Jadenu

Jadenu is part of the drug class:

• Iron chelating agents

If you take too much Jadenu call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using deferasirox and call your doctor at once if you have:

• problems with vision or hearing;

• kidney problems--urinating more or less than usual; painful or difficult urination; swelling in your feet or ankles; weakness, bone pain; feeling tired or short of breath;

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• low blood cell counts--fever, chills, flu-like symptoms, swollen gums, mouth sores, skin sores, rapid heart rate, pale skin, easy bruising, unusual bleeding, feeling light-headed; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Serious side effects may be more likely in older adults.

Common side effects may include:

• nausea, vomiting, stomach pain;

• diarrhea; or

• skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Many other medicines can increase or decrease the effects of deferasirox. Tell your doctor about all your current medicines and any you start or stop using, especially:

• repaglinide, rifampin, ritonavir, theophylline;

• cholesterol-lowering medicine--cholestyramine, colestipol, colesevelam;

• a blood thinner--warfarin, Coumadin, Jantoven;

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

• osteoporosis medicine--alendronate (Fosamax), risedronate (Actonel), and others;

• seizure medicine--carbamazepine, phenobarbital, phenytoin; or

• steroid medicine--prednisone, methylprednisolone, and others.

This list is not complete. Other drugs may interact with deferasirox, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• It is used to get rid of iron when too much is in the body.

For all patients taking this medicine:

• Tell all of your health care providers that you take Jadenu. This includes your doctors, nurses, pharmacists, and dentists.
• Very bad and sometimes deadly blood cell problems may happen. You will need to have blood tests while you take this medicine. Talk with your doctor. Tell your doctor right away if you have any signs of infection.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Jadenu affects you.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have an eye exam as you have been told by your doctor.
• Have a hearing test before starting this medicine and while you take Jadenu.
• Do not take antacids that have aluminum in them with this medicine.
• Do not switch between different forms of Jadenu without first talking with the doctor.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine with your other drugs.
• If you are 65 or older, use Jadenu with care. You could have more side effects.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking this medicine.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Jadenu (deferasirox tablets) while you are pregnant.

Children:

• If giving to your child, the dose of this medicine may need to be changed as your child's weight changes. Have your child's weight checked often. Talk with the doctor before changing your child's dose.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Belly pain.
• Upset stomach or throwing up.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

     Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)

Jadenu is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is approved under accelerated approval based on a reduction of liver iron concentrations and serum ferritin levels [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

     Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Jadenu is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L. This indication is approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

     Limitations of Use

Controlled clinical trials of Jadenu with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed [see Clinical Studies (14)].

The safety and efficacy of Jadenu when administered with other iron chelation therapy have not been established.

     Transfusional Iron Overload

Jadenu therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1000 mcg/L.

Prior to starting therapy, obtain:

• serum ferritin level
• baseline serum creatinine in duplicate (due to variations in measurements) and determine the CLcr (Cockcroft-Gault method) [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]
• serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
• baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.9)]

The recommended initial dose of Jadenu for patients 2 years of age and older is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules. Changes in weight of pediatric patients over time must be taken into account when calculating the dose.

After commencing therapy, monitor serum ferritin monthly and adjust the dose of Jadenu, if necessary, every 3 to 6 months based on serum ferritin trends. Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended.

If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Jadenu [see Warnings and Precautions (5.10)].

     Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Jadenu therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

Prior to starting therapy, obtain:

• LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy
• Serum ferritin level on at least 2 measurements 1 month apart [see Clinical Studies (14)]
• Baseline serum creatinine in duplicate (due to variations in measurements) and determine the CLcr (Cockcroft-Gault method) [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]
• Serum transaminases and bilirubin [see Dosage and Administration (2.4), Warnings and Precautions (5.2)]
• Baseline auditory and ophthalmic examinations [see Warnings and Precautions (5.9)]

Initiating therapy:

• The recommended initial dose of Jadenu is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet or nearest whole sachet content for granules.
• If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

During therapy:

• Monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.
• Monitor LIC every 6 months.
• After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.
• If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.
• When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.
• Monitor blood counts, hepatic function, and renal function [see Warnings and Precautions (5.1, 5.2, 5.4)].

Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

     Administration

Swallow Jadenu tablets once daily with water or other liquids, preferably at the same time each day. Take Jadenu tablets on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard). Do not take Jadenu tablets with aluminum-containing antacid products [see Drug Interactions (7.1)]. For patients who have difficulty swallowing whole tablets, Jadenu tablets may be crushed and mixed with soft foods (e.g., yogurt or apple sauce) immediately prior to use and administered orally. Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed and not stored for future use.

