent over another.
A retrospective cohort study found a 36% decrease in severe GI events with monthly ibandronate compared to weekly alendronate or risedronate. No trials comparing GI side effects between monthly risedronate and ibandronate are available. To date, evidence does not support differences in GI side effects between bisphosphonates prescribed on a weekly basis.
The efficacy and safety of linaclotide (Linzess™) in irritable bowel syndrome with constipation (IBS-C) was established in one phase IIb and two phase III clinical trials. One additional phase IIb and two phase III trials evaluated linaclotide in chronic idiopathic constipation (CIC). In the phase III clinical trials for IBS-C, for the first of four co-primary endpoints, a greater proportion of patients treated with linaclotide 290mcg once daily compared to placebo achieved the US Food and Drug Administration (FDA)-recommended definition of response (33.6% and 33.7% for linaclotide vs. 21.0% and 13.9% for placebo, p<0.0001 for both). Linaclotide was also statistically significantly superior to placebo for all three of the additional co-primary endpoints in both trials, as well as all pre-specified secondary endpoints in both trials. In the phase III clinical trials in CIC patients, a greater proportion of patients in the linaclotide 145mcg group vs. placebo achieved the primary endpoint of an increase of ≥ 1 complete spontaneous bowel movement (CSBM) from baseline and ≥ 3 CSBMs in ≥9/12 weeks in both trials (16.0% vs. 6.0%, p<0.01 for trial 01 and 21.2% vs. 3.3%, p<0.001 for trial 303). Linaclotide was statistically significantly superior to placebo for all pre-specified secondary endpoints in both trials.
The efficacy and safety of lubiprostone was established in 2 double-blinded, placebo-controlled trials in patients with chronic idiopathic constipation (CIC), comparing lubiprostone 24 mcg twice daily with placebo for 4 weeks. The primary endpoint was spontaneous bowel movement (SBM) frequency. Patients treated with Amitiza had a higher frequency of SBMs during each week of therapy. Lubiprostone demonstrated increases in the % of patients with SBMs in the first 24 hours (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2). Time to first SBM was shorter with lubiprostone than placebo. Signs and symptoms related to constipation were also improved with lubiprostone versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age). During a 7-week randomized withdrawal study, patients who received lubiprostone during the treatment period were randomized to receive either placebo or to continue treatment with lubiprostone. In lubiprostone patients randomized to placebo, SBM frequency rates returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients continued on lubiprostone maintained response to therapy over the additional 3 weeks of treatment.
The efficacy of lubiprostone in the treatment of opioid-induced constipation was assessed in three randomized, double-blinded, placebo-controlled studies. Patients had been receiving stable opioid therapy for at least 30 days prior and continued during the 12-week treatment period. Baseline mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130 mg for placebo-treated and lubiprostone-treated patients in Study 1, 237 mg and 265 mg in Study 2 and 330 mg and 373 mg in Study 3. The Brief Pain Inventory-Short Form (BPI-SF) was administered at baseline and monthly. In Study 1 “overall responders” were 27.1% in the lubiprostone group vs 18.9% with placebo (treatment difference = 8.2%; p-value = 0.03). Examination of gender and race subgroups did not identify differences in response to lubiprostone among these subgroups. In Study 2, overall response rates were 24.3% in the lubiprostone group and 15.4% with placebo. In Study 3, “overall responders” were 15.3% in the lubiprostone group vs 13.0% with placebo. Two double-blinded, placebo-controlled studies demonstrated similar results in women with IBS-C. Insufficient men were enrolled in this study.
The evidence of efficacy of the approved formulation and dose of crofelemer (FULYZAQ) is limited to one unpublished short-term, phase III, randomized, placebo-controlled, two stage, adaptive trial conducted in 376 HIV+ patients with noninfectious diarrhea. The primary study endpoint was clinical response (defined as ≤2 watery stools/week for at least 2 of 4 weeks of placebo-controlled treatment). Over a 4-week placebo-controlled period, more patients receiving crofelemer 125 mg BID achieved clinical response compared to those receiving placebo (17.6% vs 8.0%, P<0.01). There is no comparative effectiveness evidence for the treatment of noninfectious HIV-associated diarrhea. Subgroup analysis from the pivotal phase III trial suggests the drug is more efficacious in HIV+ patients with more severe and pretreated diarrhea.
