Pharmacy Benefit Coverage Criteria

Effective Date ...... 5/1/2021 Next Review Date… ...... 5/1/2022 Coverage Policy Number ...... P0057

Nonsteroidal Anti-inflammatory Drugs

Table of Contents Related Coverage Resources

Medical Necessity Criteria ...... 1 Quantity Limitations FDA Approved Indications ...... 3 Step Therapy Recommended Dosing ...... 4 Step Therapy - Standard Prescription Drug Lists Background ...... 7 (Employer Group Plans) References ...... 7 Step Therapy – Value Prescription Drug Lists (Employer Group Plans) Step Therapy – Legacy Prescription Drug Lists (Employer Group Plans)

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria

This policy addresses coverage criteria for nonsteroidal anti-inflammatory drugs.

Coverage for nonsteroidal anti-inflammatory drugs varies across plans. Refer to the customer’s benefit plan document for coverage details. Where coverage requires the use of preferred products, the following criteria apply.

For Employer Group Plans Non-Covered Standard / Value / Cigna Total Legacy Product Performance Advantage Savings Duexis® • Documented inability to use famotidine 20 mg or 40 mg tablets and ibuprofen 800 mg (famotidine / tablets concurrently ibuprofen) 26.6 mg – 800 mg tablet

Page 1 of 8 Pharmacy Benefit Clinical Criteria: P0057 Non-Covered Standard / Value / Cigna Total Legacy Product Performance Advantage Savings Fenortho® BOTH of the following: (fenoprofen 200 • Documented intolerance or inability to use fenoprofen capsules (400mg) or tablets mg capsule) (600 mg) and • Documented failure / inadequate response, contraindication per FDA label, intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- Fenoprofen 200 inflammatory drugs (excluding fenoprofen) mg capsule Indocin® BOTH of the following: (indomethacin) • Documented intolerance or inability to swallow indomethacin 25 mg or 50 mg capsules 25 mg/ 5 mL oral • Documented failure / inadequate response, contraindication per FDA label, suspension intolerance, or not a candidate for naproxen oral suspension Indocin® BOTH of the following: (indomethacin) • Documented intolerance or inability to use indomethacin 25 mg or 50 mg capsules 50 mg • Documented failure or inadequate response, contraindication per FDA label, suppository intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- inflammatory drugs (excluding indomethacin) Naprelan® BOTH of the following: (naproxen) 375 • Documented intolerance or inability to use naproxen 250 mg, 375 mg, or 500 mg mg, 500 mg, and immediate release tablets 750 mg extended • Documented failure / inadequate response, contraindication per FDA label, release tablet intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- inflammatory drugs (excluding naproxen) naproxen CR (naproxen) 375 mg and 500 mg controlled release tablet

naproxen ER (naproxen) 375 mg, 500 mg, and 750 mg extended release tablet Sprix® ALL of the following: (ketorolac) nasal • Documented intolerance or inability to use ketorolac 10 mg tablets solution; 15.75 • Documented failure / inadequate response, contraindication per FDA label, inability to mg / spray use, or not a candidate for diclofenac 1 % topical gel (Voltaren® gel) • Documented failure / inadequate response, contraindication per FDA label, intolerance, inability to use (for example, unable to swallow tablets and capsules), or not a candidate for THREE (3) nonsteroidal anti-inflammatory drugs (excluding ketorolac) Tivorbex® BOTH of the following: (indomethacin) • Documented intolerance or not a candidate for indomethacin 25 mg or 50 mg capsules 20 mg and 40 mg • Documented failure / inadequate response, contraindication per FDA label, capsule intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- inflammatory drugs (excluding indomethacin)

Vimovo® • Documented inability to use esomeprazole 20 mg capsules and naproxen 375 mg or (esomeprazole / 500 mg tablets concurrently naproxen) 20 mg – 375 mg or 500 mg tablet

Page 2 of 8 Pharmacy Benefit Clinical Criteria: P0057 Non-Covered Standard / Value / Cigna Total Legacy Product Performance Advantage Savings Vivlodex™ BOTH of the following: (meloxicam) 5 • Documented intolerance, inability to use or not a candidate for meloxicam 7.5 mg or mg and 10 mg 15 mg tablets capsule • Documented failure / inadequate response, contraindication per FDA label, intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- Meloxicam 5 inflammatory drugs (excluding meloxicam) mg and 10 mg capsule Zipsor® BOTH of the following: (diclofenac) 25 • Documented intolerance, inability to use or not a candidate for diclofenac 50 mg mg capsule tablets or diclofenac 25 mg delayed-release tablets • Documented failure / inadequate response, contraindication per FDA label, intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- inflammatory drugs (excluding diclofenac) Zorvolex® BOTH of the following: (diclofenac) 18 • Documented intolerance, inability to use or not a candidate for diclofenac 50 mg mg and 35 mg tablets or diclofenac 25 mg delayed-release tablets capsule • Documented failure / inadequate response, contraindication per FDA label, intolerance, inability to use, or not a candidate for FOUR (4) nonsteroidal anti- inflammatory drugs (excluding diclofenac)

Initial and reauthorization is up to 12 months.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

*If you’re a Cigna provider, please log in to the Cigna for Health Care Professionals website and search for specific patients to view their covered medications.

