Iron Chelator Drug Class Monograph

Transcription

1 Iron Chelator Drug Class Monograph Line of Business: Medi-Cal Effective Date: May 17, 2017 Revision Date: May 17, 2017 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the IEHP Pharmacy and Therapeutic Subcommittee. Drugs: Deferoxamine, Exjade (Deferasirox), Ferriprox (Deferiprone), Jadenu (Deferasirox) Policy/Criteria: A. Exjade, Jadenu (deferasirox) Diagnosis: a. FDA approved indications Specialist: Hematologist Criteria: a. Treatment of chronic iron overload due to non-transfusion dependent thalassemia syndromes evidenced by baseline serum ferritin level > 300 mcg/l OR Liver Iron Concentration (LIC ) > 5mg/g dw b. Treatment of chronic iron overload due to blood transfusions evidenced by baseline serum ferritin level > 1000 mcg/l (record of transfusions required) OR Liver Iron Concentration (LIC) > 7mg/g dw Reauthorization Criteria: a. Treatment of chronic iron overload due to non-transfusion dependent thalassemia: i. Documentation of positive clinical response to treatment ii. If ferritin < 300ng/mL and/or the LIC <3mg Fe/g, please consult IEHP Pharmacist.

2 b. Treatment of chronic iron overload due to blood transfusions: i. Documentation of positive clinical response to treatment; and continues to require therapy for serum ferritin level consistently >500mcg/L (in previous 3 months) Duration of Authorization: 6 months B. Ferriprox (deferiprone) Diagnosis: a. FDA approved indications Specialists: Hematologist Criteria: a. Treatment of transfusional iron overload due to thalassemia syndromes evidenced by baseline serum ferritin level > 300 mcg/l OR Liver Iron Concentration (LIC) > 5mg/g dw b. Failure or clinically significant adverse effects to deferasirox or deferoxamine. Reauthorization Criteria: a. Treatment of chronic iron overload due to blood transfusions: i. Documentation of positive clinical response to treatment; and continues to require therapy for serum ferritin level consistently >500mcg/L (in previous 3 months) Duration of Authorization: 6 months C. Desferal (deferoxamine) Diagnosis: a. FDA approved indications Specialists: Hematologist Criteria: a. Treatment of chronic iron overload due to blood transfusions evidenced by baseline serum ferritin level > 1000 mcg/l (record of transfusions required) OR Liver Iron Concentration (LIC) > 7mg/g dw b. Treatment of acute iron toxicity i. Considered medical emergency (i.e. hospitalization, ED) ii. Clinical features of iron toxicity include gastrointestinal features, shock and metabolic acidosis, hepatotoxicity/hepatic necrosis and/or bowel

3 obstruction. The toxicity of iron ingestion is determined by the mg/kg of elemental iron ingested and the type of iron formulation. Duration of Authorization: 6 months Clinical Justification: 1. THALASSA Trial Deferasirox reduces iron overload significantly in nontransfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. (2012) The THALASSA trial is a prospective, randomized, double-blind, placebo-controlled, phase 2 study that investigated the efficacy and safety of Deferasirox in ironoverloaded nontransfusion-dependent thalassemia (NTDT) patients. A total of 166 patients were followed for 1 year. The primary endpoint (absolute change in liver iron concentration (LIC) from baseline at 52 weeks through assessment of the number and proportion of patients with a LIC decrease of 3 mg Fe/g dry weight, those with 30% reduction in LIC, and those with LIC 7, 5, 3 mg Fe/g dw at 1 year) o In the deferasirox 5 mg/kg/d group, decreases in LIC were significantly greater than the respective placebo group (-2.33 ± 0.70 mg Fe/g dw, P= 0.001) o In the deferasirox 10 mg/kg/d group, decreases in LIC were significantly greater than the respective placebo group (-4.18 ± 0.69 mg Fe/g dw, P < 0.001) o In the placebo group, the LIC increased from baseline 0.38 ± 0.49 mg Fe/g dw (95% CI, to 1.34) Safety was evaluated through continuous monitoring and recording of adverse events and serious adverse events, laboratory testing, and clinical evaluations o No drug-related serious adverse events were reported in the placebo groups o 6 investigator-assessed drug-related serious adverse events were reported in 4 patients receiving Deferasirox (abdominal pain, pyrexia, hepatotoxicity not confirmed by a central laboratory, cellulitis, pruritus, and rash; n=1 each) Conclusion: For patients that have NTDT and have high iron burdens that require therapy, deferasirox at starting doses of 5 or 10 mg/kg/d with dose escalations up to 20 mg/kg/d were shown to decrease the high iron levels with a similar frequency of adverse reactions overall. 2. A randomized comparison of deferasirox versus deferoxamine for the treatment of in patients with beta-thalassemia and transfusional hemosiderosis This trial is a multicenter, open-label, randomized, active-comparator control study that investigated the safety and tolerability of deferasirox in comparison with