The safety profile for crofelemer across indications and doses studied appears good. The agent exerts its therapeutic effects locally in the GI tract, and there is little to no systemic absorption. Labeling contains no contraindications, warnings, or precautions, except to rule out infectious causes of diarrhea before initiating crofelemer.
The preferred treatment for Cushing’s disease is surgery, specifically transsphenoidal surgery (TSS). Surgery results in long-term remission rates of 60-90% with a recurrence risk of 26% within 10-years. Poor outcomes are seen with larger tumor size and repeat surgeries. Patients with persistent disease after surgery can be treated with pituitary irradiation; however, months to years of treatment may be required before an effect is seen. Bilateral adrenalectomy may also be performed; however, the pituitary adenoma remains in situ, negative feedback effects of cortisol are lost, and replacement gluco- and mineralocorticoids are required.
Medical therapy is used with unsuccessful surgery, patients without an adenoma image on MRI, those undergoing radiotherapy which is not yet effective, patients with severe complications of Cushing’s, and with those ineligible for surgery. Cushing’s disease can be treated with drugs which target the adenoma in the pituitary, adrenal-blocking drugs, or those which block glucocorticoid receptors.Drugs which target the pituitary include pasireotide, and the dopamine agonists bromocriptine and cabergoline. Cabergoline is a dopamine agonist which targets dopamine receptor subtype 2 (D2R) which is expressed in 80% of ACTH-secreting pituitary adenomas. Adrenal-targeting drugs include ketoconazole, metopirone, and mitotane. These agents act by inhibiting steroid formation. Ketoconazole’s actions are linked to inhibition of CYP 450 enzymes. Mitotane is typically effective in >50% of cases while ketoconazole and metoprione are effective in approximately 50% of patients. Mifepristone is the only agent available which blocks glucocorticoid receptors, more specifically the cortisol and progesterone receptors.4 However, each of these agents, with the exception of pasireotide, has been evaluated in a small number of patients. All except pasireotide and mifepristone are not FDA indicated for Cushing’s disease or syndrome. Mifepristone is FDA indicated for patients with Cushing’s syndrome with diabetes or glucose intolerance that require glycemic control.
Although several different guidelines address the diagnosis of Cushing’s disease, few address medical treatment. The European Neuroendocrine Association and the Pituitary Society last published a consensus statement in 2008 which discussed therapy options as described above. The guidelines emphasized the importance of surgery as a first line option, but did not recommend any particular medical therapy above another.
Exenatide (Byetta®, Bydureon®) and Liraglutide (Victoza®)
Byetta® is the first of a new class of antidiabetic agents known as incretin mimetics that mimic the actions of a naturally occurring incretin hormone, glucagon-like peptide 1 (GLP-1). Byetta® is indicated for use in combination with maximal doses of metformin, a sulfonylurea or a thiazolidinedione to improve glycemic control in patients with type 2 diabetes.
Byetta® stimulates glucose-dependent insulin secretion, improves first-phase insulin response, suppresses postprandial glucagons secretion, slows gastric emptying, suppresses appetite and reduces body weight. The most common adverse events seen with exenatide therapy include hypoglycemia (mild) and nausea, which improves after several weeks of use.
Byetta® typically achieves more modest A1c reduction (average 1%), but patients do not gain weight; in fact, two-year follow-up data showed that patients were able to lose five to 10 pounds per year, and weight loss continued at the two-year follow-up point. Trials in combination with insulin are ongoing.
Liraglutide acts by the same mechanism as exenatide. A1c reduction in clinical trials was comparable to the weekly exenatide (Bydureon®) and somewhat greater than twice daily Byetta®; however, rigorous head-to-head comparisons among these agents are not available.
Modafinil (Provigil®) or Armodafinil (Nuvigil®)
Provigil® and Nuvigil® have demonstrated some relative safety advantages over existing therapeutic options for wakefulness-promotion and the treatment of excessive daytime sleepiness. These agents also have an administrative prescribing advantage compared to CNS stimulants as a result of its classification as a C-IV rather than C-II controlled substance. There is no consistent evidence that doses greater than modafinil 200 mg/day or armodafinil 150 mg/day confer additional clinical benefit. Shift work sleep disorder is arguably a lifestyle issue and, as a result, may be classified as a benefit exclusion. Evidence for the short term efficacy of modafinil in this condition is limited. Efficacy in ADHD has not been consistently demonstrated in adequate clinical trials.
