Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Idiopathic Pulmonary Fibrosis Therapy Table of Contents Coverage Policy... 1 General Background... 4 Coding/Billing Information... 7 References... 7 Effective Date... 5/15/2018 Next Review Date... 5/15/2019 Coverage Policy Number Related Coverage Resources 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. Coverage Policy Idiopathic Pulmonary Fibrosis Therapy includes: Nintedanib (Ofev ) Pirfenidone (Esbriet ) Cigna covers Idiopathic Pulmonary Fibrosis Therapy as medically necessary for the treatment of idiopathic pulmonary fibrosis (IPF) when ALL of the following are met: Exclusion of other known causes of interstitial lung disease (ILD) (for example, domestic and occupational environmental exposures, connective tissue disease, and drug toxicity) ONE of the following: o In patients without surgical lung biopsy: Usual interstitial pneumonia (UIP) pattern on high resolution computed tomography (HRCT) is indicative of IPF. o In patients with surgical lung biopsy: The biopsy pattern is diagnostic of IPF, or the combination of HRCT and biopsy pattern is indicative of IPF. Esbriet and Ofev are not used concomitantly. Cigna does not cover the use of Idiopathic Pulmonary Fibrosis Therapy for any other indication because it is considered experimental, investigational or unproven. 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 Idiopathic Pulmonary Fibrosis Therapy. Page 1 of 8

2 Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indication Product Nintedanib (Ofev) Pirfenidone (Esbriet) FDA Approved Indication Ofev is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). Esbriet is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). FDA Recommended Dosing Product Nintedanib (Ofev) FDA Recommended Dosing Testing Prior to Ofev Administration Conduct liver function tests and a pregnancy test prior to initiating treatment with Ofev. Recommended Dosage The recommended dosage of Ofev is 150 mg twice daily administered approximately 12 hours apart. Ofev capsules should be taken with food and swallowed whole with liquid. Ofev capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known. Do not exceed the recommended maximum daily dosage of 300 mg. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of Ofev is 100 mg twice daily approximately 12 hours apart taken with food. Dosage Modification due to Adverse Reactions In addition to symptomatic treatment, if applicable, the management of adverse reactions of Ofev may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. Ofev treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with Ofev. Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe liver damage, interrupt treatment or reduce Ofev to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with Ofev may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily). Discontinue Ofev for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage. Pirfenidone (Esbriet) In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions. Testing Prior to Esbriet Administration Conduct liver function tests prior to initiating treatment with Esbriet. Recommended Dosage The recommended daily maintenance dosage of Esbriet is 801 mg three times daily for a total of 2403 mg/day. Doses should be taken with food at the same time each Page 2 of 8

3 Product day. FDA Recommended Dosing Upon initiation of treatment, titrate to the full dosage of 2403 mg/day over a 14-day period as follows: Table 1. Dosage Titration for Esbriet in Patients with IPF Treatment days Dosage Days 1 through mg three times daily (801 mg/day) Days 8 through mg three times daily (1602 mg/day) Days 15 onward 801 mg three times daily (2403 mg/day) Dosages above 2403 mg/day are not recommended for any patient. Patients should not take 2 doses at the same time to make up for a missed dose. Patients should not take more than 3 doses per day. Dosage Modifications due to Adverse Reactions Patients who miss 14 or more days of Esbriet should re-initiate treatment by undergoing the initial 2-week titration regimen up to the full maintenance dosage. For treatment interruption of less than 14 days, the dosage prior to the interruption can be resumed. If patients experience significant adverse reactions (i.e., gastrointestinal, photosensitivity reaction or rash), consider temporary dosage reductions or interruptions of Esbriet to allow for resolution of symptoms. Dosage Modification due to Elevated Liver Enzymes Dosage modifications or interruptions may also be necessary when liver enzyme and bilirubin elevations are exhibited. For liver enzyme elevations, modify the dosage as follows: If a patient exhibits >3 but 5 the upper limit of normal (ULN) ALT and/or AST without symptoms or hyperbilirubinemia after starting Esbriet therapy: Discontinue confounding medications, exclude other causes, and monitor the patient closely. Repeat liver chemistry tests as clinically indicated. The full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits) with subsequent retitration to the full dosage as tolerated. If a patient exhibits >3 but 5 ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia: Permanently discontinue Esbriet. Do not rechallenge patient with Esbriet. If a patient exhibits >5 ULN ALT and/or AST: Permanently discontinue Esbriet. Do not rechallenge patient with Esbriet. Dosage Modification due to Drug Interactions Strong CYP1A2 Inhibitors (e.g., fluvoxamine, enoxacin) Reduce Esbriet to 267 mg three times a day (801 mg/day) Moderate CYP1A2 Inhibitors (e.g., ciprofloxacin) With use of ciprofloxacin at a dosage of 750 mg twice daily, reduce Esbriet to 534 mg three times a day (1602 mg/day) Page 3 of 8

