UnitedHealthcare® Value & Balance Exchange Medical Benefit Drug Policy Deferoxamine Mesylate Policy Number: IEXD0206.01 Effective Date: January 1, 2021  Instructions for Use

Table of Contents Page Related Policies Applicable States ...... 1 None Coverage Rationale ...... 1 Applicable Codes ...... 2 Background ...... 2 Clinical Evidence ...... 3 U.S. Food and Drug Administration ...... 3 Centers for Medicare and Medicaid Services ...... 3 References ...... 3 Policy History/Revision Information ...... 4 Instructions for Use ...... 4

Applicable States

This Medical Benefit Drug Policy only applies to the states of Arizona, Maryland, North Carolina, Oklahoma, Tennessee, Virginia, and Washington.

Coverage Rationale

Deferoxamine mesylate is proven and medically necessary for the treatment of: Acute Intoxication when all of the following criteria are met: o Diagnosis of acute iron intoxication; and o Dose does not exceed 6 grams in 24 hours; and o Initial authorization is for no more than 30 days Chronic secondary to transfusional iron overload when all of the following criteria are met: o For initial therapy, all of the following: . Diagnosis of chronic iron overload secondary to transfusional iron overload (e.g., in patients with chronic requiring multiple RBC transfusions such as and sickle cell ); and . A serum ferritin level > 1,000 mcg/L; and . Dose does not exceed the following: Intravenous / Intramuscular: 6 grams in 24 hours; Subcutaneous: 2 grams in 24 hours and . Initial authorization is for no more than 6 months o For continuation of therapy, all of the following: . Documented benefit from therapy as shown by a decrease in serum ferritin levels as compared to pretreatment baseline; and . Dose does not exceed the following: Intravenous / Intramuscular: 6 grams in 24 hours; Subcutaneous: 2 grams in 24 hours and

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o Authorization is for no more than 12 months

Applicable Codes

The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non-covered health service. Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Guidelines may apply.

HCPCS Code Description J0895 Injection, deferoxamine mesylate, 500 mg

Diagnosis Code Description D56.0 Alpha thalassemia D56.1 D56.2 Delta-beta thalassemia D56.3 Thalassemia minor D56.5 Hemoglobin E-beta thalassemia D56.8 Other D56.9 Thalassemia, unspecified E83.111 Hemochromatosis due to repeated red blood cell transfusions T45.4X1 Poisoning by iron and its compounds, accidental (unintentional) T45.4X2A Poisoning by iron and its compounds, intentional self-harm, initial encounter T45.4X2D Poisoning by iron and its compounds, intentional self-harm, subsequent encounter T45.4X2S Poisoning by iron and its compounds, intentional self-harm, sequela T45.4X3 Poisoning by iron and its compounds, assault T45.4X4 Poisoning by iron and its compounds, undetermined T45.4X5 Adverse effect of iron and its compounds

Background

Acute iron intoxication happens primarily in children. Intoxication can be broken down into unintentional and intentional ingestion. The majority of intoxications are unintentional and involve prenatal vitamins or ferrous sulfate tablets. Most childhood poisonings result in little toxicity. Intentional ingestion mainly occurs in young adults (mainly females). The mortality rate of intentional ingestions versus accidental is 10-fold.5

The minimum toxic dose and the lethal doses of iron are not absolute. The symptoms of serious toxicity are usually found starting in doses 20 mg/kg to 60 mg/kg. Doses 60 mg/kg or more tend to result in serious toxicity.

Iron has the following toxic effects on cells: mucosal cell necrosis, impairment of capillary permeability, alteration of the lipid membrane of mitochondria, inhibition of enzymatic processes in the Krebs cycle, uncoupling of oxidative phosphorylation, direct vasodilation, and Inhibition of serum proteases.6

Iron toxicity is usually described as five phases: Gastrointestinal phase: abdominal pain, vomiting, diarrhea, hematemesis, lethargy, and metabolic acidosis; Latent phase: a period of apparent recovery hours after ingestion, though toxicity can still progress; Shock and metabolic acidosis: cardiovascular toxicity (shock, tachycardia, hypotension) and coagulopathy may occur; Hepatotoxicity: can occur days after ingestion; Bowel obstruction: GI scarring can cause obstruction weeks after toxic ingestion. 7

