Deferasirox

Pregnancy Category: B

Lactation: not known whether excreted in breast milk, use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Deferasirox is used to remove excess iron in the body in people who have received a large number of blood transfusions. Deferasirox is in a class of medications called iron chelators. It works by attaching to iron in the body so that it can be excreted (removed from the body) in feces.

Before taking deferasirox,

• tell your doctor and pharmacist if you are allergic to deferasirox, any other medications, or any of the ingredients in deferasirox tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: cholestyramine (Locholest, Questran, Prevalite), cyclosporine (Gengraf, Neoral, Sandimmune), hormonal contraceptives (birth control pills, patches, rings, or injections), other medications to remove excess iron from the body, paclitaxel (Abraxane, Taxol), phenytoin, phenobarbital, repaglinide (Prandin, in Prandimet), rifampin (Rimactane, Rifadin, in Rifamate, in Rifater), ritonavir (Norvir), and simvastatin (Zocor, in Simcor, in Vytorin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking aluminum-containing antacids such as Amphogel, Alternagel, Gaviscon, Maalox, or Mylanta, take them 2 hours before or after deferasirox.
• tell your doctor if you have an infection or severe nausea, vomiting, or diarrhea, or if you think you may be dehydrated. Also tell your doctor if you have or have ever had hearing, ear, or vision problems.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking deferasirox, call your doctor.
• you should know that deferasirox may make you dizzy. Do not drive a car or operate machinery until you know how this medication affects you.
• tell your doctor if you develop diarrhea or vomiting during your treatment. If you have these symptoms, it is important to drink plenty of fluid so you will not become dehydrated.

Cases of overdose (2-3 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 up to 80 mg per kg per day in iron overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg per kg per day were tolerated. There is no specific antidote for Exjade. In case of overdose, induce vomiting and employ gastric lavage.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Deferasirox falls into category C. In animals studies, pregnant animals were given this medication and had some babies born with problems. There are no well-controlled studies that have been done in humans with deferasirox, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Your pharmacist can provide more information about deferasirox.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Heavy metal antagonist; chelating agent for iron.1 2 3 4 5 6 7 8

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For deferasirox, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to deferasirox or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of deferasirox in children. Safety and efficacy have not been established in children with transfusional iron overload who are younger than 2 years of age, or in children with chronic iron overload and non-transfusional-dependent thalassemia who are younger than 10 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of deferasirox in the elderly. However, elderly patients are more likely to have unwanted effects and age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving deferasirox.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking deferasirox, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using deferasirox with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Oxide
• Aluminum Phosphate
• Cholestyramine
• Colesevelam
• Colestipol
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Duloxetine
• Enzalutamide
• Fosphenytoin
• Phenobarbital
• Phenytoin
• Rifampin
• Ritonavir
• Theophylline
• Tizanidine
• Warfarin

Using deferasirox with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Repaglinide

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of deferasirox. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood or bone marrow disorders (eg, agranulocytosis, anemia, neutropenia) or
• Eye problems (eg, cataracts, glaucoma) or
• Hearing problems or
• Kidney disease (eg, Fanconi's syndrome) or
• Stomach problems (eg, ulcers or bleeding, perforation)—Use with caution. May make these conditions worse.

• Bone marrow problems (eg, myelodysplastic syndrome) or
• Cancer, advanced or
• Kidney disease, severe or
• Liver disease, severe or
• Thrombocytopenia (low platelet count in the blood)—Should not be used in patients with these conditions.

• Liver disease (eg, hepatitis)—You may need a lower dose of deferasirox.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Diarrhea
• dizziness
• earache or pain in the ear
• nausea
• stomach pain
• voice changes
• vomiting

• Blindness
• blurred vision
• change in hearing
• change in vision
• pain or discomfort in the eye

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• dark-colored urine
• decrease in the amount of urine
• general feeling of tiredness or weakness
• hives, welts, skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• lower back or side pain
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• redness, soreness, itching of the skin
• sores, blisters
• stomach pain, continuing
• unusual bleeding or bruising
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• vomiting of blood or material that looks like coffee grounds
• yellow eyes or skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• ICL670

Patients with myelodysplastic syndromes (MDS) and CrCl 40 to 60 mL/minute had ~50% higher mean deferasirox trough levels compared to patients with MDS and CrCl >60 mL/minute.

Systemic exposure has been shown to be less in pediatric patients (2-16 years) compared to adults; in children 2 to 6 years, exposure was reduced by ~50% compared to adults; however, results of safety and efficacy trials using the same dose were similar in pediatric and adult patients. Patients with myelodysplastic syndromes (MDS) and CrCl of 40 to 60 mL/minute had 50% higher mean deferasirox trough concentrations compared to patients with MDS and CrCl >60 mL/minute.

Note: Calculate dose to the nearest whole tablet size or nearest whole granules packet.

Chronic iron overload due to transfusions: Oral: Note: Treatment should only be initiated with evidence of chronic iron overload (ie, transfusion of ≥100 mL/kg of packed red blood cells [eg, ≥20 units for a 40 kg individual] and serum ferritin consistently >1,000 mcg/L).

Exjade:

Initial: 20 mg/kg once daily

Maintenance: Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 5 or 10 mg/kg/day; titrate to individual response and treatment goals. In patients not adequately controlled with 30 mg/kg/day, doses up to 40 mg/kg/day may be considered for serum ferritin levels persistently >2,500 mcg/L and not decreasing over time (doses >40 mg/kg/day are not recommended). Consider interrupting therapy for serum ferritin consistently <500 mcg/L.

