Deferasirox (Page 6 of 9)

8.5 Geriatric Use

Four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. Two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. 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. In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.

8.6 Renal Impairment

Deferasirox tablet is contraindicated in patients with eGFR less than 40 mL/min/1.73 m2 [see Contraindications (4)]. For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m2), reduce the starting dose by 50% [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Exercise caution in pediatric patients with an eGFR between 40 and 60 mL/minute/1.73 m2 [see Dosage and Administration (2.4)]. If treatment is needed, use the minimum effective dose with enhanced monitoring of glomerular and renal tubular function. Individualize dose titration based on improvement in renal injury [see Dosage and Administration (2.4, 2.5)].

Deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. Monitor all patients closely for changes in eGFR and renal tubular dysfunction during deferasirox tablets treatment. If either develops, consider dose reduction, interruption or discontinuation of deferasirox tablets until glomerular or renal tubular function returns to baseline [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.1)].

8.7 Hepatic Impairment

Avoid use in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, reduce the starting dose 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 (2.4), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support. Single doses of deferasirox up to 80 mg per kg per day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy subjects, single doses of up to 40 mg per kg per day with the tablet for oral suspension formulation were tolerated.

Early signs of acute overdose are digestive effects such as abdominal pain, diarrhea, nausea, and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment.

There is no specific antidote for deferasirox. In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.

11 DESCRIPTION

Deferasirox is an iron-chelating agent provided as a tablet for oral use. Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxyphenyl)-1H -1,2,4-triazol-1-yl]benzoic acid and has the following structural formula:

Image

Deferasirox is a white to slightly yellow powder. It has a molecular formula C21 H15 N3 O4 and molecular weight of 373.4 g/mol. It is insoluble in water with a pH of suspension of 4.1.

Deferasirox tablets contain 90 mg, 180 mg, or 360 mg deferasirox. Inactive ingredients include crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, poloxamer (188), povidone (K30) and purified water. The film coating contains hypromellose, iron oxide red, macrogol, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.

12.2 Pharmacodynamics

Pharmacodynamic effects tested in an iron balance metabolic study with the tablet for oral suspension formulation showed that deferasirox (10, 20, and 40 mg per kg per day) was able to induce a mean net iron excretion (0.119, 0.329, and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.

An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure which may increase the probability of renal toxicity.

Cardiac Electrophysiology

At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (Tmax ) of about 1.5 to 4 hours. In healthy subjects, deferasirox showed comparable Tmax . The maximal concentrations (Cmax ) and area under the curve (AUC0-24h , AUCτ ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation.

Tablets

The absolute bioavailability [as measured by area under the curve over time to infinity (AUCinf )] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUCinf ) of deferasirox tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf of deferasirox tablets (i.e., 360 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however the mean Cmax was increased by 30%. The 30% increase in Cmax observed with deferasirox tablet is not clinically meaningful.

The administration of deferasirox tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUCinf and Cmax were similar to that under fasting conditions. The administration of deferasirox tablets with a high-fat meal (approximately 1,000 calories with fat content greater than 50% of total calories), increased AUCinf by 18% and Cmax by 29% compared to that under fasting conditions [see Dosage and Administration (2.3)].

Distribution

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss ) of deferasirox is 14.37 ± 2.69 L in adults.

Metabolism

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy subjects study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUCinf ) by interfering with the enterohepatic recycling of deferasirox.

Excretion

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2 ) ranged from 8 to 16 hours following oral administration.

Drug Interactions

Midazolam: The concomitant administration of deferasirox tablets for oral suspension and CYP3A4 probe substrate midazolam resulted in a decrease of midazolam Cmax by 23% and AUCinf by 17%. In the clinical setting, this effect may be more pronounced, as the study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [see Drug Interactions (7.2)].

Repaglinide: The concomitant administration of deferasirox tablets for oral suspension (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) increased repaglinide AUCinf to 2.3- fold and Cmax of 1.6-fold [see Drug Interactions (7.3)].

Theophylline: The concomitant administration of deferasirox tablets for oral suspension (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUCinf and elimination half-life. The single dose Cmax was not affected, but an increase in theophylline Cmax is expected to occur with chronic dosing [see Drug Interactions (7.4)].

Rifampicin: The concomitant administration of deferasirox tablets for oral suspension (single dose of 30 mg per kg) and the strong uridine diphosphate glucuronosyltransferase (UGT) inducer rifampicin (600 mg per day for 9 days) decreased deferasirox AUCinf by 44% [see Drug Interactions (7.5)].

Cholestyramine: The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUCinf by 45% [see Drug Interactions (7.6)].

Busulfan: Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC).

In vitro Studies: Deferasirox inhibited human CYP2A6, CYP2D6, and CYP2C19 in vitro.

Deferasirox is not a substrate of P-glycoprotein, MRP1 or MRP2.

Pharmacokinetics in Specific Populations

Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children less than 6 years of age, systemic exposure was about 50% lower than in adults.

Sex: The apparent clearance is 17.5% lower in females compared to males.

Renal Impairment: Compared to patients with MDS and eGFR greater than 60 mL/min/1.73 m2 , patients with MDS and eGFR 40 to 60 mL/min/1.73 m2 (n = 34) had approximately 50% higher mean deferasirox trough plasma concentrations.

Hepatic Impairment: 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) AUCinf 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.

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