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Iron overload due to multiple red cell transfusions over a long duration is a complication of thalassemia major and other thalassemia-like congenital anemias such as sickle cell disease, aplastic anemia, myelodysplastic syndromes, other hematologic malignancies, and hematopoietic cell transplantation. Transfusion of more than 15 to 20 units of RBCs can cause clinically significant iron overload, based on the approximation that each unit of RBCs has about 250 mg of iron. Its detrimental effect can to organ compromise (mainly hepatic fibrosis) and, eventually, death. Despite limiting transfusion to appropriate indications, many patients can develop excessive iron stores if therapy is not used.8,9

Clinical Evidence

Study by Brittenham, et al looked at the efficacy in preventing complications of iron overload. 59 patients (30 were female and 29 male; age range, 7 to 31 years) were followed periodically for 4 to 10 years or until death. A detailed clinical and laboratory evaluation was conducted and hepatic iron stores were measured with a noninvasive magnetic device. The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun later and used less deferoxamine in relation to their transfusional iron load (P < 0.001).2

U.S. Food and Drug Administration (FDA)

This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.

Deferoxamine mesylate for Injection, USP is indicated for the treatment of acute iron intoxication and of chronic iron overload due to transfusion-dependent anemias.¹

Centers for Medicare and Medicaid Services (CMS)

Medicare covers DESFERAL® (deferoxamine mesylate injection) when coverage criteria are met. See the NCD for Infusion Pumps (280.14). Local Coverage Determinations (LCDs)/Local Coverage Articles (LCAs) exist. See the LCDs/LCAs for External Infusion Pump.

In general, Medicare covers outpatient (Part B) drugs that are furnished "incident to" a physician's service provided that the drugs are not usually self-administered by the patients who take them. Refer to the Medicare Benefit Policy Manual, Chapter 15, §50 - Drugs and Biologicals. (Accessed July 9, 2020)>

References

1. Deferoxamine Mesylate [prescribing information]. Lake Forest, IL: Hospira, Inc; October, 2018. 2. Brittenham GM, et al. Efficacy of Deferoxamine in Preventing Complications of Iron Overload in Patients With Thalassemia Major. New England Journal of Medicine. 1994 Sep 1;331(9):567-73 3. Porter J, Garbowski M. Consequences and Management of Iron Overload in Sickle Cell Disease. Hematology Am Soc Hematol Educ Program. 2013;2013:447-56 4. UpToDate: Transfusion in sickle cell disease. Accessed July 7, 2020. 5. Gummin DD,, et al. 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System. Clin Toxicology Dec 2019; 57:1220-1413. 6. Tenenbein M. Toxicokinetics and toxicodynamics of . Toxicology Letters Dec1998; 102-103.

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7. Mills KC, Curry SC. Acute iron poisoning. Emergency Medical Clinics of North America. May 1994; 12:397-413. 8. Angelucci E, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. May 2008;93(5):741-752. 9. Porter JB, Shah FT. Iron overload in thalassemia and related conditions: therapeutic goals and assessment of response to chelation therapies. Hematology and Oncology Clinics of North America. Dec 2010;24(6):1109-1130.

Policy History/Revision Information

Date Summary of Changes 01/01/2021 • New Medical Benefit Drug Policy

Instructions for Use

This Medical Benefit Drug Policy provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the member specific benefit plan document must be referenced as the terms of the member specific benefit plan may differ from the standard benefit plan. In the event of a conflict, the member specific benefit plan document governs. Before using this policy, please check the member specific benefit plan document and any applicable federal or state mandates. UnitedHealthcare reserves the right to modify its Policies and Guidelines as necessary. This Medical Benefit Drug Policy is provided for informational purposes. It does not constitute medical advice.

UnitedHealthcare may also use tools developed by third parties, such as the InterQual® criteria, to assist us in administering health benefits. UnitedHealthcare Medical Benefit Drug Policies are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice.

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