PHARMACY / UTILIZATION MANAGEMENT GUIDELINE

COVERAGE GUIDELINE
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Medical Necessity Criteria for Pharmacy Edits

Number 5.01.605*

Effective Date June 9, 2015

Revision Date(s) 06/09/15; 05/12/15; 04/14/15; 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

Replaces N/A

*This policy is managed through the Pharmacy benefit.

Coverage Guideline

Index of Drugs, Drug Classes and Disease States

The medications in the following table are affected by the Company’s Pharmacy Prior Authorization program:

Drug Class

Indications

Individual Agents

ADHD Drugs, brands

ADHD

Aptensio XR™ Daytrana®, Evekeo™ Focalin XR® 5mg, 10mg, 20mg, Quillivant XR®, Ritalin LA® 10mg, Strattera®, Vyvanse®, Zenzedi

Angiotensin II Receptor Blockers, brands

Hypertension, Cardiovascular Disease, Diabetes

Benicar®, Benicar/HCT®, Edarbi®, Edarbyclor®, Teveten/HCT®

Antipsychotics (2nd Gen., “Atypicals”), brands

Psychoses, Bipolar Disorder, MDD, etc.

Abilify®, Fanapt®, Invega®, Latuda®, Saphris®, Seroquel XR®,Versacloz

Constipation

IBS-C, CIC

Amitiza® Linzess

     

Homozygous Familial Hypercholesterolemia

HoFH

Juxtapid®, Kynamro

Hypnotics, non-benzodiazepine, brands

Insomnia

Edluar®, Intermezzo®, Rozerem®, Zolpimist, Belsomra®

Inhaled Corticosteroid/Beta Agonist Products

Asthma, COPD

Advair Diskus®, Advair HFA ®, Breo Ellipta®

Intranasal corticosteroid products, brands

Allergic Rhinitis

Beconase AQ®, Nasonex®, Omnaris®, Qnasl®, Veramyst®, Zetonna®

Nitrogen scavenging agents

Urea Cycle Disorder

Ravicti

Non-Insulin Antidiabetic Agents, brands

Type 2 Diabetes

ActoPlus MetXR®, Avandia®, Avandamet®, Avandaryl®, Byetta®, Bydureon®, Farxiga, Invokana, Invokamet®Janumet/XR®,Januvia®, Jardiance®, Jentadueto, Kazano®, Kombiglyze XR, Nesina®, Onglyza®, Oseni®, PrandiMet®, Tanzeum, Tradjenta®,Trulicity™ Victoza®, Xigduo™XR & combinations of these, etc.

Ophthalmic Prostaglandin Analogs, brands

Glaucoma

Lumigan®, Travatan Z®, and Zioptan®

Proton Pump Inhibitors (PPI)

Acid-Peptic Disease, GERD, Ulcers

Aciphex® Sprinkle™, Dexilant, Esomeprazole Strontium, First®-Lansoprazole, First®-Omeprazole, Omeprazole+SyrSpend® , Prilosec® suspension, Zegerid® packets

Solodyn®

Acne

Solodyn®

Testosterone Replacement

Low Testosterone

Axiron®, Fortesta®, Natesto™, Testim®, Testosterone gel, Vogelxo

Wake promoting agents

Idiopathic Hypersomnia, Narcolepsy, Sleep Apnea, Depression

Nuvigil® Provigil® (modafinil)

Xyrem®

Narcolepsy

Xyrem®

Stimulants and Non-Stimulants for ADHD and other psychiatric conditions

Brand non-stimulants for ADHD and other psychiatric conditions may be considered medically necessary when:

  • Patient failed a previous adequate trial* of a stimulant agent; or
  • Patient history or assessment suggests likelihood of abuse or diversion of stimulant; or
  • Patient has contraindication(s) to stimulant use; or
  • A suitable generic alternative is not currently available.

The use of two or more branded non-stimulant medications for ADHD or other psychiatric conditions is considered to be not medically necessary.

Branded non-stimulants are considered to be not medically necessary for psychiatric conditions for which there is no credible published scientific evidence of efficacy or effectiveness.