Jadenu:

Initial: 14 mg/kg once daily

Maintenance: Adjust dose every 3 to 6 months based on serum ferritin trends; adjust by 3.5 or 7 mg/kg/day; titrate to individual response and treatment goals. In patients not adequately controlled with 21 mg/kg/day, doses up to 28 mg/kg/day may be considered for serum ferritin levels persistently >2,500 mcg/L and not decreasing over time (doses >28 mg/kg/day are not recommended). Consider interrupting therapy for serum ferritin consistently <500 mcg/L.

Chronic iron overload in non-transfusion-dependent thalassemia syndromes: Oral: Note: Treatment should only be initiated with evidence of chronic iron overload (hepatic iron concentration ≥5 mg Fe/g dry weight and serum ferritin >300 mcg/L).

Exjade:

Initial: 10 mg/kg once daily. Consider increasing to 20 mg/kg once daily after 4 weeks if baseline hepatic iron concentration is >15 mg Fe/g dry weight.

Maintenance: Dependent upon serum ferritin measurements (monthly) and hepatic iron concentrations (every 6 months):

If serum ferritin is <300 mcg/L: Interrupt therapy and obtain hepatic iron concentration

If hepatic iron concentration:

<3 mg Fe/g dry weight: Interrupt therapy; resume treatment when hepatic iron concentration is >5 mg Fe/g dry weight

3 to 7 mg Fe/g dry weight: Continue treatment at a dose ≤10 mg/kg/day

>7 mg Fe/g dry weight: Increase dose to 20 mg/kg/day; Maximum dose: 20 mg/kg/day

Jadenu:

Initial: 7 mg/kg once daily. Consider increasing to 14 mg/kg once daily after 4 weeks if baseline hepatic iron concentration is >15 mg Fe/g dry weight.

Maintenance: Dependent upon serum ferritin measurements (monthly) and hepatic iron concentrations (every 6 months):

If serum ferritin is <300 mcg/L: Interrupt therapy and obtain hepatic iron concentration

If hepatic iron concentration:

<3 mg Fe/g dry weight: Interrupt therapy; resume treatment when hepatic iron concentration is >5 mg Fe/g dry weight

3 to 7 mg Fe/g dry weight: Continue treatment at a dose ≤7 mg/kg/day

>7 mg Fe/g dry weight: Increase dose to 14 mg/kg/day; Maximum dose: 14 mg/kg/day

Dosage adjustment with concomitant medications: Bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol) or potent UGT inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Avoid concomitant use; if coadministration is necessary, consider increasing the initial dose of deferasirox dose by 50%; monitor serum ferritin and clinical response.

Conversion from Exjade to Jadenu: The dose for Jadenu should be ~30% lower

Tablets for oral suspension: Bioavailability increased variably when taken with food; take on empty stomach 30 minutes before a meal.

Granules and Tablets: Bioavailability decreased slightly (not clinically meaningful) after a low-fat meal and increased after a high fat meal; take on an empty stomach or with a light meal (containing ~250 calories and <7% fat content).

>10%:

Dermatologic: Skin rash (dose related; 6% to 11%)

Gastrointestinal: Abdominal pain (dose related; 21% to 28%), nausea (dose related; 11% to 23%), vomiting (dose related; 10% to 21%), diarrhea (dose related; 5% to 20%)

Genitourinary: Proteinuria (19%)

Renal: Increased serum creatinine (dose related; 2% to 38%)

1% to 10%: Hepatic: Increased serum ALT (2% to 8%)

Frequency not defined:

Central nervous system: Headache (Phatak 2010; Vichinsky 2007)

Gastrointestinal: Constipation (Vichinsky 2007)

Hepatic: Increased serum bilirubin (Vichinsky 2007)

Infection: Viral infection (Vichinsky 2007)

Neuromuscular & skeletal: Arthralgia (Vichinsky 2007), back pain (Vichinsky 2007)

Respiratory: Cough (Vichinsky 2007), nasopharyngitis (Vichinsky 2007), pharyngitis (Vichinsky 2007), respiratory tract infection (Vichinsky 2007)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acute pancreatitis, acute renal failure, agranulocytosis, alopecia, anaphylaxis, anemia (worsening), cataract, cholelithiasis, drug fever, duodenal ulcer, dyschromia, edema, erythema multiforme, Fanconi syndrome, fatigue, gastric ulcer, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, glycosuria, hearing loss (including high frequency), fever, hepatic failure, hepatic insufficiency, hepatitis, hyperactivity, hypersensitivity angiitis, hypersensitivity reaction, IgA vasculitis, increased intraocular pressure, interstitial nephritis, maculopathy, neutropenia, nontuberculous mycobacterial infection, optic neuritis, pancreatitis (associated with gallstones), pharyngolaryngeal pain, purpura, renal tubular disease, renal tubular necrosis, retinopathy, sleep disorder, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis, visual disturbance

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of abdominal ulcers (severe abdominal or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or abnormal swelling), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of infection, severe loss of strength and energy, hearing impairment, hearing loss, vision changes, severe abdominal pain, rash, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Creatinine clearance 40 to 60 mL/min:
-Reduce starting dose by 50%, closely monitor serum creatinine and creatinine clearance.
-Reduce, interrupt, or discontinue based on increases in serum creatinine.

Creatinine clearance under 40 mL/min or serum creatinine more than twice the upper limit of normal: Contraindicated

Comments:
Closely monitor for efficacy and adverse reactions that may require dose titration.