Non-benzodiazepine Hypnotics Agents (branded single source)
There are clear pharmacokinetic differences between zaleplon, zolpidem, eszopiclone, and benzodiazepines for the treatment of insomnia. Among the non-benzodiazepine agents, zolpidem seems to have optimal pharmacokinetics, and is, therefore, recommended as a preferred agent. Current evidence does not clearly demonstrate any advantage among zaleplon, eszopiclone, and zolpidem in efficacy.
Proton Pump Inhibitors
Strong evidence from numerous head-to-head clinical trials demonstrates the interchangeability of PPIs. In trials where there was a statistically significant difference in efficacy, the effect size was not clinically meaningful. Long-term studies show the PPIs to be safe and well tolerated. The incidence of nuisance side effects is very modest. Anecdotally, a small number of the most severe patients respond to esomeprazole (Nexium®) therapy when omeprazole has not provided adequate control. This is probably due to the higher concentration of the active S-isomer in this capsule. No controlled studies have been reported in this population, nor are any likely to be published. The Company concurs with the FDA’s finding that over-the-counter omeprazole 20mg can be used safely and effectively in self-management of uncomplicated GERD symptoms, with appropriate patient education. However, as currently positioned, the OTC product does not completely replace legend omeprazole.
Proton pump inhibitors are considered first-line therapy for laryngo pharyngeal reflux (LPR). As compared to GERD, LPR requires more aggressive and prolonged therapy. It often takes at least 6 months for laryngeal symptoms to achieve resolution.
Sitagliptin (Januvia™) and other DPP4 Inhibitors
Sitagliptin is the first of a new class of antidiabetic agents known as DPP-4 inhibitors that decrease the rate of clearance of endogenous incretins. It is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus as monotherapy or in combination with metformin or a thiazolidinedione when a single agent alone does not provide adequate glycemic control. Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Sitagliptin stimulates glucose-dependent insulin secretion, improves first-phase insulin response, suppresses postprandial glucagons secretion, slows gastric emptying, suppresses appetite and reduces body weight. The most common adverse events seen with sitagliptin therapy include hypoglycemia (mild) and nausea, which improves after several weeks of use.
Sitagliptin typically achieves more modest A1c reduction (average 1%), but patients do not gain weight; in fact, two-year follow-up data showed that patients were able to lose 5-10 pounds per year, and weight loss continued at the two-year follow-up point. Trials in combination with insulin are ongoing.
Other agents in this class approved by the FDA include alogliptin (Nesina®), saxagliptin (Onglyza®) and linagliptin (Tradjenta®). Vildagliptin was approved in Europe but is not currently available in the U.S. Clinical trial results are similar for all these agents, without direct comparisons. Combinations of DPP4 inhibitors with metformin, sulfonylureas and pioglitazone are also available.
Extended-release Solodyn® tablets are available in eight strengths (45 mg, 55 mg, 65 mg, 80 mg, 90 mg, 105 mg, 115 mg, and 135 mg) for more precise weight-based dosing of Solodyn® that narrows the actual dose ranges toward the target of 1 mg/kg/day for patients with non-nodular, moderate to severe inflammatory acne 12 years and older weighing 99-300 lbs. In clinical trials of the 45 mg, 90 mg, and 135 mg strengths with 1,038 patients, Solodyn® demonstrated efficacy in a low dose (1 mg/kg/day). There was no evidence of improved efficacy with 2 mg/kg/day and 3 mg/kg/day.5 Higher doses of Solodyn® have not been shown to be of additional benefit in the treatment of inflammatory lesions of acne, and may be associated with more acute vestibular adverse events. Clinical studies also showed that Solodyn® tablets were well-tolerated, with an adverse event profile similar to placebo.
In a Phase II dose-response study of 233 subjects with the 45 mg, 90 mg, and 135 mg strengths, 1 mg/kg/day extended-release Solodyn® tablets provided statistically significant inflammatory lesion reduction vs. placebo (n=114, 56.8% vs. 39.4%, p=0.015). In two Phase III clinical studies with the 45 mg, 90 mg, and 135 mg strengths, the mean percent improvement in inflammatory lesions was greater in patients treated with Solodyn® tablets than with placebo (Study 1, n=451, 43.1% vs. 31.7%, p=0.001; Study 2, n=473, 45.8% vs. 30.8%, p<0.001, respectively). There was no evidence of improved efficacy with 2 mg/kg/day and 3 mg/kg/day. No head-to-head data are reported. The manufacturers’ trials are all unpublished and placebo-controlled, making it impossible to assess comparative effectiveness.