Brand stimulants for ADHD and other psychiatric conditions may be considered medically necessary when:

  • Patient failed a previous adequate trial of a generic stimulant agent; or
  • A suitable generic alternative is not currently available
  • Patient failed a previous adequate trial of an oral stimulant agent (brand or generic) and is or will be placed on a transdermal brand stimulant.

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

Vyvanse™ (dextroamphetamine dimesylate) may be considered medically necessary for the treatment of ADHD without requiring a trial of or a contraindication to a generic stimulant when the individual has a history of drug abuse or dependence.

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:

  • candesartan/HCT
  • irbesartan, irbesartan/HCT
  • losartan, losartan/HCT
  • telmisartan/HCT
  • Telmisartan
  • Valsartan, valsartan/HCT

Brand ARBs are:

  • Benicar/HCT® (olmesartan/HCT)
  • Benicar® (olmesartan)
  • Edarbi® (azilsartan medoxomil)
  • Edarbyclor® (azilsartan medoxomil/ chlorthalidone)
  • Teveten/HCT® (eprosartan/hydrochlorothiazide)

Antipsychotics, Second Generation

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:

  • Psychotic disorders, psychotic symptoms
  • Schizoaffective Disorder, Bipolar Disorders
  • Disorders with subtle psychotic thinking (eating disorders, Post Traumatic Stress Disorder, personality disorders)
  • Severe agitation
  • Augmentation of antidepressant medication for depressive disorders
  • Augmentation of medication in treatment-resistant Obsessive Compulsive Disorder (OCD)
  • Augmentation of medication in treatment-resistant Generalized Anxiety Disorder

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:

  • Psychotic disorders
  • Psychotic symptoms
  • Schizoaffective Disorder
  • Bipolar 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 irritability or agitation associated with 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).

Constipation

Linaclotide (Linzess™) may be considered medically necessary for the following labeled indications:

  • Adults with Irritable Bowel Syndrome with constipation (IBC-C)
  • Adults with Chronic Idiopathic Constipation (CIC) who have had an adequate trial and failure, intolerance or contraindication to at least one other therapy (e.g. laxatives, spasmodics).

All other uses of linaclotide are considered investigational.

Lubiprostone (Amitiza®) may be considered medically necessary for the following labeled indications:

  • Females at least 18 years of age with Irritable Bowel Syndrome with constipation (IBC-C)
  • Adults with Chronic Idiopathic Constipation (CIC).

All other uses of lubiprostone are considered investigational.

Crofelemer (Fulyzaq™)

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:

  • Patient is currently on anti-retroviral therapy; AND
  • Patient has experienced one or more loose or watery stools per day for at least one month, despite treatment with at least two nonspecific antidiarrheals; AND
  • A dispensing quantity limit of 60 tablets per 30 days applies.

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.

Hypnotics

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.

Inhaled Corticosteroid/Beta-Agonist Products

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

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.

Nitrogen Scavenging Agents

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.

Non-Insulin Antidiabetic Agents

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.

Ophthalmic Prostaglandin Analogs

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.

Proton Pump Inhibitors (PPI)

Nonpreferred Proton Pump Inhibitors may be considered medically necessary for acid peptic diseases such as GERD, esophagitis or ulcer in cases when:

  • Patient has failed trials of two preferred or
  • Patient has had an adverse reaction to at least 2 preferred PPIs
  • Patient is less than six years of age.

Preferred Proton Pump inhibitors:

  • Prilosec (omeprazole)
  • Prevacid (lansoprazole)
  • Protonix (pantoprazole)
  • Nexium (esomeprazole)
  • rabeprazole

Nonpreferred Proton Pump Inhibitors:

• Aciphex Sprinkles

  • Dexilant
  • Esomeprazole Strontium
  • First-Omeprazole
  • First-Lansoprazole
  • Omeprazole+Syrspend
  • Prilosec packets
  • Zegerid Packets

Solodyn

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.