4 deferoxamine in patients with beta-thalassemia and transfusional hemosiderosis. A total of 586 patients were randomized into the Exjade or deferoxamine groups. The primary endpoint was a reduction in LIC of 3 mg Fe/g dry weight for baseline values 10 mg Fe/g dry weight, reduction in baseline values between 7 and < 10 to <7 mg Fe/g dw, or maintenance or reduction for baseline values <7 mg Fe/g dw. 533 patients at baseline and 12 months had their LIC evaluated and 52.9% of the Exjade and 66.4% of the deferoxamine patients reached the primary endpoint. 3. Oral deferiprone for iron chelation in people with thalassaemia. This is a meta-analysis that pulled date from trials on the clinical efficacy and safety of deferiprone and to compare it to the efficacy and safety of deferoxamine. It included randomized controlled trials that compared deferiprone with another iron chelator or compared 2 schedules or doses of deferiprone in people with transfusiondependent thalassemia. This study included 17 trials with a total of 1061 patients. From this analysis, there was no conclusive or consistent evidence for the improved efficacy of combined deferiprone and deferoxamine therapy over monotherapy from the direct or indirect measures of liver iron. They both produced a significant reduction in iron stores in the iron-overloaded, transfusion-dependent population alone. From what the author s found, they concluded that due to the absence of data from some of the trials, there is no evidence to suggest the need to change the current FDA treatment recommendations (deferiprone is indicated for iron overload in patients with thalassemia major only when deferoxamine is contraindicated or inadequate). Intensified deferoxamine treatment, other iron chelator use, or both remains the treatment of choice to reverse cardiac dysfunction due to iron overload. 4. Prospective, planned, pooled analysis of patients on the efficacy of Ferriprox in Transfusion-dependent iron overload patients in whom previous iron chelation therapy had failed or was considered inadequate. This was a prospective, planned, pooled analysis of patients from several studies that analyzed the efficacy of Ferriprox (75 mg/kg/day) in transfusion-dependent iron overload in patients in whom previous iron chelation therapy had failed or was considered inadequate due to poor tolerance. A total of 236 patients were analyzed with a 1 year follow-up period. o Criteria for past chelation failure was serum ferritin > 2,500 mcg/l before treatment with Ferriprox The primary endpoint was a 20% decline in serum ferritin within one year of starting therapy. This was met in 50% (of 236 subjects) with a 95% CI of 43-57%. 5. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA) This was a prospective, multinational, randomized, open-label, parallel-group, phase 2 study trial that compares deferasirox and subcutaneous deferoxamine for