FDA Approved Indications

Product FDA Approved Indications Duexis Duexis, a combination of the NSAID ibuprofen and the histamine H2-receptor antagonist (famotidine / famotidine, is indicated for the relief of signs and symptoms of rheumatoid arthritis and ibuprofen) tablet osteoarthritis and to decrease the risk of developing upper gastrointestinal ulcers, which in the clinical trials was defined as a gastric and/or duodenal ulcer, in patients who are taking ibuprofen for those indications. Fenortho Fenortho (fenoprofen calcium) is a nonsteroidal anti-inflammatory drug indicated for the (fenoprofen relief of the signs and symptoms of osteoarthritis; the relief of mild to moderate pain in calcium) capsule adults; and the relief of the signs and symptoms of rheumatoid arthritis. Indocin Indocin (indomethacin) is a nonsteroidal anti-inflammatory drug indicated for: (indomethacin) • Moderate to severe rheumatoid arthritis including acute flares of chronic disease oral suspension • Moderate to severe ankylosing spondylitis suppository • Moderate to severe osteoarthritis • Acute painful shoulder (bursitis and/or tendinitis) • Acute gouty arthritis. Naprelan Naprelan is a nonsteroidal anti-inflammatory drug indicated for the treatment of: • rheumatoid arthritis (RA) • osteoarthritis (OA)

Page 3 of 8 Pharmacy Benefit Clinical Criteria: P0057 Product FDA Approved Indications (naproxen) • ankylosing spondylitis (AS) extended release • tendinitis, bursitis tablet • acute gout • primary dysmenorrhea (PD) • the relief of mild to moderate pain. Sprix Sprix is indicated in adult patients for the short term (up to 5 days) management of (ketorolac) nasal moderate to moderately severe pain that requires analgesia at the opioid level. solution Limitations of Use: • Sprix is not for use in pediatric patients less than 2 years of age. Tivorbex Tivorbex is indicated for treatment of mild to moderate acute pain in adults. (indomethacin) capsule Vimovo Vimovo, a combination of naproxen and esomeprazole magnesium, is indicated in adult (esomeprazole / and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen) tablet naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk for developing naproxen-associated gastric ulcers.

The naproxen component of Vimovo is indicated for relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. • juvenile idiopathic arthritis (JIA) in adolescent patients.

The esomeprazole magnesium component of Vimovo is indicated to decrease the risk of developing naproxen-associated gastric ulcers.

Limitations of Use: • Do not substitute Vimovo with the single-ingredient products of naproxen and esomeprazole magnesium. • Vimovo is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen- containing products. • Controlled studies do not extend beyond 6 months Vivlodex Vivlodex is a non-steroidal anti-inflammatory drug indicated for management of (meloxicam) osteoarthritis (OA) pain. capsule Zipsor Zipsor is indicated for relief of mild to moderate acute pain in adults (18 years of age or (diclofenac) older). capsule Zorvolex Zorvolex is indicated for: (diclofenac) • Management of mild to moderate acute pain capsule • Management of osteoarthritis pain

Recommended Dosing

Product FDA Recommended Dosing Duexis The recommended daily dose of Duexis (ibuprofen and famotidine) 800 mg/26.6 mg is a single tablet administered orally three times per day. Fenortho Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed.

Rheumatoid Arthritis and Osteoarthritis

Page 4 of 8 Pharmacy Benefit Clinical Criteria: P0057 Product FDA Recommended Dosing For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. Indocin Indocin suppositories 50 mg can be substituted for indomethacin capsules, USP; however, there will be significant differences between the two dosage regimens in indomethacin blood levels [see Clinical Pharmacology (12.3)]

Oral dosage recommendations for active stages of the following: Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis Indomethacin capsules, USP 25 mg twice a day or three times a day. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 - 200 mg is reached. Doses above this amount generally do not increase the effectiveness of the drug.

Acute painful shoulder (bursitis and/or tendinitis) Indomethacin capsules, USP 75-150 mg daily in 3 or 4 divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7-14 days.