Adverse reactions reported in the clinical trials of Solodyn® were not statistically different from placebo.1 No comparative data versus other forms of minocycline or doxycycline were found. A recent review article recommends doxycycline as a first choice oral tetracycline for acne patients, due to the overall lower side effect profile.
Sodium oxybate is a CNS depressant. The mechanism of action of Xyrem in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA. Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma and death. It is hypothesized that the therapeutic effects of Xyrem on cataplexy and excessive daytime sleepiness are mediatedthrough GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. Xyrem is a Schedule III controlled substance. Because of its abuse/diversion potential, it is only available from a single pharmacy through a limited distribution scheme, the Xyrem Success Program. Both prescribers and patients must be registered in this program to obtain the drug. Serious side effects observed in patients taking Xyrem include hallucinations, agitation, severe confusion, abnormal thinking, sleep disturbances and depression. In 2011, Jazz Pharmaceuticals, the manufacturer, was cited for failure to properly submite adverse event reports to the FDA.
Sodium oxybate is eliminated by cytosolic metabolism and exhibits saturable kinetics. This has not been studied in children under 18, and data in elderly populations are limited. Clearance was reduced by more than half in patients with cirrhosis, both Child’s Class A and C.
The efficacy of Xyrem in the treatment of cataplexy was evaluated in two 4-week randomized, double-blind, placebo-controlled, multicenter, parallel-group trials, n=136 and 55 respectively. The high percentages of concomitant stimulant use in these studies make it impossible to assess the efficacy and safety independent of stimulant use. Doses of 6-9 g per night resulted in statistically significant reductions in frequency of cataplexy attacks. The 3 g per night dose had little effect. Overall, the evidence supporting this indication is of low quality.
The efficacy of Xyrem in the treatment of excessive daytime sleepiness in patients with narcolepsy was evaluated in an 8-week randomized, double-blind, placebo-controlled trial, n=228. Most of these patients were also being treated with CNS stimulants. Statistically significant improvements in Epworth Sleepiness Scale Scores were seen with 6 and 9 g doses. A second multicenter randomized, double-blind, placebo-controlled, parallel-group trial evaluated 222 patients on modafinil at baseline, who were randomized to placebo, Xyrem, modafinil, or Xyrem plus modafinil. Xyrem dose was 6 g per night for 4 weeks, followed by 9 g per night for 4 weeks. Modafinil was continued in the modafinil groups at the patient’s prior dose. A statistically significant improvement in in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Xyrem and Xyrem plus modafinil groups compared to placebo. The trial was not designed to compare Xyrem with modafinil.
Studies have been conducted to demonstrate the efficacy of Xyrem in fibromyalgia patients; however, all of these have been placebo-controlled. In 2010, FDA rejected an application for use in fibromyalgia. FDA panel members expressed serious concerns about the potential for abuse and diversion of sodium oxybate. This concern was felt to outweigh any benefits that might accrue, and is supported by the lack of any head-to-head comparison with alternative treatments for fibromyalgia, none of which have the level of abuse potential seen with Xyrem. The manufacturer is currently conducting clinical trials in a number of other diseases including Parkinson’s, schizophrenia, chronic insomnia, obstructive sleep apnea, PTSD, Alzheimer’s and essential tremor.
Add to Prescription Drug Section - New Policy—effective January 1, 2006.
Replace Policy - Policy reviewed with literature search by Pharmacy and Therapeutic Committee on July 25, 2006. Policy statement updated with exenatide and thiazolindinediones added as medically necessary; Policy Guidelines and Rationale sections updated; references added.
Replace Policy - Policy statement for exenatide updated with additional criteria; Policy Guidelines updated to reflect addition to policy statement. Reviewed by P&T on March 27, 2007.
Replace Policy - Policy statement on coverage criteria for exenatide (Byetta®), sitagliptin and esomeprazole (Nexium®) expanded; medically necessary indications for 5HTR3R antagonists, Actiq® and Fentora™ added to policy statement. Policy Guidelines updated and Rationale updated; references added
Replace Policy - Policy reviewed with literature search by Pharmacy and Therapeutic Committee on May 15, 2007.Policy statement updated to include Pregabalin as either medically necessary or investigational under the criteria. Acyclovir, famciclovir and valacyclovir as medically necessary under criteria. References added.
