"The US Food and Drug Administration (FDA) has approved Bayer AG's unmodified, full-length recombinant antihemophilic factor VIII product, Kovaltry, for the treatment of hemophilia A in children and adults, the company said.
Renal Toxicity, Renal Failure, And Proteinuria
Exjade can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, Exjade-treated patients experienced dosedependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3) [see ADVERSE REACTIONS].
Measure serum creatinine in duplicate (due to variations in measurements) and determine the creatinine clearance (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or creatinine clearance more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary [see DOSAGE AND ADMINISTRATION].
Exjade is contraindicated in patients with creatinine clearance less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate upper limit of normal.
Renal tubular damage, including Fanconi's Syndrome, has been reported in patients treated with Exjade, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels < 1500 mcg/L.
Intermittent proteinuria (urine protein/creatinine ratio > 0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. In clinical trials in patients with transfusional iron overload, Exjade was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain [see ADVERSE REACTIONS].
Hepatic Toxicity And Failure
Exjade can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued Exjade because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [see ADVERSE REACTIONS].
Measure transaminases (AST and ALT) and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.
Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment [see DOSAGE AND ADMINISTRATION, Use In Specific Populations]. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.
Gastrointestinal (GI) Ulceration, Hemorrhage, And Perforation
GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade [see ADVERSE REACTIONS]. Monitor for signs and symptoms of GI ulceration and hemorrhage during Exjade therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome) [see ADVERSE REACTIONS].
Bone Marrow Suppression
Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with Exjade. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with Exjade in patients who develop cytopenias until the cause of the cytopenia has been determined. Exjade is contraindicated in patients with platelet counts below 50 x 109/L.
Increased Risk Of Toxicity In The Elderly
Exjade has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with Exjade more frequently for toxicity [see Use in Specific Populations].
Exjade may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment [see ADVERSE REACTIONS]. If reactions are severe, discontinue Exjade and institute appropriate medical intervention. Exjade is contraindicated in patients with known hypersensitivity to Exjade.
Severe Skin Reactions
Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have been reported during Exjade therapy [see ADVERSE REACTIONS]. If SJS or erythema multiforme is suspected, discontinue Exjade immediately and do not reintroduce Exjade therapy.
Rashes may occur during Exjade treatment [see ADVERSE REACTIONS]. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with Exjade. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.
Auditory And Ocular Abnormalities
Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of < 1% with Exjade therapy in the clinical studies. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting Exjade treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.
For patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with Exjade, since overchelation may increase Exjade toxicity [see DOSAGE AND ADMINISTRATION].
For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt Exjade administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt Exjade and obtain a confirmatory LIC [see Clinical Studies].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg per kg per day (0.48 times the MRHD on a mg/m² basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg per kg per day (0.81 times the MRHD on a mg/m² basis) in males and 300 mg per kg per day (1.21 times the MRHD on a mg/m² basis) in females.
Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests.
Deferasirox at oral doses up to 75 mg per kg per day (0.6 times the MRHD on a mg/m² basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg per kg/day in rats and 50 mg per kg/day in rabbits) 0.8 times the maximum recommended human dose (MRHD) on a mg/m² basis. These doses resulted in maternal toxicity but no fetal harm was observed.
In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg per kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m² basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m² basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD on a mg/m² basis.
It is not known whether Exjade is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Of the 700 patients with transfusional iron overload who received Exjade during clinical studies, 292 were pediatric patients 2- < 16 years of age with various congenital and acquired anemias, including 52 patients age 2- < 6 years, 121 patients age 6- < 12 years and 119 patients age 12- < 16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2- < 6 years have a systemic exposure to Exjade approximately 50% of that of adults [see CLINICAL PHARMACOLOGY]. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults [see Clinical Studies, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION].
Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials.
Sixteen pediatric patients (10 to < 16 years of age) with chronic iron overload and NTDT were treated with Exjade in clinical studies. The safety and efficacy of Exjade in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT [see Clinical Studies, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION].
Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age.
Four hundred thirty-one (431) patients ≥ 65 years of age were studied in clinical trials of Exjade in the transfusional iron overload setting. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
For patients with renal impairment (ClCr 40–60 mL/min), reduce the starting dose by 50% [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Exjade is contraindicated in patients with a creatinine clearance < 40 mL/min or serum creatinine > 2 times the age-appropriate upper limit of normal [see CONTRAINDICATIONS].
Exjade can cause renal failure. Monitor serum creatinine and calculate creatinine clearance (using Cockcroft- Gault method) during treatment in all patients. Reduce, interrupt or discontinue Exjade dosing based on increases in serum creatinine [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.
Avoid the use of Exjade in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 8/21/2015
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