Testosterone Replacement Products

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:

  • Axiron® (testosterone topical solution),
  • Fortesta® (testosterone gel),
  • Testim® (testosterone gel),
  • Testosterone 1% gel (brand name)
  • Vogelxo™ (testosterone gel)

Wake Promoting Agents

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:

  • Major depressive episode(s) as defined in the current edition of the DSM (Diagnostic and Statistical Manual of Mental Disorders);
  • Persistent significant fatigue and/or excessive sleepiness that have been determined to be either unresponsive depressive symptomatology or antidepressant-induced adverse effects, and, that impair normal daily functioning;
  • The fatigue and/or sleepiness have not resolved with trials of at least two different antidepressant medications, or there are compelling clinical reasons to not use antidepressants other than the first one initiated; and
  • The fatigue and/or sleepiness have not responded adequately to methylphenidate or amphetamine preparations; adverse medication effects have precluded adequate trials of methylphenidate or amphetamine preparations; or there are contraindications to the use of methylphenidate and amphetamine preparations.

Modafinil (Provigil®) or armodafinil (Nuvigil®) may also be considered medically necessary for the treatment of bipolar depression when ALL of the following are present:

  • Major depressive episode(s) as defined in the current edition of the DSM (Diagnostic and Statistical Manual of Mental Disorders);
  • Persistent significant fatigue and/or excessive sleepiness that have been determined to be unresponsive depressive symptomatology or adverse effects secondary to standard antidepressants or to medications used specifically for bipolar depression, and, that impair normal daily functioning; and
  • The fatigue and/or sleepiness have not resolved with trials of two or more established pharmacological treatments for bipolar depression (lithium, valproate, lamotrigine, Symbyax, quetiapine), or, there are compelling clinical reasons to not use any of these that have not been attempted.

Modafinil (Provigil®) may also be considered medically necessary for the treatment of Attention Deficit/Hyperactivity Disorder (AD/HD) if treatment with at least one methylphenidate formulation and at least one amphetamine formulation have been unsuccessful or intolerable, or there is a bona-fide contraindication to the use of methylphenidate and amphetamine formulations.

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:

  • Therapy with Nuvigil® will be approved ONLY when the prescriber has documented an adverse reaction or intolerance to generic modafinil or Provigil.
  • Therapy with modafinil should not exceed 200 mg per day.
  • Therapy with armodafinil should not exceed 150 mg per day.
  • Therapy should be reviewed after one year.

Xyrem®

Xyrem® (sodium oxybate) may be considered medically necessary for the following labeled indications:

  • Treatment of cataplexy in narcolepsy patients when diagnosis of narcolepsy has been documented by a sleep study.
  • Treatment of excessive daytime sleepiness in narcolepsy patients, when ALL of the following conditions are met:
  • Diagnosis of narcolepsy has been documented by a sleep study; AND
  • Prior therapy with a stimulant medication (e.g., methylphenidate) was ineffective, not tolerated or contraindicated; AND
  • Prior therapy with modafinil (Provigil®) or armodafinil (Nuvigil®) was ineffective, not tolerated or contraindicated.

Quantity dispensed is not more than 9 grams per day.

Doses greater than 9 grams per day are not supported by clinical evidence and therefore are considered not medically necessary.

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.

Coding

N/A

Related Guidelines / Policies

2.01.503

Diagnosis of Obstructive Sleep Apnea Syndrome

2.01.533

Upper Gastrointestinal Endoscopy in Adults

5.01.520

Antidepressants: Pharmacy Medical Necessity Criteria for Brands

5.01.521

Pharmacologic Treatment of Neuropathy, Fibromyalgia and Seizure Disorders

5.01.529

Opioid and Non-Opioid Analgesics

5.01.541

Medical Necessity Exception Criteria for Closed Formulary Benefits and Dispense as Written (DAW) Exception Reviews

5.01.547

Medical Necessity Criteria and Dispensing Quantity Limits for Exchange Formulary Benefits

5.01.552

Tasimelteon (Hetlioz™)

Scope

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.