Replace Policy - Policy updated with literature search by Pharmacy. Policy statement was updated to include fibromyalgia as a medically necessary indication under Pregabalin. References added.
Replace Policy - Policy updated with literature search by Pharmacy. Policy statement updated to include the use of leukotrience modifiers for the treatment of allergic rhinitis refractory to nasal corticosteroids under the medically necessary indication.
Replace Policy - Policy updated with literature search by Pharmacy. Policy statement updated to delete medically necessary and investigational statements relating to Pregabalin. Pregabalin statements moved to PR.5.01.521
Replace Policy - Policy updated with literature search by Pharmacy. Policy statement updated with addition of Nuvigil. Reference added
Replace Policy - Policy updated with literature search by Pharmacy. No change to the policy statement. Policy guidelines section updated.
Replace Policy - Policy updated with literature search. Policy statement updated with medically necessary indications for provigil and nuvigil when all criteria are met. New diabetes drugs also added to medically necessary statement. References added.
Replace Policy - Policy updated with literature search. Policy statement updated with medically necessary indication added for Leukotriene modifiers. References added.
Replace Policy - Policy updated with literature search. Pantoprazole added to policy guidelines. Reference added.
Replace Policy - Policy updated with the addition of 300mcg strength to Fentora Buccals (new strength available) in policy guideline; bolding of the beginning of paragraph in policy guidelines for antivirals; and the addition of HAS in sentence for leukotriences in policy guidelines, and a paragraph formatting in rationale/source.
Replace Policy - Reference to COX II inhibitors and transmucosal fentanyl citrate removed from the Policy statements and entirety of the policy and are now discussed in 5.01.529. References removed.
Replace Policy - Policy updated based on review by P&T May 2011. List of point-of-sale program drugs updated; antiemetics removed from the list and the medically necessary policy statement has been removed from the Policy section. The medically necessary policy statement on non-benzodiazepine hypnotic drugs has been updated to include zaleplon as one of the agents required for failed trial; Rationale updated. Phased-in additional changes are: August - Solodyn® (extended-release minocycline) considered medically necessary for the treatment of inflammatory lesions of acne following a failed trial of any generic tetracycline product, e.g., doxycycline or minocycline; September - Nonpreferred atypical antipsychotics considered medically necessary for labeled indications following failed trial of a preferred atypical antipsychotic agent AND orally-administered brand Bisphosphonate products considered medically necessary for treatment of osteoporosis following a failed a trial of generic alendronate; October - Nonpreferred ARBs considered medically necessary for the treatment of cardiovascular disease and diabetes following failed trial of a preferred ARB. Policy Guidelines updated for the October phase indicating preferred ARB allowable for patients unable to tolerate nonpreferred ARBs.
Replace Policy - Preapproved edits for August implementation added to policy; policy published.
Replace Policy – Preapproved edits for September implementation added to policy: September - Nonpreferred atypical antipsychotics considered medically necessary for labeled indications following failed trial of a preferred atypical antipsychotic agent AND orally-administered brand Bisphosphonate products considered medically necessary for treatment of osteoporosis following a failed a trial of generic alendronate.
Replace Policy – Policy updated and published with final changes, originally scheduled for October. The changes are as follows and carry the effective date of 9/7/11: Nonpreferred ARBs considered medically necessary for the treatment of cardiovascular disease and diabetes following failed trial of a preferred ARB; Policy Guidelines updated for the October phase indicating preferred ARB allowable for patients unable to tolerate nonpreferred ARBs. Description section updated: Atelvia™ (risendronate sodium delayed release) added to the list of biophosphates included in the Pharmacy Point-of-Sale program.
Replace policy. Policy updated with an additional policy statement indicating brand ophthalmic prostaglandin analogs as medically necessary to reduce intraocular pressure in patients with glaucoma when the patient has failed trial of generic latanoprost. Sitagliptin and simvastatin (Juvisync™) added to the approved medically necessary medications to treat type 2 diabetes within the category of incretin mimetics or DPP4 inhibitors. Edarbi® added to the list of ARBs approved for medically necessary treatment of CV and diabetes. Reviewed by P&T on January 24, 2012.
