Effective Date

Date of Origin   

07-01-2024           

10-01-2021

Exjade^®*

(deferasirox)

Tablets for oral suspension

Treatment of chronic iron overload due to blood transfusions in patients 2 years and over

Treatment of chronic iron overload in patients 10 years and older with non-transfusion dependent thalassemia syndromes and with a liver iron concentration (LIC) of at least 5 mg iron per gram of dry weight and a serum ferritin greater than 300 mcg/L

Limitations of Use:

The safety and efficacy of Exjade when administered with other iron chelation therapy have not been established

* – generic available

1

Ferriprox^®

(deferiprone)

Oral solution

Treatment of transfusional iron overload in adult and pediatric patients 3 years of age and older with thalassemia syndromes

Treatment of transfusional iron overload in adult and pediatric patients 3 years of age and older with sickle cell disease or other anemias

Limitations of Use:

Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia

4

Ferriprox^®*

(deferiprone)

Tablet

Treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with thalassemia syndromes

Treatment of transfusional iron overload in adult and pediatric patients 8 years of age and older with sickle cell disease or other anemias

Limitations of Use:

Safety and effectiveness have not been established for the treatment of transfusional iron overload in patients with myelodysplastic syndrome or in patients with Diamond Blackfan anemia

*– generic available

2 ; 3

Jadenu®*

(deferasirox)

Tablets

Sprinkle granules

Treatment of chronic iron overload due to blood transfusions in patients 2 years and older

Treatment of chronic iron overload in patients 10 years and older with non-transfusion dependent thalassemia syndromes and with a liver iron concentration of at least 5 mg iron per gram of dry weight and a serum ferritin greater than 300 mcg/L

Limitations of Use:

The safety and efficacy of Jadenu when administered with other iron chelation therapy have not been established

* – generic available

5

Iron Overload

Patients with certain conditions (e.g., thalassemia, sickle cell disease, myelodysplastic syndrome, aplastic anemia, hemolytic anemia) are often transfusion dependent and receive excess iron with each transfusion. Chronic iron overload represents a serious complication of regular blood transfusions administered for a variety of hereditary and refractory anemias including thalassemia major, myelodysplastic syndromes, and sickle cell anemia.(6-10)  Without treatment, the prognosis for patients with iron overload is poor.(6-9) Blood transfusions can markedly extend life expectancy in patients with chronic anemia and with the value of transfusion therapy in various chronic anemias becoming more widely appreciated, its use is likely to increase in the future.(6) Every unit of transfused blood contains 200-250 mg of iron, and the body has no inherent mechanism for removing excess iron.(8) Therefore, iron overload is an inevitable consequence in patients who require repeated blood transfusions.(6-10)

Thalassemia syndrome is a group of conditions that cause the body to make fewer healthy red blood cells and less hemoglobin. Some patients with thalassemia require frequent transfusions of red blood cells to maintain an adequate level of hemoglobin and iron overload is common in these patients. Non-transfusion dependent thalassemia (NTDT) is a milder form of thalassemia that does not require individuals to get frequent red blood cell transfusions. Though, over time, some patients with NTDT are at risk for iron overload that may lead to damage to vital organs.(6-11)

Circulating iron is bound to transferrin during normal iron homeostasis. When iron overload occurs, transferrin becomes saturated, resulting in the presence of non-transferrin bound iron (NTBI) in the plasma.(6,8-9) The toxicity of iron results from two related events: 1) excess iron deposits in various tissues of the body, particularly the liver, heart, and endocrine organs, and 2) free iron catalyzes the formation of highly reactive hydroxyl radicals that lead to membrane damage and denaturation of proteins. Without intervention, clinical complications due to excessive body iron levels leads to tissue damage, ultimately resulting in organ failure and death.(6,8-9) Therefore, initiating iron chelation therapy as early as possible reduces exposure to toxic levels of body iron and, in turn, minimizes the risk of developing iron overload-related complications.(11)

Multiple organs are affected by iron overload including heart, lung, liver, and endocrine glands. Cardiac involvement is a major determinant of the prognosis of iron-overloaded states. The average time for the development of heart failure in transfused, un-chelated patients is 10 years. Iron chelating agents can reverse cardiac changes and improve cardiac function. Mortality in chronically transfused patients with thalassemia and sickle cell disease is 3 times that of the general U.S. population. The most common cause of mortality is cardiomyopathy (30%) induced by iron overload.(12)