Take Jadenu Sprinkle granules on an empty stomach or with a light meal [see Pharmacokinetics (12.3)]. Administer Jadenu Sprinkle granules by sprinkling the full dose on soft food (e.g. yogurt or apple sauce) immediately prior to use and administered orally. Jadenu Sprinkle granules should be taken once a day, preferably at the same time each day. Do not take Jadenu Sprinkle granules with aluminum-containing antacid products [see Drug Interactions (7.1)].

For patients who are currently on chelation therapy with Exjade tablets for oral suspension and converting to Jadenu, the dose should be about 30% lower, rounded to the nearest whole tablet or nearest whole sachet content for granules. The table below provides additional information on dosing conversion to Jadenu.

     Use in Patients with Baseline Hepatic or Renal Impairment

Patients with Baseline Hepatic Impairment

Mild (Child-Pugh A) hepatic impairment: No dose adjustment is necessary.

Moderate (Child-Pugh B) hepatic impairment: Reduce the starting dose by 50%.

Severe (Child-Pugh C) hepatic impairment: Avoid Jadenu tablets or Jadenu Sprinkle granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

Patients with Baseline Renal Impairment

For patients with CLcr 40 to 60 mL/min, reduce the starting dose by 50% [see Use in Specific Populations (8.6)]. Do not use Jadenu in patients with serum creatinine greater than two times the age-appropriate upper limit of normal (ULN) or CLcr less than 40 mL/min [see Contraindications (4)].

     Dose Modifications for Increases in Serum Creatinine

For serum creatinine increases while receiving Jadenu [see Warnings and Precautions (5.1)] modify the dose as follows:

Transfusional Iron Overload

Adults and Adolescents (ages 16 years and older):

• If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.

Pediatric Patients (ages 2 to 15 years):

• Reduce the dose by 7 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate upper limit of normal (ULN).

All Patients (regardless of age):

• Discontinue therapy for serum creatinine greater than two times the age-appropriate ULN or for creatinine clearance less than 40 mL/min. [see Contraindications (4)]

Non-Transfusion-Dependent Thalassemia Syndromes

Adults and Adolescents (ages 16 years and older):

• If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg.

Pediatric Patients (ages 10 to 15 years):

• Reduce the dose by 3.5 mg per kg if serum creatinine increases to greater than 33% above the average baseline measurement and greater than the age appropriate ULN.

All Patients (regardless of age):

• Discontinue therapy for serum creatinine greater than 2 times the age-appropriate ULN or for creatinine clearance less than 40 mL/min [see Contraindications (4)].

     Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

Concomitant use of UGT inducers decreases systemic exposure. Avoid the concomitant use of strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). If you must administer Jadenu tablets or Jadenu Sprinkle granules with a strong UGT inducer, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.5)].

Bile Acid Sequestrants

Concomitant use of bile acid sequestrants decreases systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer Jadenu tablets or Jadenu Sprinkle granules with a bile acid sequestrant, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration (2.1, 2.2), Drug Interactions (7.6)].

     Mechanism of Action

Jadenu (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.

     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.

     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, Jadenu 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 Jadenu tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf 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 Cmax was increased by 30%. The 30% increase in Cmax 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 AUCinf and Cmax 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 AUCinf by 18% and Cmax by 29% compared to that under fasting conditions [see Dosage and Administration (2.3)].

Granules

The bioavailability (as measured by AUCinf) of Jadenu Sprinkle granules was 52% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf 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 Cmax was increased by 34%. The 34% increase in Cmax 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 AUCinf and Cmax 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 AUCinf 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 (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)].

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) 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.

More common side effects

The more common side effects of Jadenu can include:

• diarrhea

• vomiting

• nausea

• stomach pain

• skin rashes

• increase in lab readngs of serum creatinine

Serious side effects

Call your doctor right away if you have serious side effects. Call 9-1-1 or your local emergency services if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• Severe skin reactions. These can include Stevens-Johnson syndrome and erythema multiforme. Symptoms can include:

  • a painful rash
  • blistering and peeling skin

• Eye problems. Symptoms can include:

  • blurry vision
  • eye pain
  • double vision

• Hearing changes. Symptoms can include:

  • hearing loss
  • hearing trouble

• Stomach and intestinal bleeding. Symptoms can include:

  • bright red blood in your stool
  • black, tarry stool
  • stomach pain
  • vomiting blood