4 Drug Availability Product Nintedanib (Ofev) Pirfenidone (Esbriet) Drug Availability Available as 100 mg and 150 mg capsules Available as 267 mg capsules and 267 mg and 801 mg film-coated tablets General Background Pharmacology Product Nintedanib (Ofev) Pirfenidone (Esbriet) Pharmacology Nintedanib is an inhibitor of multiple tyrosine kinases, including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF), which contribute to fibrosis formation. It is unknown how pirfenidone works in the treatment of IPF. Pirfenidone may exhibit anti-inflammatory and antifibrotic properties that may lend to the mechanism of action. Guidelines Recognizing the recent treatment advances in IPF therapy, the collaborative team of the American Thoracic Society (ATS), European Respiratory Society (ERS), the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) convened in 2015 to update the treatment recommendations section of their 2011 guidelines. (Raghu, 2015). IPF is diagnosed by excluding other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity) and by the presence of a usual interstitial pneumonia (UIP) pattern on high resolution computed tomography (HRCT) with or without a surgical lung biopsy. The international guidelines criteria for a UIP pattern on HRCT is described in Table 1. The histopathological criteria for a UIP pattern is described in Table 2. For individuals who have HRCT and a surgical lung biopsy, the diagnostic criteria for IPF are detailed in Table 3. (Raghu, 2011) Table 1 High-Resolution Computed Tomography Criteria for UIP Pattern (Raghu, 2011) UIP Pattern (All Four Features) Possible UIP Pattern (All Three Features) Inconsistent with UIP Pattern (Any of the Seven Features) Subpleural, basal predominance Reticular abnormality Absence of features listed as inconsistent with UIP pattern (see third column) Subpleural, basal predominance Reticular abnormality Honeycombing with or without traction bronchiectasis Absence of features listed as inconsistent with UIP pattern (see third column) Upper or mid-lung predominance Peribronchovascular predominance Extensive ground glass abnormality (extent > reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honey combing) Diffuse mosaic attenuation/airtrapping (bilateral in three or more lobes) Consolidation in bronchopulmonary segment(s)/ lobe(s) Table 2 Histopathological Criteria for UIP Pattern (Raghu, 2011) UIP Pattern (All Four Criteria) Probable UIP Pattern Possible UIP Pattern (All Three Criteria) Evidence of marked Evidence of Patchy or diffuse fibrosis/architectural marked fibrosis/ involvement of Not UIP Pattern (Any of the Six Criteria) Hyaline membranes* Page 4 of 8

5 distortion, +/- honeycombing in a predominantly subpleural/ paraseptal distribution Presence of patchy involvement of lung parenchyma by fibrosis Presence of fibroblast foci Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column) architectural distortion, +/- honeycombing Absence of either patchy involvement or fibroblastic foci, but not both Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column) OR Honeycomb changes only lung parenchyma by fibrosis, with or without interstitial inflammation Absence of other criteria for UIP (see UIP Pattern column) Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column) Organizing pneumonia* Granulomas Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway centered changes Other features suggestive of an alternate diagnosis * Can be associated with acute exacerbation of IPF An isolated or occasional graunulom and/or a mild component of organizing pneumonia pattern may rarely be coexisting in lung biopsies with an otherwise UIP pattern. This scenario usually represents end-stage fibrotic lung disease where honeycombed segments have been sampled but where a UIP pattern might be present in other areas. Such areas are usually represented by overt honeycombing on HRCT and can be avoided by pre-operative targeting of biopsy sites away from these areas using HRCT. Table 3 Combination HRCT and Surgical Lung Biopsy for the Diagnosis of IPF (Raghu, 2011) HRCT Pattern* Surgical Lung Biopsy Pattern (when performed)** Diagnosis of IPF? UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis YES Possible UIP Inconsistent with UIP * Table 1, ** Table 2 Not UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP UIP Probable UIP Possible UIP Nonclassifiable fibrosis Not UIP No YES Probable No Possible No The 2015 updated guidelines provide a reassessment of treatment options reviewed in 2011, as well as evaluation of newer agents. The guidelines are categorized into four classifications: strong recommendation for or against use, and conditional recommendation for or against use. The guidelines explain that from a clinician s perspective, a strong recommendation should be interpreted that most IPF individuals should receive the intervention, and that most patients with IPF would want the intervention. In regards to therapies with conditional recommendations, clinicians should consider that treatment decisions should be personalized, and offering a therapy with a conditional recommendation may require the clinician to assist the patient in coming to a treatment decision which meets individual values and preferences. The guideline explains that therapies with conditional recommendations might be acceptable to most IPF individuals, but many would not find it Page 5 of 8