Iron chelation therapy is first-line therapy in patients with chronic iron overload due to blood transfusions. It reduces the risk for developing co-morbidities and improves patient survival.(6-8) The primary aim of iron chelation therapy is to bind to and remove iron from the body at a rate that is either equal to the rate of transfusional iron input or greater than iron input, and 24-hour protection from the harmful effects of toxic iron (NBTI).(6)

The primary goal of iron chelation is to prevent the accumulation of harmful iron levels by matching iron intake from transfusions with excreted iron by chelation. Initiation of chelation therapy is a decision that has to be individualized but in general, transfusions exceeding 100 mL/kg is enough to merit evaluation of chelation therapy.(12)

Efficacy

Deferasirox products (Exjade and Jadenu) are orally active chelators for patients with chronic iron overload due to blood transfusions in patients 2 years of age and older.(1) The indication is based on reduction in serum ferritin and liver iron concentration. Deferasirox is also indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion dependent thalassemia (NTDT) syndromes and with a liver iron (Fe) concentration of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L. Exjade has a half-life of 8 to 16 hours and is present in the plasma for 24 hours.(1) Therefore, Exjade is unique in providing constant chelation coverage with a convenient once-daily dosing.(1) In contrast, chelation coverage with deferoxamine (DFO) is limited to periods of drug exposure only.(6-10) Exjade has been shown to induce a mean net iron excretion within the clinically relevant range of 0.1-0.5 mg/kg/day and has shown to be effective for patients who were previously inadequately chelated with DFO.(1) Patients that have benefited from deferasirox in clinical trials include patients with beta-thalassemia and other congenital or chronic anemias, including myelodysplastic syndrome.(1) Initiation of Exjade should be considered when patients have evidence of chronic iron overload, such as the transfusion of approximately 100 milliliters/kilogram (kg) of packed red blood cells (approximately 20 units for a 40 kg patient) and a serum ferritin level consistently greater than 1000 mcg/liter.(1)

The primary efficacy for Exjade was evaluated in a multicenter, open-label, randomized active comparator-controlled trial to compare Exjade (n of 276) and deferoxamine (n of 277) in 586 patents with beta-thalassemia and transfusional hemosiderosis. The primary efficacy endpoint was defined as a reduction in liver iron concentration (LIC) of greater than or equal to 3 mg Fe/g dry weight for baseline values greater than or equal to 10 mg Fe/g, reduction of baseline values between 7 and less than 10 to less than 7 Fe/g dry weight, or maintenance or reduction for baseline values less than 7 mg Fe/g.  The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine.  The relative efficacy of Exjade to deferoxamine cannot be determined from this study.(1)  

The second study conducted for Exjade was a non-comparative study in 184 patients with chronic anemias and transfusional hemosiderosis patients. This study showed a reduction in absolute LIC from baseline to study end.(1)

Study 3 was a comparative study of Exjade (n of 132) to deferoxamine (n of 63) conducted in 195 patients with sickle cell disease and transfusional hemosiderosis.  The mean change in LIC compared to baseline was -1.3 mg Fe/g for Exjade (n of 113) and -0.7 mg Fe/g for deferoxamine (n of 54).  This was a statistically significant result.(6)

The safety and efficacy of Exjade to treat chronic iron overload in patients with NTDT were established in two clinical trials designed to measure the number of patients whose LIC was reduced to less than 5 mg/g dry weight after 52 weeks of treatment. Results showed 15% (5 mg/kg dose) and 27% (10 mg/kg dose) of Exjade treated patients achieved the target LIC compared with 4% of the placebo treated patients. The second trial looked at 133 patients from the first study that either received an additional year of Exjade treatment, or switched from placebo to Exjade treatment. Thirty-five percent of the evaluable patients in this trial achieved the target LIC.(1)

There is no clinical data in patients with Jadenu. Jadenu contains the same active ingredient as Exjade tablets for oral suspension. Jadenu tablets simplify administration of treatment for chronic iron overload as they can be consumed with or without a light meal, while Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Ferriprox (deferiprone) is a chelating agent with an affinity for ferric ions (iron iii). Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH.(2)