Additional Information

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:

  • To improve the quality of pharmacotherapy and its outcomes;
  • To promote the appropriate and cost-effective use of medications; and
  • To ensure the appropriate length of drug therapy for each patient.

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)

Rationale

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.

  • Major Depression augmentation – Among the SGAs, only Ability® and Seroquel XR® have large size positive RCTs for this use. Immediate-release quetiapine has a negative RCT, olanzapine and risperidone have positive RCTs only with small size studies bu also have negative RCTs, and there are no good RCTs for the other SGAs for this use.
  • Bipolar depression – The other established medications for the treatment of bipolar depression are more problematic for the following reasons:
  • Symbyax- the fixed dose combination makes dose adjustments difficult, and olanzapine metabolic side-effects are considerably more problematic than Latuda or Seroquel XR.
  • Lithium- multiple daily dosing needed, plus small window between therapeutic and toxic serum levels, plus more problematic side-effects, plus augmentation with a SGA antipsychotic is not infrequently needed.
  • Lamotrigine- multiple daily dosing needed, plus risk of SJ syndrome (and have to d/c with any rash, even if eventually not SJ syndrome), plus sub-optimal efficacy for acute depressive symptoms.
  • Immediate-release quetiapine- multiple daily dosing needed, plus more sedating that Latuda, plus XR formulation has a “smoother” clinical effect.

Bisphosphonates

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.

Esophageal Cancer

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.

Atrial Fibrillation

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.

Gastrointestinal

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.

Constipation

Linaclotide

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.

Lubiprostone

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.

Crofelemer (Fulyzaq™)

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.

Cushing’s Disease

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.

Solodyn®

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.

Xyrem®

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.