6 acceptable. The guideline does not state a preference for one treatment over another or endorse treatment sequence. (Raghu, 2015) Regarding recommendations for use of nintedanib and pirfenidone, the guidelines point out the likely positive impact both drugs on outcomes that are valued by IPF patients (e.g. disease progression) and place lower importance on potential adverse events and cost of therapy. Despite nintedanib s apparent positive impact on outcomes important to these patients, the guidelines mention that the drug has not demonstrated significant impact on overall mortality. The most recent evidence from studies of pirfenidone comes from three trials. Pooled results indicated improvement in mortality and reduction in the rate of decline in FVC (one study was not included in the pooled FVC analysis owing to differences in reporting). Because of heterogeneity in the inclusion criteria for these trials, the results may not be easily extrapolated to cases of more severe IPF, or in individuals with comorbidities. The recommendations state there is a wide range of adverse effects with pirfenidone, which may not be acceptable to some individuals despite the potential benefit of treatment. Table 4 displays the medication treatment recommendations described in the international guidelines. (Raghu, 2015) Table 4 International Guideline Recommendations for Idiopathic Pulmonary Fibrosis (Raghu, 2015) Conditional recommendation for Nintedanib use Pirfenidone Conditional recommendation against use Strong recommendation against use Antacid therapy Macitentan, Bosentan Sildenafil N-acetylcysteine monotherapy Anticoagulation (warfarin) Prednisone + azathioprine + N-acetylcysteine combination therapy Ambrisentan Imatinib Several other therapies which were addressed in 2011 were not slated for update in 2015 (e.g. lung transplantation in general, acute exacerbation treatment with corticosteroids). Review of antipulmonary hypertension therapy for IPF associated pulmonary hypertension will be addressed in a future update. (Raghu, 2015) The guidelines recommend monitoring for disease progression every 4 to 6 months or sooner as clinically indicated and note that forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) be performed during routine monitoring. (Raghu, 2011) NICE (United Kingdom) guidelines for treating IPF, updated in January 2016, address the role of pirfenidone and nintedanib in IPF. (NICE, 2018; NICE, 2016) NICE recommends either drug as a treatment option in patients with IPF whose FVC is 50% to 80% of predicted. Discontinuation is recommended if FVC declines at a rate of 10% or more per year during treatment with either drug. NICE does not recommend using any of the following medications alone or in combination for managing IPF: ambrisentan, azathioprine, bosentan, mycophenolate mofetil, prednisolone, sildenafil, sulfamethoxazole/trimethoprim, or warfarin. Oral N- acetylcysteine is considered a treatment option with uncertain benefits in IPF. Other key elements to consider when treating IPF include pulmonary rehabilitation, supportive care and symptom relief, discontinuation of ineffective or harmful therapies and consideration of lung transplant. (NICE, 2017; NICE, 2016) Clinical Efficacy Nintedanib (Ofev) Two pivotal phase 3 trials and one pivotal phase 2 trial in IPF are published. Nintedanib was only studied in patients with FVC > 50% of predicted, so it has not been studied in patients with the most severe disease. In the two phase 3 studies, rate of forced vital capacity (FVC) decline was significantly slowed by nintedanib (114 to 115 ml/year) compared with placebo (207 to 240 ml/year; p<0.001). Rate of FVC decline was not significantly different between nintedanib 150 mg twice daily (60 ml/year) and placebo (190 ml/year) in the phase 2 trial despite a large numerical difference in this value. Death from any cause and death from respiratory causes were not significantly different between nintedanib and placebo in a pooled analysis of phase 3 trials. (Richeldi, 2011; Richeldi, 2014a; Richeldi, 2014b) Page 6 of 8