The efficacy of deferiprone was assessed in a prospective, planned, pooled analysis of patients with thalassemia syndromes from several studies. The study evaluated transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. The main criterion for chelation failure was serum ferritin greater than 2,500 mcg/L before treatment with deferiprone. Deferiprone therapy was considered successful in individual patients who experienced at least a 20% decline in serum ferritin within one year of starting therapy. For the patients in the analysis, the endpoint of at least a 20% reduction in serum ferritin was met in 50%, with a 95% confidence interval of 43 to 57%.(2)

Study LA38-0411, an actively-controlled non-inferiority study compared the efficacy of Ferriprox to that of deferoxamine in patients with sickle cell disease and other transfusion-dependent anemias by evaluating liver iron concentration (LIC). The efficacy of Ferriprox was established based upon the change in LIC from baseline after 12 months of Ferriprox compared to deferoxamine. After adjusting for the type I (alpha) error, the non-inferiority criterion was established as the upper limit of the 96.01% confidence interval for the difference between treatments being 2 mg/g dry weight.(2)

Ferriprox tablets (twice daily formulation) were evaluated in trials in healthy subjects. Ferriprox tablets (twice daily formulation) contain deferiprone the same active ingredient as Ferriprox tablets (three times daily formulation) and Ferriprox oral solution.(3-4)

Safety

BOXED WARNINGS:

Both Exjade and Jadenu have a boxed warning regarding acute kidney injury including acute renal failure requiring dialysis and renal tubular toxicity including Fanconi syndrome and death; hepatic toxicity including failure and death; and gastrointestinal hemorrhage which may be fatal. Patients should be monitored regularly for serum ferritin levels as well as signs of adverse events.(1,5)

Ferriprox contains a boxed warning regarding agranulocytosis and neutropenia:(2,4)

• Ferriprox can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis
• Measure the absolute neutrophil count (ANC) before starting Ferriprox and monitor weekly while on therapy
• Interrupt Ferriprox if infection develops and monitor the ANC more frequently
• Advise patients taking Ferriprox to report immediately any symptoms indicative of infection

CONTRAINDICATIONS:

Exjade (deferasirox) is contraindicated in:(1)

• Estimated GFR less than 40 mL/min/1.73 m^2
• Patients with poor performance status
• Patients with high-risk myelodysplastic syndrome (MDS)
• Patients with advanced malignancies
• Patients with platelet counts less than 50 X 10^9/L
• Known hypersensitivity to deferasirox or any component of Exjade

Ferriprox (deferiprone) is contraindicated in patients with a hypersensitivity to deferiprone or to any of the excipients in the formulations.(2,4)

Jadenu (deferasirox) is contraindicated in:(5)

• Estimated GFR less than 40 mL/min/1.73 m^2
• Patients with poor performance status
• Patients with high-risk myelodysplastic syndrome (MDS)
• Patients with advanced malignancies
• Patients with platelet counts less than 50 X 10^9/L
• Known hypersensitivity to deferasirox or any component of Jadenu

1

Exjade Prescribing Information. Novartis Pharmaceuticals Corporation. July 2020.

2

Ferriprox tablets prescribing Information. Apotex Inc. November 2021.

3

Ferriprox 1000 mg tablet Prescribing Information. Apotex Inc. November 2021. Reference no longer used.

4

Ferriprox oral solution prescribing information. Apotex Inc. November 2021.

5

Jadenu prescribing information. Novartis Pharmaceuticals Corporation. July 2020.

6

Cappellini, M. Exjade (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion. Therapeutics and Clinical Risk Management 2007:3(2); 291-299.

7

Brittenham, GM, Griffith PM, Nienhuis AW, et al. 1994. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 331:567-73.

8

Porter JB. 2001a. Practical management or iron overload. Br J Haematol. 115:239-52.

9

Andrews NC, Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986095.

10

Porter JB. 2001b. Deferoxamine pharmacokinetics. Semin Hematol. 38:63-8.

11

Yang L, Keam SJ, Keating GM. Deferasirox: A Review of its Use in the Management of Transfusional Chronic Iron Overload. Drugs. 2007; 67(15): 2211-2230.

12

Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008;88:24-29.