5 noninferiority in the removal of myocardial iron in β-thalassemia major patients with myocardial siderosis and no signs of cardiac dysfunction. The primary endpoint of the study was the change in myocardial T2* and was assessed as the ratio of the geometric mean T2* at the end of the study divided by that at baseline (GmeanEOS/Gmeanbaseline). o Deferasirox: 12% (12.6 milliseconds at EOS/11.2 milliseconds at baseline) o Deferoxamine: 7% (12.3 milliseconds at EOS/11.6 milliseconds at baseline) o A trend for superiority was seen with Deferasirox but was not statistically significant (P = 0.057) The primary efficacy endpoint was the ratio of Gmean myocardial T2* after 1 year of treatment with Deferasirox divided by the ratio of Gmean for Deferoxamine. o At the end of the trial, the ratio was (95% CI, 0.998, 1.133) which indicates noninferiority of Deferasirox compared with Deferoxamine. Exjade (Deferasirox) Jadenu (Deferasirox) MOA Selectively binds iron in a 2:1 ratio, forming a complex that is excreted primarily through the feces Usual Dosing 20 mg/kg QD 14 mg/kg QD Administration Take on an empty stomach at least 30 min prior to food at the same time every day. Disperse the tablets in water, orange or apple juice and drink Take on an empty stomach or light meal ( <7% fat content and approximately 250 calories) at the same time every day immediately. Dosage adjustment in renal Yes impairment CrCl 60 ml/min Dosage adjustment in hepatic impairment Yes Moderate (Child-Pugh B) PK/PD Distribution: Adults 14.4 ± 2.7 L Protein binding: ~99% to serum albumin Metabolism: hepatic via glucuronidation by UGT1A1 and UGT1A3; minor oxidation by CYP450; undergoes enterohepatic recirculation Bioavailability: o Tablets for oral suspension: 70% o Tablets: 36% greater than tablets for oral suspension Half-life elimination: 8-16 hrs Time to peak, plasma: ~1.5-4 hrs Excretion: feces (84%); urine (8%) o Clearance moderately lower in women than men Drug-drug interaction Aluminum-containing antacids, CYP 1A2, CYP 2C8, CYP3A4 substrates Common Side effects Abdominal pain, diarrhea, nausea, vomiting, skin rash, elevated serum creatinine FDA Labeled Indications Chronic iron overload due to transfusions (patients 2 years old) or nontransfusion-dependent thalassemia syndromes (patients 10 years old) Serious allergic and hypersensitivity Yes Anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema

6 multiforme, and angioedema US Boxed Warning Renal failure, hepatic failure, gastrointestinal hemorrhages Contraindications SCr > 2 x age-appropriate ULN or ClCr < 40 ml/min, poor performance status, high-risk myelodysplastic syndromes, advanced malignancies, platelet count < 50 x 10 9 /L, known hypersensitivity Infection Risk Acute renal failure Hepatotoxicity Cytopenias (e.g. agranulocytosis, neutropenia) Pregnancy C Lactation Unknown if it is excreted in breast milk. Recommended to consider discontinuation while weighing the risks vs benefits due to the adverse reactions. Storage and stability Store at 25 C (77 F; excursions are permitted to C (59-86 F) Protect from moisture How supplied Tablets for oral suspension 125 mg, 250 mg, 500 mg Tablets 90 mg, 180 mg, 360 mg Ferriprox (Deferiprone) Desferal (Deferoxamine) MOA Binds to ferric ion and forms a 3:1 complex that is excreted in the urine Complexes with trivalent ions (ferric ions) in a 1:1 complex to form ferrioxamine, which is eliminated by the kidneys in the urine. Usual Dosing 75 mg/kg/d mg/d IM Administration Take the first dose in the morning, the second dose at midday, and the third dose in the evening. Take with meals if nausea occurs. IM: preferred route SQ, IV: requires slow infusion (10-12 hr continuous infusion) Reconstitution needed for all routes of administration Dosage adjustment in renal impairment No Yes CrCl 50 ml/min Dosage adjustment in hepatic impairment No No PK/PD Absorption: rapid Distribution: 1.6 L/kg (in thalassemia patients) Protein binding: <10% Metabolism: primarily by UGT 1A6, major metabolite (3-Oglucuronide) lacks iron-binding capacity Absorption: IM, SQ - well absorbed Distribution: throughout body fluids Protein binding < 10% Metabolism: plasma enzymes, binds with iron to form ferrioxamine (iron complex) Bioavailability: tablets and oral solution are considered bioequivalent Half-life elimination: 14 hours; plasma: min Excretion: primarily urine (as Half life elimination: ~2 hours unchanged drug and Time to peak: ~1-2 hours ferrioxamine); feces (via bile) Excretion: urine (75-90%; primarily as metabolite) Dialyzable: yes Drug-drug interaction Avoid use with other drugs associated Avoid with multivitamins, ascorbic