Acute Gouty Arthritis Indomethacin capsules, USP 50 mg three times a day. Until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days. Naprelan Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis The recommended starting dose of Naprelan Tablets in adults is two Naprelan 375 mg tablets (750 mg) once daily, one Naprelan 750 mg (750 mg) once daily, or two Naprelan 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with Naprelan tablets as a single daily dose.

Management of Pain, Primary Dysmenorrhea, and Acute Tendinitis and Bursitis The recommended starting dose is two Naprelan 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two Naprelan 750 mg tablets (1,500 mg) or three Naprelan 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two Naprelan 500 mg tablets (1,000 mg).

Acute Gout The recommended dose on the first day is two to three Naprelan 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two Naprelan 500 mg tablets (1,000 mg) once daily, until the attack has subsided. Sprix Adult Patients < 65 Years of Age (ketorolac) nasal The recommended dose is 31.5 mg Sprix (one 15.75 mg spray in each nostril) every 6 to solution 8 hours. The maximum daily dose is 126 mg (four doses).

Reduced Doses for Special Populations For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg Sprix (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses).

Page 5 of 8 Pharmacy Benefit Clinical Criteria: P0057 Product FDA Recommended Dosing

Discard Used SPRIX Bottle after 24 Hours Do not use any single Sprix bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid.

Sprix is not an inhaled product. Do not inhale when administering this product. Tivorbex For treatment of mild to moderate acute pain, the dosage is 20 mg three times daily or 40 mg two or three times daily. Vimovo The recommended dosage of Vimovo by indication is shown in the table:

Indication Patient Population Recommended Dosage Rheumatoid Arthritis, Adults One Vimovo tablet twice daily Osteoarthritis, and of either: 375 mg Ankylosing Spondylitis naproxen/20 mg of Greater than 50 kg esomeprazole; or 500 mg Juvenile Idiopathic naproxen/20 mg of Arthritis in Adolescent esomeprazole Patients 12 Years of 38 kg to less than 50 kg One Vimovo tablet twice daily Age and Older and of: 375 mg naproxen/20 mg Weighing at Least 38 kg of esomeprazole

Vimovo does not allow for administration of a lower daily dose of esomeprazole magnesium. If a total daily dose of less than 40 mg esomeprazole is more appropriate, a different treatment should be considered. Vivlodex For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of Vivlodex is 10 mg. Zipsor For treatment of mild to moderate acute pain, the dosage is 25 mg four times a day. Zorvolex Acute Pain For management of mild to moderate acute pain, the dosage is 18 mg or 35 mg orally three times daily. Osteoarthritis Pain For management of osteoarthritis pain, the dosage is 35 mg orally three times daily.

Drug Availability Product Drug Availability Duexis Duexis is available as a tablet containing 26.6 mg of famotidine and 800 mg of ibuprofen. Fenortho Fenortho is available as a capsule containing 400 mg of fenoprofen. Indocin Indocin is available as a suppository containing 50 mg of indomethacin and an oral suspension containing 25 mg of indomethacin per 5 mL. Naprelan Naprelan is available as a controlled-release tablet containing 375 mg, 500 mg or 750 mg of naproxen. Sprix Sprix is available as a nasal spray delivering 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays. Tivorbex Tivorbex is available as a capsule containing either 20 mg or 40 mg of indomethacin. Vimovo Vimovo is available as an enteric-coated tablet containing 20 mg of esomeprazole and either 375 mg or 500 mg of naproxen. Vivlodex Vivlodex is available as a capsule containing 5 mg or 10 mg of meloxicam. Zipsor Zipsor is available as an oral liquid filled capsule containing 25 mg of diclofenac. Zorvolex Zorvolex is available as a capsule containing either 18 mg or 35 mg of diclofenac.

Page 6 of 8 Pharmacy Benefit Clinical Criteria: P0057 Background

Therapeutic Alternatives: Therapeutic alternatives to Duexis, Fenortho, Indocin oral suspension, indomethacin suppository, Naprelan, Sprix, Tivorbex, Vimovo, Vivlodex, Zipsor, and Zorvolex include the following classes of medication: nonsteroidal anti-inflammatory drugs (NSAIDs).

