Jadenu (Page 5 of 8)

8.6 Renal Impairment

For patients with creatinine clearance (CLcr) 40 to 60 mL/min, reduce the starting dose by 50% [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. JADENU is contraindicated in patients with a CLcr less than 40 mL/min or serum creatinine greater than two times the age-appropriate upper limit of normal (ULN) [see Contraindications (4)].

JADENU can cause renal failure. Monitor serum creatinine and calculate creatinine clearance during treatment in all patients. Reduce, interrupt or discontinue JADENU dosing based on increases in serum creatinine [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), Pharmacokinetics (12.3)].

10 OVERDOSAGE

Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. 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. There is no specific antidote for JADENU. In case of overdose, induce vomiting and employ gastric lavage.

11 DESCRIPTION

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

Deferasirox structural formula.
(click image for full-size original)

Deferasirox is a white to slightly yellow powder. It has a molecular formula C21H15N3O4 and molecular weight of 373.4. It is insoluble in water with a pH of suspension of 4.1.

JADENU tablets contain 90 mg, 180 mg, or 360 mg deferasirox. Inactive ingredients include microcrystalline cellulose, crospovidone, povidone (K30), magnesium stearate, colloidal silicon dioxide, and poloxamer (188). The film coating contains opadry blue.

JADENU Sprinkle granules contain 90 mg, 180 mg, or 360 mg deferasirox. Inactive ingredients include microcrystalline cellulose, crospovidone; povidone (K30), magnesium stearate, colloidal silicon dioxide, poloxamer (188).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

JADENU (deferasirox) is an orally active chelator that is selective for iron (as Fe 3+). 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.

Cardiac Electrophysiology

The effect of 20 and 40 mg per kg per day of deferasirox (tablets for oral suspension) on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female subjects age 18 to 65 years. No evidence of prolongation of the QTc interval was observed in this study.

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 (t max ) of about 1.5 to 4 hours. In healthy subjects, JADENU showed comparable t max . The maximal concentrations (C max ) and area under the curve (AUC 0-24h , AUC τ ) 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 (AUC inf )] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUCinf) of JADENU tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUC inf of JADENU 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 C max was increased by 30%. The 30% increase in C max observed with JADENU tablets is not clinically meaningful.

The administration of JADENU tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUC inf and C max were similar to that under fasting conditions. The administration of JADENU tablets with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories), increased AUC inf by 18% and C max by 29% compared to that under fasting conditions [see Dosage and Administration (2.3)].

Granules

The bioavailability (as measured by AUC inf ) of JADENU Sprinkle granules was 52% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUC inf of the JADENU Sprinkle granules (i.e., 4 x 90 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however, the mean C max was increased by 34%. The 34% increase in C max observed with JADENU Sprinkle granules is not clinically meaningful.

The administration of JADENU Sprinkle granules with a soft meal (e.g., yogurt and apple sauce) or with a low-fat (approximately 450 calories with fat content approximately 30% of total calories) indicated that the AUC inf and C max after a low-fat meal or soft foods were similar to that under fasting conditions. The administration of JADENU Sprinkle granules with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories) increased AUC inf by 18% with no changes in Cmax 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 (V ss ) 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 (AUC inf ) 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 (t 1/2 ) 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 C max by 23% and AUC inf 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 AUC inf to 2.3-fold and C max 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 AUC inf and elimination half-life. The single dose C max was not affected, but an increase in theophylline C max 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 AUC inf 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 AUC inf by 45% [see Drug Interactions (7.6)].

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 CLcr greater than 60 mL/min, patients with MDS and CLcr 40 to 60 mL/min (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) AUC inf 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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