7 Common Side effects FDA Labeled Indications Serious allergic and hypersensitivity with neutropenia or agranulocytosis; mineral supplements, antacids that contain polyvalent cations Chromaturia, nausea, vomiting, abdominal pain, ALT increase, arthralgia, neutropenia Transfusion iron overload due to thalassemia syndromes when current chelation therapy is inadequate in adults Yes; Henoch-Scholein purpura, urticaria, periorbital edema with skin acid (Vitamin C), & prochlorperazine Flushing, hypotension, dizziness, headache, skin rash, hearing loss, tinnitus, cataracts,, diarrhea, ARDS, growth retardation, infection (Yersinia, Mucormycosis), infusion/injection site reactions, urine discoloration (frequency not defined) Acute iron intoxication, Chronic iron overload due to transfusiondependent anemias Patients 3 years old Yes; Anaphylaxis with or without shock, angioedema rash US Boxed Warning Agranulocytosis, Neutropenia N/A Contraindications Hypersensitivity Hypersensitivity, severe renal disease or anuria Infection Risk Acute renal failure Hepatotoxicity Cytopenias (e.g. agranulocytosis, neutropenia) Hazardous Drug Handling Pregnancy D C Lactation Unknown if it is excreted in breast milk. Recommended to consider discontinuation while weighing the risks vs benefits due to the adverse reactions. Storage and stability Store at C (68-77 F); excursions permitted to C (59-86 F) How supplied Store oral solution in original carton Use contents within 35 d after first opening bottle, discard remaining after 35 d Film-coated tablets 500 mg Prior to reconstitution: store at 25 C ( 77 F) After reconstitution: store at room temperature for 24 hours Use should begin within 3 hours of reconstitution Solution Reconstituted Injection, as mesylate 500 mg 2 g References: 1. Package Insert: Exjade. Novartis Pharmaceuticals Corporation, East Hanover, NJ, Package Insert: Jadenu. Novartis Pharmaceuticals Corporation, East Hanover, NJ, Package Insert: Ferriprox. ApoPharma Corporation, Rockville, MD, 2015.

8 4. Package Insert: Desferal. Novartis Pharmaceuticals Corporation, East Hanover, NJ, A Randomized, Open-label, Multi-center, Phase II Study to Evaluate the Safety and Efficacy of Deferasirox (ICL670) 20 mg/kg/day Relative to Subcutaneous Deferoxamine in Sickle Cell Disease Patients With Iron Overload From Repeated Blood Transfusions. Novartis Clinical Trials, Kontoghiorghes GJ, Eracleous E, Economides C, et al. Advances in iron overload therapies. Prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NAll and their combinations. Curr Med Chem 2005;12(23): Vichinsky et al. A randomized comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol Feb;136(3): Roberts DJ, Brunskill S, Doree C, Williams S, Howard J, Hyde C. Oral deferiprone for iron chelation in people with thalassaemia. Cochrane Database Syst Rev. 2007;(3):CD Maggio A, Filosa A, Vitrano A, et al. Iron chelation therapy in thalassemia major: a systematic review with meta-analysis of 1520 patients included on randomized clinical trials. Blood Cells Mol Dis. 2011;47(3): Taher, Ali T. et al "Deferasirox reduces iron overload significantly in nontransfusiondependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study." Blood (2012): Web. 21 Feb Facts and Comparisons, deferiprone monograph. December Change Control Date Change 05/17/2017 Added reauthorization criteria for treatment of chronic iron overload due to non-transfusion dependent thalassemia: o Documentation of positive clinical response to treatment o If ferritin < 300ng/mL and/or the LIC <3mg Fe/g, please consult IEHP Pharmacist. Added reauthorization criteria for treatment of chronic iron overload due to blood transfusions: o Documentation of positive clinical response to treatment; and continues to require therapy for serum ferritin level consistently >500mcg/L (in previous 3 months) Revised criteria for treatment of acute iron toxicity: o Considered medical emergency (i.e. hospitalization, ED) o Clinical features of iron toxicity include gastrointestinal features, shock and metabolic acidosis, hepatotoxicity/hepatic necrosis and/or bowel obstruction. The toxicity of iron ingestion is determined by the mg/kg of elemental iron ingested and the type of iron formulation.