Professional Societies/Organizations American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the Treatment of Ankylosing Spondylitis (AS) state the goals of treatment of AS are to reduce symptoms, maintain spinal flexibility and normal posture, reduce functional limitations, maintain work ability, and decrease disease complications. For individuals with active Ankylosing Spondylitis (AS), the guidelines provide strong recommendations for the use of nonsteroidal anti-inflammatory drugs (NSAIDs), the use of physical therapy and advocate for hip arthroplasty for patients with advanced hip arthritis. When activity persists despite NSAID treatment, the guidelines recommend the use of a tumor necrosis factor inhibitors (TNFi). The guidelines recommend against the use of systemic glucocorticoids. One NSAID is not recommended over another. (Ward, 2016)

American College of Rheumatology (ACR) guidelines for the management of gout recommend NSAIDs or a COX-2 inhibitor, corticosteroids, or oral colchicine as monotherapy options for an acute gout attack. If there is an inadequate response, options include switching to alternate monotherapy or adding-on for combination therapy. While indomethacin (and other NSAIDs such as naproxen and sulindac) are FDA approved for treatment of acute gout, other NSAIDs when dosed at analgesic and anti-inflammatory doses may be effective. (Khanna, 2012)

American College of Rheumatology (ACR) guidelines for Juvenile Idiopathic Arthritis state NSAID monotherapy may be initiated in treatment naive individuals for up to one month and that continued use for more than 2 months would be inappropriate. (Ringold, 2013)

American College of Rheumatology (ACR) guidelines for the Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis (OA) conditionally recommend, for the management of hand OA, the provision of assistive devices, use of thermal modalities and trapeziometacarpal joint splints, and use of oral and topical nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and topical capsaicin. Pharmacologic modalities conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections. Recommendations for hip OA were similar to those for the management of knee OA. The guidelines do not prefer one NSAID over another. (Hochberg, 2012)

American Family Physician guidelines for the Diagnosis and Initial Management of Dysmenorrhea state nonsteroidal anti-inflammatory drugs should be used as first-line treatment for primary dysmenorrhea. The guidelines do not prefer one NSAID over another. (Osayande, 2014)

Off label uses: AHFS Drug Information 2019 Edition supports severe primary dysmenorrhea as an off-label use for indomethacin. AHFS notes that other NSAIDs are preferred due to availability of more data and due to more adverse events with indomethacin.

Comparative Studies There are no clinical studies comparing diclofenac, fenoprofen, ibuprofen, indomethacin, ketorolac, meloxicam or naproxen with each other or other therapeutic alternatives.

References

1. Almatica Pharma, Inc. Naprelan (naproxen) Controlled-Release Tablets [product information]. Pine Brook, NJ: Almatica Pharma, Inc. July 2019.

Page 7 of 8 Pharmacy Benefit Clinical Criteria: P0057 2. Depomed, Inc. Zipsor (diclofenac potassium) Liquid Filled Capsule, for oral use [product information]. Newark, CA: Depomed, Inc. May 2016. 3. Egalet US Inc. Sprix (ketorolac tromethamine) Nasal Spray [product information]. Wayne, PA: Egalet US Inc. January 2018. 4. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care & Research 2012; 64 (4): 465-74. 5. Horizon Pharma USA, Inc. Duexis (ibuprofen/famotidine) Tablets [product information]. Lake Forest, IL: Horizon Pharma USA, Inc. July 2019. 6. Horizon Pharma USA, Inc. Vimovo (naproxen and esomeprazole magnesium) Delayed-Release Tablets [product information]. Lake Forest, IL: Horizon Pharma USA, Inc. July 2019. 7. Iroko Pharmaceuticals, LLC. Indocin (indomethacin) Oral Suspension, for rectal use [product information]. Philadelphia, PA: Iroko Pharmaceuticals, LLC. March 2019. 8. Iroko Pharmaceuticals, LLC. Indocin (indomethacin) Suppositories, for rectal use [product information]. Philadelphia, PA: Iroko Pharmaceuticals, LLC. March 2019. 9. Iroko Pharmaceuticals, LLC. Tivorbex (indomethacin) Capsules [product information]. Philadelphia, PA: Iroko Pharmaceuticals, LLC. March 2019. 10. Iroko Pharmaceuticals, LLC. Vivlodex (meloxicam) Capsules [product information]. Philadelphia, PA: Iroko Pharmaceuticals, LLC. May 2016. 11. Iroko Pharmaceuticals, LLC. Zorvolex (diclofenac) capsules, for oral use [product information]. Philadelphia, PA: Iroko Pharmaceuticals, LLC. May 2016. 12. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: Therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care & Research 2012; 64 (10): 1447-61. 13. McEvoy GK, ed. 2019. AHFS Drug Information® - 60th Ed. Bethesda, MD. American Society of Health- System Pharmacists. 14. Osayande AS and Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1; 89(5):341-6. 15. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013; 65 (10): 2499-512. 16. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2016 Feb; 68 (2): 282-98. 17. Xspire Pharma LLC. Fenortho (fenoprofen) Tablets [product information]. Madison, MS: Xspire Pharma LLC. May 2016.

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