References

  1. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 2000; 54:1166-1175.
  2. Drover D. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives. Clinical Pharmacokinetics 2004; 43:227-238.
  3. Michelson D, Faries D, Wernicke J et al. Atomoxetine in the Treatment of children and adolescents with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled, dose-response study. Pediatrics 2001; 108(5):1.
  4. Michelson D, Adler L, Spencer T et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 2003; 53:112-120.
  5. Kratochvil CJ, Heiligenstein JH, Dittman R et al. Atomoxetine and methylphenidate treatment in children with ADHD: A prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 2002; 41(7):776.
  6. Nussbaum A, Stroup TS. Paliperidone for Schizophrenia. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006369.
  7. Komossa K, Rummel-Kluge C, Schwarz S, et.al. Risperidone versus Other Atypical Antipsychotics for Schizophrenia. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD006626.
  8. Komossa K, Rummel-Kluge C, Hunger H, et al. Olanzapine versus Other Atypical Antipsychotics for Schizophrenia. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD006654.
  9. Komossa K, Rummel-Kluge C, Hunger H, et al. Ziprasidone versus Other Atypical Antipsychotics for Schizophrenia. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006627.
  10. Komossa K, Rummel-Kluge C, Schmid F, et al. Aripiprazole versus Other Atypical Antipsychotics for Schizophrenia. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006627.
  11. Cranney A, Tugwell P, Adachi J et al. Meta-analysis of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:517-523.
  12. Bonnick SL, Harris ST, Kendler DL, et al. Management of osteoporosis in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17(1):25-54.
  13. Cummings SR, Black DM, Thompson DE, et al. Alendronate reduces the risk of vertebral fractures in women without pre-existing vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082.
  14. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333: 1437-1443.
  15. MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197-213.
  16. Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab 2010;95:1174-1181.
  17. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008; Issue 1. Art. No.:CD00115. DOI: 10.1002/14651858.CD001155.pub2.
  18. Jamal SA, Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the Fracture Intervention Trial. J Bone Miner Res 2007;22:503-508.
  19. Vakil N and Fennerty MB. Systematic review: direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther 2003; 18: 559–568.
  20. Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005; 294:1534-1540.
  21. McDonagh MS, Carson S, Thakurta S. Drug Class Review: Proton Pump Inhibitors. Drug Effectiveness Review Project, Oregon Evidence-based Practice Center, Oregon Health & Science University. June 2009. Last accessed March 6, 2015.
  22. Zanchetti A, Omboni S, Di Biagio C. Candesartan cilexetil and enalapril are of equivalent efficacy in patients with mild to moderate hypertension. J Hum Hypertens 1997; 11(supp 2): S57 S59.
  23. Gradman AH, Arcuri KE, Goldberg AI et al. A randomized, placebo-controlled, double blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 1995; 25:1345-1350.
  24. Stumpe KO, Hawirtg D, Hoglund C et al. Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for treatment of hypertension. Blood Press 1998, (1): 31-37.
  25. Corea L, Cardoni O, Fogari R et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: A comparative study of the efficacy and safety against amlodipine. Clin Pharmacol Ther 1996; 60(3):341-346.
  26. Dormandy JA, Charbonnel B, Eckland DJA et al. The PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in Macrovascular Events.): a randomized controlled trial. Lancet 2005;366:1279-1289.
  27. DeFronzo RA, Ratner RE, Han J et al. Effects of exenatide (exendin-4) on glycemic control and weight control over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28(5):1092-100.
  28. Buse JB, Henry RR, Han J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004;27(11):2628-35.
  29. Kendall DM, Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005;28(5)1083-91.
  30. Heine RJ, Van Gall LF, Johns D et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143(8):559-69.
  31. Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. In press. Merck internal data.
  32. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. In press. Merck internal data.
  33. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled on metformin alone. Diabetes Care. In press. Merck internal data.
  34. Oliver TN. Update on anti-emetics for chemotherapy-induced emesis. Intern Med J. 2005;35(8):478-81. Review.
  35. Package inserts for acyclovir, famciclovir and valacyclovir.
  36. Manual of Clinical Psychopharmacology, 6th edition; Schatzberg, Cole, and DeBattista; American Psychiatric Publishing, 2007 (7th edition due out in 2010).
  37. Evidence-Based Psychopharmacology; Stein, Lerer, and Stahl (editors); Cambridge University Press, 2005.
  38. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. AACE Medical Guidelines for Clinical Practice for Deceloping a Diabetes Mellitus Comprehensive Care Plan. 2011. Last accessed March 6, 2015.
  39. Reviewed and recommended by the Pharmacy and Therapeutics Committee, May 15, 2007.
  40. Package insert, Nuvigil (armodafinil).
  41. Littleton ET, Hobart JC, Palace J. Modafinil for multiple sclerosis fatigue: does it work? Clin Neurol Neurosurg. 2010 Jan;112(1):29-31.
  42. Kumar R. Approved and investigational uses of modafinil: an evidence-based review. Drugs. 2008;68(13):1803-39.
  43. SOLODYN Tablets Package Insert. Scottsdale, AZ: Medicis, The Dermatology Company; August 2010. Data on file with the manufacturer. (Unpublished.)
  44. Kircik LH. Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol 2010;9(11):1407-1411.
  45. Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne vulgaris. A review. Br J Dermatol 2008;158:208-216.
  46. Package insert, Xyrem (sodium oxybate), Jazz Pharmaceuticals.
  47. FDA warning letter to Jazz Pharmaceuticals, October 11, 2011. Available at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm275565.htm, Last accessed February 4, 2015.
  48. Mc Millen M. FDA Panel Rejects Xyrem as Fibromyalgia Treatment. Advisory Panel Members Worry About Potential for Abuse of Drug That’s Similar to GHB. WebMD Health News, August 20, 2010. Available at http://www.webmd.com/fibromyalgia/news/20100820/fda-panel-rejects-xyrem-as-fibromyalgia-treatment%20 Last accessed February 4, 2015.
  49. ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/results?term=xyrem. Last accessed February 4, 2015.
  50. Van der Pas R, de Herder WW, Hofland LJ, Feelders RA. Recent developments in drug therapy for Cushing’s disease. Drugs 2013 June 5 [Epub ahead of print].
  51. Castinetti F, Moragne I, Conte-Devolx B, and Brue T. Cushing’s disease. Orpahnet J Rare Dis 2012;7:41-50.
  52. Hammer GD, Tyrell JB, Lamborn KR, et al. Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J Clin Endocrinol Metab 2004;89(12):6348-6357.
  53. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2007;92(3):976-981.
  54. Fleseriu M, Petersenn S. Medical management of Cushing’s disease: what is the future? Pituitary 2012;15:330-341.
  55. Niemann LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-1540.
  56. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008;93:2454-2462.
  57. Product information for Amitiza (lubiprostone). Takeda Pharmaceuticals. Available at http://www.amitiza.com. Last accessed February 4, 2015.
  58. Product information for Linzess (linaclotide). July 2014, Forest Pharmaceuticals. Available at http://pi.actavis.com/data_stream.asp?product_group=1904&p=pi&language=E. Last accessed February 4, 2015.

