"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.
Clinical Trials Experience
The following adverse reactions are also discussed in other sections of the labeling:
- Renal Toxicity, Renal Failure, and Proteinuria [see WARNINGS AND PRECAUTIONS]
- Hepatic Toxicity and Failure [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal (GI) Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Bone Marrow Suppression [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity [see WARNINGS AND PRECAUTIONS]
- Severe Skin Reactions [see WARNINGS AND PRECAUTIONS]
- Skin Rash [see WARNINGS AND PRECAUTIONS]
- Auditory and Ocular Abnormalities [see WARNINGS AND PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Transfusional Iron Overload
A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were < 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks.
Six hundred twenty-seven patients with MDS were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (AEs 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on Exjade at the completion of the study.
Table 1 displays adverse reactions occurring in > 5% of Exjade-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool). Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.
Table 1: Adverse Reactions* Occurring in > 5% of
Exjade-treated Patients in Study 1, Study 3, and MDS Pool
|Preferred Term||Study 1
(Sickle Cell Disease)
N=296 n (%)
N=290 n (%)
N=132 n (%)
N=63 n (%)
N=627 n (%)
|Abdominal Pain**||63 (21)||41 (14)||37 (28)||9 (14)||145 (23)|
|Diarrhea||35 (12)||21 (7)||26 (20)||3 (5)||297 (47)|
|Creatinine Increased* * *||33 (11)||0 (0)||9 (7)||0||89(14)|
|Nausea||31 (11)||14 (5)||30 (23)||7 (11)||161 (26)|
|Vomiting||30 (10)||28 (10)||28 (21)||10 (16)||83 (13)|
|Rash||25 (8)||9 (3)||14 (11)||3 (5)||83 (13)|
|*Adverse reaction frequencies are based on adverse events
reported regardless of relationship to study drug.
**Includes 'abdominal pain', 'abdominal pain lower', and 'abdominal pain upper' which were reported as adverse events.
***Includes 'blood creatinine increased' and 'blood creatinine abnormal' which were reported as adverse events. Also see Table 2.
In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related [see WARNINGS AND PRECAUTIONS]. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [see WARNINGS AND PRECAUTIONS]. An additional 2 patients, who did not have elevations in SGPT/ALT > 5 times the upper limit of normal, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).
In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 separate occasions (Table 2) [see WARNINGS AND PRECAUTIONS]. Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.
In the MDS pool, in the first year, a total of 229 (37%) patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued [see WARNINGS AND PRECAUTIONS]. A total of 5 (0.8%) patients developed SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients [see Clinical Studies].
Table 2: Number (%) of Patients with Increases in
Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool
|Laboratory Parameter||Study 1 (Beta-thalassemia)||Study 3 (Sickle Cell Disease)||MDS Pool|
N=296 n (%)
N=290 n (%)
N=132 n (%)
N=63 n (%)
N=627 n (%)
|Creatinine increase > 33% at 2 consecutive postbaseline visits||113 (38)||41 (14)||48 (36)||14 (22)||229 (37)|
|Creatinine increase > 33% and > ULN at 2 consecutive postbaseline visits||7 (2)||1 (0)||3 (2)||2 (3)||126 (20)|
|SGPT/ALT > 5 x ULN at 2 postbaseline visits||25 (8)||7 (2)||2 (2)||0||9 (1)|
|SGPT/ALT > 5 x ULN at 2 consecutive postbaseline visits||17 (6)||5 (2)||5 (4)||0||5 (1)|
Non-Transfusion-Dependent Thalassemia Syndromes
In Study 4, 110 patients with NTDT received 1 year of treatment with Exjade 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 5, 130 of the patients who completed Study 4 were treated with open-label Exjade at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies]. Table 3 displays adverse reactions occurring in > 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea.
Table 3: Adverse Reactions Occurring in > 5% in NTDT
|Study 4||Study 5|
|Any adverse reaction||31 (28)||9 (16)||27 (21)|
|Nausea||7 (6)||4 (7)||2 (2)|
|Rash||7 (6)||1 (2)||2 (2)|
|Diarrhea||5 (5)||1 (2)||7 (5)|
In Study 4, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to > 5 times ULN and > 2 times baseline (Table 4). Three Exjade-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases > 33% from baseline and > ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 4.
Table 4: Number (%) of NTDT Patients with Increases in
Serum Creatinine or SGPT/ALT
|Laboratory Parameter||Study 4||Study 5|
|Serum creatinine ( > 33% increase from baseline and > ULN at ≥ 2 consecutive postbaseline values)||3 (3)||0||2 (2)|
|SGPT/ALT ( > 5 x ULN and > 2 x baseline)||1 (1)||1 (2)||2 (2)|
In clinical studies, urine protein was measured monthly. 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 [see WARNINGS AND PRECAUTIONS].
Other Adverse Reactions
In the population of more than 5,000 patients with transfusional iron overload who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi's Syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.
The following adverse reactions have been spontaneously reported during post-approval use of Exjade in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.
Hepatobiliary disorders: hepatic failure
Gastrointestinal disorders: gastrointestinal hemorrhage, gastrointestinal perforation
Blood and lymphatic system disorders: worsening anemia
Read the Exjade (deferasirox) Side Effects Center for a complete guide to possible side effects
Aluminum Containing Antacid Preparations
The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of Exjade with aluminum-containing antacid preparations due to the mechanism of action of Exjade.
Agents Metabolized By CYP3A4
Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [see CLINICAL PHARMACOLOGY].
Agents Metabolized By CYP2C8
Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If Exjade and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other CYP2C8 substrates [see CLINICAL PHARMACOLOGY].
Agents Metabolized By CYP1A2
Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with Exjade. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with Exjade. Closely monitor patients for signs of exposure related toxicity when Exjade is coadministered with other drugs metabolized by CYP1A2 [see CLINICAL PHARMACOLOGY].
Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism
Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of Exjade with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Exjade efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with Exjade. Consider increasing the initial dose of Exjade if you must coadminister these agents together [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Bile Acid Sequestrants
Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with Exjade due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of Exjade [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Read the Exjade Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/21/2015
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