Drug and Biologic Coverage Policy

Effective Date ...... 7/1/2021 Next Review Date… ...... 7/1/2022 Coverage Policy Number ...... IP0009

H. Pylori Infection Products

Table of Contents Related Coverage Resources

Overview ...... 1 Coverage Policy Statement ...... 1 FDA Indication Criteria ...... 2 Other Uses with Supportive Evidence Criteria .... 2 Specific Additional Criteria ...... 2 Preferred Product Requirement Criteria ...... 2 Conditions Not Covered...... 3 Background ...... 3 References ...... 4

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.

Overview

This policy supports medical necessity review for H. Pylori Infection products.

Coverage Policy Statement

H. Pylori Infection products are medically necessary when the following are met:

1. Criteria associated with FDA Indications 2. Criteria associated with Other Uses with Supportive Evidence 3. Specific Additional Criteria [when part of Cigna managed drug list or plan requirements] 4. Preferred Product Requirement Criteria [when part of Cigna managed drug list or plan requirements]

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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.

Approval duration is 12 months unless otherwise stated.

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

Documentation: When documentation is required, the prescriber must provide written documentation supporting the trials of these other agents. Documentation may include, but is not limited to, chart notes, prescription claims records, and/or prescription receipts

Refer to each criteria section below. FDA Indication Criteria

NONE

Other Uses with Supportive Evidence Criteria

NONE

Specific Additional Criteria

NONE

Preferred Product Requirement Criteria

Coverage 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:

Approve for an individual when there is documentation of ONE of the following:

• The individual has had inadequate efficacy OR contraindication according to FDA label OR significant intolerance to ALL of covered alternatives according to the table below OR

• The individual is not a candidate for ALL covered alternatives according to the table below due to being subject to a warning per the prescribing information (labeling), having a disease characteristic, individual clinical factor[s], or other attributes/conditions or is unable to administer and requires this dosage formulation

Approval duration: 1 month

Employer Group Non-Covered Products and Preferred Covered Alternatives by Drug List: Non-Covered Standard / Value / Cigna Total Legacy Product Performance Advantage Savings Helidac® Either of the following (1 or 2): (bismuth 1. BOTH of the following (A and B): subsalicylate / A) Single-entity products in a regimen for peptic ulcer disease due to Helicobacter metronidazole / pylori (e.g., bismuth subcitrate, metronidazole, tetracycline, clarithromycin, tetracycline amoxicillin, rifabutin, PPIs [e.g., omeprazole, lansoprazole]; AND 262.4 mg -250 B) Any pre-packaged product for peptic ulcer disease due to Helicobacter pylori: mg - 500mg) amoxicillin/clarithromycin/lansoprazole (Prevpac*, generics), Omeclamox-Pak*, Pylera*, or Talicia*

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Non-Covered Standard / Value / Cigna Total Legacy Product Performance Advantage Savings 2. Individual has already been started on Helidac in order to complete the course of therapy. Omeclamox®- Either of the following (1 or 2): Pak 1. BOTH of the following (A and B): (amoxicillin / A) Single-entity products in a regimen for peptic ulcer disease due to Helicobacter clarithromycin / pylori (e.g., bismuth subcitrate, metronidazole, tetracycline, clarithromycin, omeprazole amoxicillin, rifabutin, PPIs [e.g., omeprazole, lansoprazole]; AND 500 mg – 500 B) Any pre-packaged product for peptic ulcer disease due to Helicobacter pylori: mg – 20 mg) amoxicillin/clarithromycin/lansoprazole (Prevpac*, generics), Talicia*, or Pylera*

2. Individual has already been started on Omeclamox-Pak in order to complete the course of therapy. Prevpac® Either of the following (1 or 2): (amoxicillin / 1. BOTH of the following (A and B): clarithromycin / A) Single-entity products in a regimen for peptic ulcer disease due to Helicobacter lansoprazole pylori (e.g., bismuth subcitrate, metronidazole, tetracycline, clarithromycin, 500 mg – 500 amoxicillin, rifabutin, PPIs [e.g., omeprazole, lansoprazole]; AND mg – 30 mg) B) Any pre-packaged product for peptic ulcer disease due to Helicobacter pylori: amoxicillin/clarithromycin/lansoprazole (generics), Talicia*, or Pylera*

2. Individual has already been started on PrevPac in order to complete the course of therapy. Pylera® BOTH of the following (A and B): (bismuth A) Single-entity products in a regimen for peptic ulcer disease due to Helicobacter subcitrate / pylori (e.g., bismuth subcitrate, metronidazole, tetracycline, clarithromycin, metronidazole / amoxicillin, rifabutin, PPIs [e.g., omeprazole, lansoprazole]; AND tetracycline B) Any pre-packaged product for peptic ulcer disease due to Helicobacter pylori: 140 mg – 125 amoxicillin/clarithromycin/lansoprazole (Prevpac*, generics), Omeclamox-Pak*, or mg – 125 mg Talicia* capsules) Talicia® Either of the following (1 or 2): (omeprazole 1. BOTH of the following (A and B): magnesium, A) Single-entity products in a regimen for peptic ulcer disease due to Helicobacter amoxicillin and pylori (e.g., bismuth subcitrate, metronidazole, tetracycline, clarithromycin, rifabutin) amoxicillin, rifabutin, PPIs [e.g., omeprazole, lansoprazole]; AND delayed- B) Any pre-packaged product for peptic ulcer disease due to Helicobacter pylori: release amoxicillin/clarithromycin/lansoprazole (Prevpac*, generics), Omeclamox-Pak*, or capsules Pylera*

2. Individual has already been started on Talicia in order to complete the course of therapy. * Products may require prior authorization

Conditions Not Covered

Any other exception is considered not medically necessary.