Exjade ; Jadenu ; Jadenu sprinkle

deferasirox granules packet  ; deferasirox tab  ; deferasirox tab for oral susp

125 MG ; 180 MG ; 250 MG ; 360 MG ; 500 MG ; 90 MG

M ; N ; O ; Y

O ; Y

Ferriprox ; Ferriprox twice-a-day

deferiprone (twice daily) tab  ; deferiprone oral soln  ; deferiprone tab

100 MG/ML ; 1000 MG ; 500 MG

M ; N ; O ; Y

N ; O ; Y

Exjade

Deferasirox Tab For Oral Susp 125 MG

125 MG

30

Tablets

30

DAYS

Exjade

Deferasirox Tab For Oral Susp 250 MG

250 MG

30

Tablets

30

DAYS

Exjade

Deferasirox Tab For Oral Susp 500 MG

500 MG

90

Tablets

30

DAYS

Ferriprox

Deferiprone Oral Soln 100 MG/ML

100 MG/ML

2700

mLs

30

DAYS

Ferriprox

Deferiprone Tab 1000 MG

1000 MG

270

Tablets

30

DAYS

Ferriprox

Deferiprone Tab 500 MG

500 MG

540

Tablets

30

DAYS

Ferriprox twice-a-day

Deferiprone (Twice Daily) Tab 1000 MG

1000 MG

270

Tablets

30

DAYS

Jadenu

Deferasirox Tab 180 MG

180 MG

30

Tablets

30

DAYS

Jadenu

Deferasirox Tab 360 MG

360 MG

180

Tablets

30

DAYS

Jadenu

Deferasirox Tab 90 MG

90 MG

30

Tablets

30

DAYS

Jadenu sprinkle

Deferasirox Granules Packet 180 MG

180 MG

30

Packets

30

DAYS

Jadenu sprinkle

Deferasirox Granules Packet 360 MG

360 MG

180

Packets

30

DAYS

Jadenu sprinkle

Deferasirox Granules Packet 90 MG

90 MG

30

Packets

30

DAYS

Exjade ; Jadenu ; Jadenu sprinkle

deferasirox granules packet  ; deferasirox tab  ; deferasirox tab for oral susp

125 MG ; 180 MG ; 250 MG ; 360 MG ; 500 MG ; 90 MG

Ferriprox ; Ferriprox twice-a-day

deferiprone (twice daily) tab  ; deferiprone oral soln  ; deferiprone tab

100 MG/ML ; 1000 MG ; 500 MG

Exjade

Deferasirox Tab For Oral Susp 125 MG

125 MG

Exjade

Deferasirox Tab For Oral Susp 250 MG

250 MG

Exjade

Deferasirox Tab For Oral Susp 500 MG

500 MG

Ferriprox

Deferiprone Oral Soln 100 MG/ML

100 MG/ML

Ferriprox

Deferiprone Tab 1000 MG

1000 MG

Ferriprox

Deferiprone Tab 500 MG

500 MG

Ferriprox twice-a-day

Deferiprone (Twice Daily) Tab 1000 MG

1000 MG

Jadenu

Deferasirox Tab 180 MG

180 MG

Jadenu

Deferasirox Tab 360 MG

360 MG

Jadenu

Deferasirox Tab 90 MG

90 MG

Jadenu sprinkle

Deferasirox Granules Packet 180 MG

180 MG

Jadenu sprinkle

Deferasirox Granules Packet 360 MG

360 MG

Jadenu sprinkle

Deferasirox Granules Packet 90 MG

90 MG

Exjade, Jadenu

Initial Evaluation

Exjade (deferasirox) or Jadenu (deferasirox) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of chronic iron overload due to blood transfusions (transfusional hemosiderosis) AND BOTH of the following:
      1. The patient’s baseline (pretreatment) serum ferritin is greater than 1,000 mcg/L AND
      2. If the patient has been treated with a deferasirox agent within the past 90 days, the patient’s current (within the last 30 days) serum ferritin is greater than 500 mcg/L OR
   2. The patient has a diagnosis of chronic iron overload due to a non-transfusion dependent thalassemia syndrome AND BOTH of the following:
      1. ONE of the following:
         1. The patient’s baseline (pretreatment) liver iron (FE) concentration (LIC) is at least 5 mg FE/g of dry weight OR
         2. The patient’s serum ferritin is greater than 300 mcg/L OR
         3. MRI confirmation of iron deposition AND
      2. If the patient has been treated with a deferasirox agent within the past 90 days, the LIC is greater than 3 mg FE/g of dry weight OR
   3. The patient has another FDA approved indication for the requested agent and route of administration OR
   4. The patient has another indication that is supported in compendia for the requested agent and route of administration AND
2. If the patient has an FDA approved indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
3. If the request is for one of the following brand agents with an available generic equivalent (listed below), then ONE of the following:
   1. The patient has an intolerance or hypersensitivity to the generic equivalent that is not expected to occur with the brand agent OR
   2. The patient has an FDA labeled contraindication to the generic equivalent that is not expected to occur with the brand agent OR
   3. There is support for the use of the requested brand agent over the generic equivalent AND