History

Date

Reason

12/13/05

Add to Prescription Drug Section - New Policy—effective January 1, 2006.

08/08/06

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.

05/08/07

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.

06/12/07

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

12/11/07

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.

04/08/08

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.

12/16/08

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.

02/10/09

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

7/14/09

Replace Policy - Policy updated with literature search by Pharmacy. Policy statement updated with addition of Nuvigil. Reference added

02/09/10

Replace Policy - Policy updated with literature search by Pharmacy. No change to the policy statement. Policy guidelines section updated.

03/09/10

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.

04/13/10

Replace Policy - Policy updated with literature search. Policy statement updated with medically necessary indication added for Leukotriene modifiers. References added.

06/08/10

Replace Policy - Policy updated with literature search. Pantoprazole added to policy guidelines. Reference added.

08/10/10

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.

02/08/11

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.

06/13/11

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.

08/01/11

Replace Policy - Preapproved edits for August implementation added to policy; policy published.

09/10/11

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.

09/07/11

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.

02/27/12

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.

03/30/12

Minor update, Valtuma (aliskiren/valsartan) no longer covered by this policy; it was removed.

04/10/12

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.

05/08/12

Qnasl® added to the list in intranasal steroids within the Policy section. Statins were removed from the policy.

05/30/12

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.

07/31/12

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.

10/09/12

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.

11/26/12

Update Related Policies. Add 5.01.529.

03/11/13

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.

03/15/13

Replace policy. Added ibrandronate to the Bisphosphonates within the Policy section; removed text in Brand Non-Insulin Agents within the Description.

04/11/13

Minor update. Clarification made in Description section; brand SGAs bullet now preceded by "including but not limited to..."

05/13/13

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.

06/14/13

Update Related Policies. Add 11.01.504.

07/08/13

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.

08/12/13

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.

09/09/13

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.

10/14/13

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.

12/04/13

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.

03/10/14

Annual review. Policy section updated to reflect expansion of brand stimulants and non-stimulants, previously only addressing ADHD, to now include other psychiatric conditions.

04/14/14

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.

05/12/14

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.

06/19/14

Update Related Policies. Add 5.01.552.

08/11/14

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.

09/08/14

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.

10/13/14

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.

11/10/14

Interim update. Policy section updated with the addition of a medically necessary statement for nitrogen scavenging agents

12/08/14

Interim update. Additional drugs added to the Non-Insulin Antidiabetic Agents, brands section of the Policy section.

12/22/14

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.

01/28/15

Annual review. Policy updated with the addition of 2 proton pump medications to support recent edits: Aciphex and Zegerid.

02/10/15

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.

03/10/15

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.

04/14/15

Interim update. Natesto added to the list of Testosterone therapy agents. A not medically necessary policy statement for branded non-stimulants for psychiatric conditions for which there is no credible published scientific evidence of efficacy or effectiveness.

05/27/15

Interim Update. Added verbiage about additional formulary alternative needing to be tried for MSB medications and removed requirement for MedWatch form for both MSB and DAW reviews. Dosage information on Xyrem added.

06/09/15

Interim update. Policy update with a new ADHD drug, Aptension XR; criteria added for Vyvanse regarding drug abuse or dependence. Removed Intuniv and criter for Fulyzaq since the PA is being removed.


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).
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