Minor update, Valtuma (aliskiren/valsartan) no longer covered by this policy; it was removed.
Replace policy. Policy updated with a new medically necessary policy statement for Intranasal brand corticosteroid products (e.g., Beconase AQ®, Nasonex®, Rhinocort Aqua®, Omnaris®, Veramyst®) for allergic rhinitis when the patient has failed a trial of at least one generic intranasal corticosteroid. Newly approved brand and POS drugs added to policy.
Qnasl® added to the list in intranasal steroids within the Policy section. Statins were removed from the policy.
Minor update: irbesartan and irbesartan/HCT added to the list of nonpreferred angiotensin II receptor blockers approved as medically necessary when a preferred medication has failed; and lansoprazole added to the list of proton pump inhibits approved as medically necessary for treatment of acid peptic diseases.
Minor update. Two updates were made to the Policy Guidelines: 1. an additional bullet point under the limitations of coverage for modafinil (Provigil®) or armodafinil (Nuvigil®) was added, indicating therapy with Nuvigil® will be approved ONLY when the prescriber has documented an adverse reaction or intolerance to generic modafinil or Provigil; 2. clarification was added to the paragraph on non-benzodiazepines hypnotic agents (branded single source), pointing out zolpidem or zaleplon as examples of generic agents requiring a trial failure for approval. These edits are effective as of 8/1/12 for prior authorization and were approved by P&T May 2012.
Replace Policy – Policy section revised, Abilify has been added with 2 medically necessary statements; There is now a double-step edit requiring the use of metformin unless contraindicated; the use of any two generics or a generic and an insulin must be tried.
Update Related Policies. Add 5.01.529.
Replace policy. Policy updated with the following: 1) Brand non-insulin agents for the treatment of type 2 diabetes and TZD’s combined – remove THIAZOLIDINEDIONES (TZD) language, and slight change in the Brand non-insulin products language. (There will be one Diabetic Agent Policy); Second generation antipsychotics (SGA) - Paragraph added to further clarify the SGA prior authorization criteria; Bisphosphonates - Addition of new medication, BINOSTO® and remove BONIVA®; Angiotensin receptor blockers - move DIOVAN HCT® from preferred to non-preferred list and addition of 2 new generics to preferred list; Proton Pump Inhibitors – increase the number of failed trials to at least two of the listed medications before this class of drug would be approved for medical necessity in treating GERD, esophagitis or ulcer. 2) Policy updated with medically necessary indications for Abilify®, with or without the failure of a generic SGA, removing criteria of the need for a legitimate medical reason to avoid the potential weight gain or metabolic effects of other SGAs and for concern about potential QT prolongation with ziprasidone: psychotic disorder or psychotic symptoms, Schizoaffective Disorder, Bipolar Disorders, disorders with subtle psychotic thinking (eating disorders, Post Traumatic Stress Disorder, personality disorders), severe agitation or Autism or Autism Spectrum Disorders, augmentation of antidepressant medication for depressive disorders when at least two antidepressants medications have failed, for the augmentation of an anxiolytic for Generalized Anxiety Disorder when at least two anxiolytic medications have failed and at least one of which is or was an SSRI, and for the augmentation of medication for Obsessive Compulsive Disorder when there have been at least two failed trials of medications for OCD.
Replace policy. Added ibrandronate to the Bisphosphonates within the Policy section; removed text in Brand Non-Insulin Agents within the Description.
Minor update. Clarification made in Description section; brand SGAs bullet now preceded by "including but not limited to..."
Replace policy. Policy updated with two new policy statements: 1) Non-Preferred Combination Beta-2 Agonist / Corticosteroid Inhalers; Advair Diskus® (fluticasone propionate / salmeterol) and Advair HFA® (fluticasone propionate / salmeterol) may be considered medically necessary after the trial and falure of at least one Preferred Combination Beta-2 Agonist/Corticosteroid Inhalers (these have been defined); 2) Nonpreferred Testosterone Replacement agents (examples provided) may be considered medically necessary when the patient has failed a trial of the preferred agent, Androgel® (testosterone gel). Policy Guidelines section updated with coverage criteria of newly added agents, which have also been listed in the Description section.
Update Related Policies. Add 11.01.504.