4. The patient does NOT have severe hepatic impairment (Child-Pugh-Turcotte C) AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient will NOT be using the requested agent in combination with another iron chelating agent targeted in this program AND
7. The patient does NOT have any FDA labeled contraindications to the requested agent 

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

Length of Approval:  12 months

NOTE: If Quantity Limit applies please see Quantity Limit Criteria

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Renewal Evaluation

Exjade (deferasirox) or Jadenu (deferasirox) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The patient has a diagnosis of chronic iron overload due to blood transfusions, AND BOTH of the following:
      1. The patient has had a decrease in serum ferritin from baseline (pretreatment) AND
      2. The patient’s current serum ferritin is greater than 500 mcg/L OR
   2. The patient has a diagnosis of non-transfusional iron overload due to thalassemia syndromes AND the patient’s current serum ferritin is greater than 300 mcg/L OR
   3. The patient has another diagnosis and has had clinical benefit with the requested agent AND
3. The patient does NOT have severe hepatic impairment (Child-Pugh-Turcotte C) AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient will NOT be using the requested agent in combination with another iron chelating agent targeted in this program AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent 

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please see Quantity Limit Criteria

Ferriprox

Initial Evaluation

Ferriprox (deferiprone) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The patient has a diagnosis of transfusional iron overload with thalassemia syndromes OR
   2. The patient has a diagnosis of transfusional iron overload with sickle cell disease or other anemias AND BOTH of the following:
      1. The patient does NOT have myelodysplastic syndrome AND
      2. The patient does NOT have Diamond Blackfan anemia OR
      3. The patient has another FDA approved indication for the requested agent and route of administration OR
      4. The patient has another indication that is supported in compendia for the requested agent and route of administration AND
2. The patient has an absolute neutrophil count (ANC) greater than or equal to 1.5 X 10^9/L AND
3. If the patient has an FDA approved indication, then ONE of the following:
   1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
   2. There is support for using the requested agent for the patient’s age for the requested indication AND
4. If the request is for a brand agent, then ONE of the following:
   1. The patient has tried and had an inadequate response to a generic deferiprone OR
   2. The patient has an intolerance or hypersensitivity to a generic deferiprone that is not expected to occur with the brand agent OR
   3. The patient has an FDA labeled contraindication to a generic deferiprone that is not expected to occur with the brand agent OR
   4. There is support for the use of the requested brand agent over a generic deferiprone (NOTE: patient compliance will only be accepted after a trial of a generic) AND
5. ONE of the following:
   1. The patient has tried and had an inadequate response to Exjade (deferasirox) or Jadenu (deferasirox) OR
   2. The patient has an intolerance or hypersensitivity to Exjade (deferasirox) or Jadenu (deferasirox) OR
   3. The patient has an FDA labeled contraindication to BOTH Exjade (deferasirox) AND Jadenu (deferasirox) AND
6. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
7. The patient will NOT be using the requested agent in combination with another iron chelating agent targeted in this program AND
8. The patient does NOT have any FDA labeled contraindications to the requested agent

Compendia Allowed: AHFS, or DrugDex 1 or 2a level of evidence

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please see Quantity Limit Criteria

Renewal Evaluation

Ferriprox (deferiprone) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The patient has an absolute neutrophil count (ANC) greater than or equal to 1.5 X 10^9/L AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient will NOT be using the requested agent in combination with another iron chelating agent targeted in this program AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval:  12 months

NOTE: If Quantity Limit applies, please see Quantity Limit Criteria

Quantity limit for the Target Agent(s) will be approved when ONE of the following are met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
   3. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
3. ALL of the following:
   1. The requested quantity (dose) exceeds the program quantity limit AND
   2. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
   3. There is support of therapy with a higher dose for the requested indication

Length of approval: up to 12 months