7 Pirfenidone (Esbriet) There are 3 pivotal trials ASCEND and CAPACITY studies 004 and 006 evaluating pirfenidone for the treatment of IPF. Along with confirmed IPF, inclusion criteria were predicted FVC of at least 50% but less than 90%, 6-minute walking distance (6MWD) of at least 150 meters, predicted carbon monoxide diffusing capacity of at least 30% to 35% but less than 90%. The decline in percent predicted (%predicted) FVC was smaller with pirfenidone (-3.7% to -8%) than placebo (-6.6% to -12.4%, p<0.001) in the ASCEND and CAPACITY study 004. There was no difference in predicted FVC change from baseline between treatment groups in CAPACITY study 006. There was a significant difference in all-cause mortality (HR 0.52, 95% CI 0.31 to 0.87; p<0.01) and death due to IPF (HR 0.32, 95% CI 0.14 to 0.76; p=0.006) with pirfenidone compared with placebo in a post-hoc analysis of pooled data from the ASCEND and CAPACITY trials. (King, 2014; Noble 2011) Comparative Evidence There are no published trials directly comparing nintedanib to pirfenidone. A network meta-analysis was conducted comparing the effects of various IPF treatments for slowing the rate of FVC decline. All data were from randomized, placebo-controlled trials. None of the included trials directly compared FVC effects of different active treatments. Azathioprine, sildenafil, oral N-acetylcysteine, and inhaled N-acetylcysteine did not significantly slow FVC decline compared with placebo. Nintedanib (OR 0.38; 95% CI, 0.22 to 0.66) and pirfenidone (OR 0.68; 95% CI, 0.54 to 0.85) both significantly slowed the rate of FVC decline. The comparison between nintedanib and pirfenidone numerically favored nintedanib, but the difference was not statistically significant (OR 0.56; 95% CI, 0.31 to 1.03). These results must be interpreted cautiously because they only included data from one Phase 2 nintedanib trial (n=85), where the rate of FVC decline was slower than demonstrated in later Phase 3 studies. Two of the 4 pirfenidone trials used a dose lower than the US labeled dose. There was moderate heterogeneity (I2=45%) when the 4 pirfenidone trials were pooled. (Loveman, 2014) Experimental, Investigational, or Unproven Uses While nintedanib has been investigated for the following: colorectal cancer, endometrial cancer, glioblastoma multiforme, non-small cell lung cancer, ovarian cancer, and prostate cancer, it is not currently listed in the National Comprehensive Cancer Network s (NCCN) Drugs & Biologics Compendium. (NCCN, 2018) While pirfenidone has been evaluated in adults and children with neurofibromatosis type 1 (Wideman, 2014), in myelofibrosis with myeloid metaplasia (Mesa, 2001), and in progressive multiple sclerosis (Walker, 2005), there is insufficient evidence at this time to support its use in these conditions. Coding/Billing Information Note: Nintedanib and pirfenidone are typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use. References 1. Boehringer Ingelheim Pharmaceuticals, Inc. Ofev (nintedanib) capsules, for oral use [product information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January InterMune, Inc. Esbriet (pirfenidone) capsules, for oral use [product information]. Brisbane, CA: InterMune, Inc.; January King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. The New England journal of medicine. May ; 370 (22): Loveman E, Copley VR, Colquitt JL, et al. The effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: systematic review, network meta-analysis and health economic evaluation. BMC Pharmacol Toxicol. 2014;15: Mesa RA, et al. A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia. Br J Haematol Jul;114(1): PubMed PMID: National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. 2018; Available at: Accessed April 5, Page 7 of 8

8 7. National Institute for Health and Care Excellence. Managing idiopathic pulmonary fibrosis. NICE. Updated May Accessed March 27, National Institute for Health and Care Excellence. Nintedanib for treating idiopathic pulmonary fibrosis. NICE technology appraisal guidance Published January Accessed March 27, National Institute for Health and Care Excellence. Pirfenidone for treating idiopathic pulmonary fibrosis. NICE technology appraisal guidance Updated February Accessed March 27, Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. May ;377(9779): Raghu G, Rochwerg B, Yuan Z, et al. An official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. Jul ; 192 (2): e3-e Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. Mar ; 183 (6): Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. Sep ; 365 (12): Richeldi L, Cottin V, Flaherty KR, et al. Design of the INPULSIS trials: two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med. Jul 2014; 108 (7): Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. May ; 370 (22): Walker JE, Giri SN, Margolin SB. A double-blind, randomized, controlled study of oral pirfenidone for treatment of secondary progressive multiple sclerosis. Mult Scler Apr;11(2): PubMed PMID: Wideman BC, et al. Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Pediatr Blood Cancer Sep;61(9): PubMed PMID: Cigna Companies refers to operating subsidiaries of Cigna Corporation. All products and services are provided exclusively by or through such operating subsidiaries, including Cigna Health and Life Insurance Company, Connecticut General Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., QualCare, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. The Cigna name, logo, and other Cigna marks are owned by Cigna Intellectual Property, Inc Cigna. Page 8 of 8