Background

Indications: Pylera; lansoprazole capsules, amoxicillin capsules, and clarithromycin tablets (LAC) Pac (Prevpac, generics); and Omeclamox-Pak are all indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease to eradicate H. pylori. Talicia is indicated for the treatment of H. pylori infection in adults.

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Helidac, in combination with an H2 antagonist, are indicated for the eradication of H. pylori for treatment of patients with H. pylori infection and duodenal ulcer disease (active or a history of duodenal ulcer).

How Supplied: Pylera and Talicia are three-in-one capsules; the other products in this class are supplied as individual components packaged for daily administration. The individual components of each of these products are available generically (lansoprazole, omeprazole, tetracycline, metronidazole, amoxicillin, clarithromycin, and rifabutin) or over-the-counter [OTC] (bismuth subsalicylate). While rifabutin is available generically, it is not available in a strength that would allow dosing to match Talicia.

Clinical and Comparative Efficacy: It is difficult to compare efficacy and eradication rates among the combination products due to a lack of comparative trials and variations in study design. In addition, the increasing rate of antibiotic resistance to clarithromycin and metronidazole further confounds the ability to compare the efficacy across combination products. Eradication rates reported in the pivotal trials for each product were: 77% to 82% (Helidac), 69% to 83% (Omeclamox-Pak), 81% to 86% (LAC Pac), 87.7% (Pylera), and 76.6% to 83.8% (Talicia).

Guidelines: The 2017 American College of Gastroenterology (ACG) guidelines for the management of H. pylori infection recommend regimens which include at least two drugs. Current first-line regimens include a proton pump inhibitor (PPI) and at least two antibiotics administered for 10 to 14 days. Antibiotics include clarithromycin, amoxicillin, metronidazole, bismuth, tetracycline, and levofloxacin. Common regimens include clarithromycin triple therapy (PPI, clarithromycin, and amoxicillin), bismuth quadruple therapy (PPI, bismuth, tetracycline, and metronidazole), and levofloxacin triple therapy (PPI, levofloxacin, and amoxicillin). With the increasing clarithromycin resistance, the ACG recommends clarithromycin triple therapy in regions with clarithromycin resistance < 15% and in patients who have not received a macrolide antibiotic for any indication. The components of Omeclamox-Pak, LAC Pac, or Pylera plus a PPI are examples of first-line therapy options. Salvage therapy regimens recommended by the ACG include a PPI and at least one antibiotic administered for 10 to 14 days. Regimens include bismuth quadruple therapy, levofloxacin triple therapy (PPI, amoxicillin, and levofloxacin) or rifabutin triple therapy (PPI, amoxicillin, and rifabutin).

Adverse Events (AEs): The AE profile for the combination products appears to be similar with gastrointestinal events and headache the most commonly reported AEs.

Conclusions: All four combination products are indicated for the treatment of H. pylori infection and all have demonstrated similar high eradication rates in the pivotal studies. It is important to note that the components of the combination products are available generically or OTC. Data are lacking to make direct comparisons across products. There is also increased H. pylori resistance to the antibiotics included in eradication regimens which further confounds the ability to compare the efficacy of the products. The AE profiles of the products appear to be similar. The ACG guidelines for the treatment of H. pylori recommend a number of regimens for first-line eradication therapy, including clarithromycin triple therapy (Omeclamox-Pak and LAC Pac) and bismuth quadruple therapy (Pylera plus a PPI). Clarithromycin-containing triple therapy regimens should be limited to areas with low clarithromycin resistance and in patients who have not received a macrolide previously for any indication. Rifabutin triple therapy is a recommended second-line treatment option for H. pylori, although the recommended doses for the individual components are different than that provided by Talicia. ACG does not recommend one regimen over another for the eradication of H. pylori, therapy is individualized based on the patient’s previous antibiotic history and local resistance patterns.

References

1. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology. 2017; 153:420-429. 2. Crowe SE. Helicobacter pylori Infection. New Engl J Med. 2019; 380:1158-1165. 3. Bravo D, Hoare A, Soto C, et al. Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects. World J Gastroenterol. 2018; 24:3071-3089.

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4. Chey WD, Leontiadis GI, Howden CW, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017; 112:212-238. 5. Chey WD, Wong BCY, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007; 102:1808-1825. 6. Fallone CA, Moss SF, Malfertheiner P. Reconciliation of recent Helicobacter pylori treatment guidelines in a time of increasing resistance to antibiotics. Gastroenterology. 2019; 157:44-53. 7. Omeclamox-Pak® [prescribing information]. Nashville, TN: Cumberland Pharmaceuticals; October 2016. 8. Prevpac [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; June 2018. 9. Pylera® capsules [prescribing information]. Madison, NJ: Allergan USA, Inc.; October 2018. 10. Talicia® capsules [prescribing information]. Raleigh, NC: RedHill Biopharma Inc.; November 2019. 11. Shiota S, Reddy R, Alsarraj A, et al. Antibiotic resistance of Helicobacter pylori among male United States veterans. Clin Gastroenterol Hepatol. 2015; 13:1616-1624. 12. Hulten KG, Graham DY, Gottlieib AB, Kalfus IN. National and regional US antibiotic resistance to Helicobacter pylori identified from a Phase 3 clinical trial of treatment naïve patients in the United States [poster]. Presented at: 2019 American College of Gastroenterology Annual Scientific Meeting; San Antonio, TX: October 25-30, 2019. 13. Helidac® [prescribing information]. San Diego, CA: Prometheus Laboratories Inc.; June 2015.

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