Replace policy. Policy section updated with Breo Ellipta™ (fluticasone furoate/ vilanterol) as an added product to the list of non-preferred combination beta-2 agonist/corticosteroid inhalers approved following trial and failure of at least on preferred product. Clarification was added to the policy that it is managed through the member’s pharmacy benefit; this is now listed in the header and within the coding section.
Replace policy. Policy updated with the addition of crofelemer as medically necessary for symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS. The leukotriene modifier edit has been removed from the Policy section, as Singular went generic. The policy statement for brand ADHD drugs has been updated to indicate all brand ADHD drugs are subject to review and may be approved when a generic has failed, is not available, or is inappropriate as outlined. Travoprost is now added to the list of generics which must be tried and failed for a patient to qualify for coverage for brand ophthalmic prostaglandin analogs. Policy section reorganized for clarification with a table added to outline specifically those medications addressed in this policy which are subject to the Company’s Pharmacy Prior Authorization program.
Replace policy. Xyrem® added to Policy section with a medically necessary indication for treating narcolepsy when diagnosed through a sleep study. Rational section updated in support of this addition.
Replace policy. Policy section updated with addition of Homozygous Familial Hypercholesterolemia Agents Mipomersen (Kynamro™) and lomitapide (Juxtapid®), considered medically necessary as adjunctive therapy to lower low-density cholesterol (LDL), apolipoprotein B, total cholesterol and non-HDL cholesterol. Policy Guidelines section also updated. Change title to policy 2.01.503.
Replace policy. Policy updated with medical necessity criteria for brand stimulant and brand non-stimulant ADHD drugs; Seroquel XR® (quetiapine fumarate) added as medically necessary in the treatment of depressive disorders when criteria are met; and, Latuda® (lurasidone HCL) and Seroquel XR® (quetiapine fumarate) added as medically necessary to treat bi-polar disorder. Rationale section updated.
Annual review. Policy section updated to reflect expansion of brand stimulants and non-stimulants, previously only addressing ADHD, to now include other psychiatric conditions.
Interim review. Policy updated with the addition of Abilify® (aripiprazole) as medically necessary for the augmentation of medication for OCD (without trial and failure of at least one generic SGA) when criteria are met; Versacloz™ (clozapine) Oral solution as medically necessary for Schizoaffective Disorder and bipolar disorder when trial and failure criteria are met; and, Versacloz™ (clozapine) Oral solution as medically necessary for patients who require a liquid formulation instead of a pill.
Interim review. Policy updated with the addition of a new drug, Hetlioz, now included in the hypnotics category; Lunesta was removed from this same category, as it is now available generically. Eszopiclone has been added as a qualifier for coverage of a brand name hypnotic drug.
Update Related Policies. Add 5.01.552.
Interim review. Testosterone gel, Vogelxo™ added to the list of medically necessary agents for testosterone replacement therapy; Amitiza® Linzess™ added to treat constipation; treatment of Cushing’s removed (addressed in another policy). References 50 – 56 added.
Interim review. Jardiance® added to the list of approved drugs within the category of non-insulin antidiabetic agents, brands as listed on the drug class table. A policy statement was added to indicate that the use of two or more branded non-stimulant medications for ADHD or other psychiatric conditions is considered to be not medically necessary. Another policy statement was added to clarify that the simultaneous use of two or more stimulant medications for ADHD or other psychiatric conditions is considered to be not medically necessary except when a short-acting stimulant is used to provide coverage for an additional few hours after a long-acting stimulant wears off.
Interim update. Removed all multisource brand medications as this policy will now only target SSB medications. Also cleaned up the formatting for superscript so that all were the same.
Interim update. Policy section updated with the addition of a medically necessary statement for nitrogen scavenging agents
Interim update. Additional drugs added to the Non-Insulin Antidiabetic Agents, brands section of the Policy section.
Interim update. Belsomra® added to the list of non-benzodiazepine hypnotic brand drugs. Approved by P&T November 2014. Related Policy 11.01.504 updated; it is renumbered to 6.01.522.
Annual review. Policy updated with the addition of 2 proton pump medications to support recent edits: Aciphex and Zegerid.
Minor update. Policy converted to UM Guideline. Modafinil: criterion removed requiring trial of two or more standard antidepressant medications that need to be stopped due to triggering or worsening hypomania or mania as related to fatigue and/or sleepiness.
Annual review. Updated criteria for ARB and PPI and added some additional language on the ADHD guidelines. Drugs that will no longer require a PA review removed from the policy.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).