ibrutinib

Ibrutinib is a novel targeted therapy for certain cancers of white blood cells in adults and is also used for the treatment of chronic graft versus host disease in adult and pediatric patients.

Ibrutinib is typically used to treat patients who have received at least one prior therapy. Ibrutinib is an anticancer (antineoplastic) drug that belongs to a class of medications known as tyrosine kinase inhibitors which work by blocking the activity of tyrosine kinases, a family of enzymes that play important roles in the growth, division, and proliferation of cells.

Ibrutinib blocks the activity of Bruton’s tyrosine kinase (BTK), a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. B-cells are a type of white cells (lymphocytes) in the blood, which grow and proliferate uncontrollably in B-cell lymphoma cancers. Activation of the BCR and cytokine receptor signaling pathways is essential for the survival of cancerous B-cells. By blocking the BTK signaling, ibrutinib inhibits the survival and proliferation of malignant B-cells.

Ibrutinib is approved by the FDA for use in the treatment of the following types of B-cell cancers in adults:

• Mantle cell lymphoma (MCL)
• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
• Waldenstrom’s macroglobulinemia (WM)
• Marginal zone lymphoma (MZL)

Ibrutinib is also approved by the FDA for the treatment of chronic graft versus host disease (cGVHD) in adult and pediatric patients. GVHD is a serious complication that can occur after stem cell transplantation, a condition in which the donor cells attack the host cells.

Ibrutinib has orphan designation and is also investigated for use in other cancers including:

• Diffuse large B-cell lymphoma
• Follicular lymphoma
• Multiple myeloma
• Pancreatic cancer
• Gastric cancer, including gastroesophageal junction adenocarcinoma

• Bleeding events, some of them fatal, have been observed in patients receiving ibrutinib treatment. These included bruising, intracranial hemorrhage, gastrointestinal hemorrhage, blood in urine (hematuria), and post-procedural hemorrhage.
  • Concurrent use of anticoagulant and antiplatelet therapy can increase the risk of hemorrhage. Consider the risks and benefits of anticoagulant or antiplatelet therapy before administering concomitantly with ibrutinib. Monitor patients for signs of bleeding.
  • Consider the risk and benefit of withholding ibrutinib for at least 3 to 7 days before and after surgery, depending on the type of procedure and risk of bleeding.
• A significant number of patients receiving ibrutinib have developed fatal and non-fatal viral, bacterial, and fungal infections. Monitor patients for infections and fever and treat appropriately. Consider preventive treatment (prophylaxis) for infections in patients who are at increased risk for opportunistic infections.
• Ibrutinib can increase blood pressure. Monitor patients for hypertension and treat appropriately, and modify ibrutinib dosage as per guidelines.
• Treatment with ibrutinib has resulted in irregular heart rhythms (arrhythmia), cardiac failure, and sudden death in some patients. Patients with preexisting hypertension or cardiovascular diseases are at a higher risk. Monitor patients for cardiac function and arrhythmia and manage appropriately. Follow ibrutinib dosage modifications and consider risks and benefits of continued treatment with ibrutinib.
• Ibrutinib can cause fetal harm:
  • Verify pregnancy status in women patients of reproductive potential before initiating ibrutinib treatment.
  • Advise women of pregnancy potential and males with women partners who can get pregnant to use effective contraception during treatment and for at least one month after the final dose.
  • Apprise pregnant women of potential hazard to the fetus from ibrutinib treatment.
• Ibrutinib treatment can cause blood disorders including anemia, neutropenia and thrombocytopenia. Monitor the patient’s complete blood count every month.
• Second primary malignancies including non-skin carcinoma, and non-melanoma skin cancer have been reported in some patients.
• In some patients, there have been reports of tumor lysis syndrome, serious complication of cancer treatment in which a large number of cancer cells die and release their contents into the bloodstream. Assess the patient's risk, take precautions, closely monitor, and treat appropriately should this complication arise.

Common side effects of ibrutinib include:

• Major hemorrhage
• Gastrointestinal hemorrhage
• Postprocedural hemorrhage
• Blood in urine (hematuria)
• Bruising
• Round pin-point spots on skin from bleeding (petechiae)
• Blood disorders including:
  • Low red blood cell count (anemia)
  • Low count of neutrophil immune cells (neutropenia)
  • High count of lymphocytes (lymphocytosis)
  • Low platelet count (thrombocytopenia)
• Low serum antibody levels (hypogammaglobulinemia)
• Low albumin levels in blood (hypoalbuminemia)
• Low potassium in blood (hypokalemia)
• Excessive uric acid in blood (hyperuricemia)
• Dehydration
• Weight loss
• Bacterial, fungal or viral infection
• Reactivation of hepatitis B virus
• Sepsis
• Fever
• Urinary tract infection
• Upper respiratory tract infection
• Pneumonia
• Sinus inflammation (sinusitis)
• Bronchial inflammation (bronchitis)
• Cough
• Shortness of breath (dyspnea)
• Mouth and throat (oropharyngeal) pain
• Nasal bleeding (epistaxis)
• Swelling of extremities (peripheral edema)
• High blood pressure (hypertension)
• Heart failure
• Rapid heart rate in the sinus node (sinus tachycardia)
• Rapid and irregular rhythm in the atria (atrial fibrillation)
• Atrial flutter
• Irregular rhythms in the ventricles including:
  • Ventricular arrhythmia
  • Ventricular flutter
  • Ventricular fibrillation
  • Ventricular premature contractions
  • Ventricular tachycardia
• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Reduced appetite
• Indigestion (dyspepsia)
• Oral inflammation (stomatitis)
• Gastroesophageal reflux disease (GERD)
• Increase in liver enzyme alanine aminotransferase (ALT)
• Increase in serum creatinine
• Skin rash
• Skin infection
• Itching (pruritus)
• Anxiety
• Fatigue
• Dizziness
• Falling
• Headache
• Weakness (asthenia)
• Chills
• Musculoskeletal pain
• Muscle spasm
• Joint pain (arthralgia)
• Bone tissue death (osteonecrosis)
• Dry eye syndrome
• Blurred vision
• Increased tearing (lacrimation)
• Reduced visual acuity
• Second primary malignancy including:
  • Non-skin carcinoma
  • Non-melanoma skin carcinoma
• Cerebrovascular disease including:
  • Impaired blood flow to the brain (cerebral ischemia)
  • Ischemic stroke
  • Transient ischemic attacks (TIAs)
  • Cerebrovascular accident
  • Intracranial hemorrhage
  • Blood pooling under the brain membrane (subdural hematoma)

Less common side effects of ibrutinib include:

• Cardiac conduction disorder
• Supraventricular cardiac arrhythmia
• Low blood sodium (hyponatremia)
• Tumor lysis syndrome
• Abnormal platelet aggregation
• Damage to peripheral nerves (peripheral neuropathy)
• Progressive multifocal leukoencephalopathy, a disease that affects brain’s white matter
• Abnormal gait
• Lethargy
• Inflammation of fat tissue under the skin (panniculitis)
• Liver failure
• Liver cirrhosis
• Acute kidney injury
• Inflammation in the kidney (interstitial nephritis)
• Kidney failure syndrome
• Lung inflammation (pneumonitis)
• Pneumonia due to Pneumocystis jirovecii
• Interstitial pulmonary disease
• Skin reactions including:
  • Hives (urticaria)
  • Autoinflammatory skin conditions (neutrophilic dermatoses)
  • Separation of the nail from the nail bed (onychoclasis)
  • Stevens-Johnson syndrome
• Hypersensitivity reactions including:
  • Swelling under the skin and in the mucous tissue (angioedema)
  • Shock from severe allergic reaction (anaphylactic shock)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 70 mg
• 140 mg

Tablet

• 140 mg
• 280 mg
• 420 mg
• 560 mg (Adult only)

Oral suspension (Pediatric only)

• 70 mg/mL

Adult:

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

• Also indicated for CLL/SLL in patients with 17p deletion
• Monotherapy or in combination with rituximab or obinutuzumab, or with bendamustine and rituximab (BR) combination: 420 mg orally once daily
• Continue until unacceptable toxicity or disease progression

Mantle Cell Lymphoma

• Indicated in patients who have received at least 1 previous therapy
• 560 mg orally once daily
• Continue until disease progression or unacceptable toxicity

Waldenstrom Macroglobulinemia

• Indicated as monotherapy or in combination with rituximab
• 420 mg orally once daily
• Continue until disease progression or unacceptable toxicity

Marginal Zone Lymphoma

• Indicated in patients who require systemic therapy and have received at least one prior anti-CD20-based therapy
• 560 mg orally once daily
• Continue until disease progression or unacceptable toxicity

Chronic Graft vs Host Disease

• Indicated for chronic graft versus host disease (cGVHD) in adults who failed more than 1 line of systemic therapy
• 420 mg orally once daily
• Continue until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity
• If therapy is no longer required, consider discontinuing therapy based on medical assessment of individual patient

Dosage Modifications

Grade 2 cardiac failure

• Evaluate benefit-risk before resuming treatment
• MCL and MZL
  • First occurrence: Restart at 420 mg once daily
  • Second occurrence: Restart at 280 mg once daily
  • Third occurrence: Discontinue therapy
• CLL/SLL, WM, and cGVHD
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Restart at 140 mg once daily
  • Third occurrence: Discontinue therapy

Grade 3 cardiac arrhythmias

• MCL and MZL
  • First occurrence: Restart at 420 mg once daily
  • Second occurrence: Discontinue therapy
• CLL/SLL, WM, and cGVHD
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Discontinue therapy

Grade 3 or above cardiac failure or Grade 4 cardiac arrhythmias

• First occurrence: Discontinue therapy

Nonhematological and hematologic toxicities

• Other Grade 3 or 4 nonhematological toxicities
• Grade 3 or 4 neutropenia with infection or fever
• Grade 4 hematological toxicities
• MCL and MZL
  • First occurrence: Restart at 420 mg once daily
  • Second occurrence: Restart at 280 mg once daily
  • Third occurrence: Discontinue therapy
• CLL/SLL, WM, and cGVHD
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Restart at 140 mg once daily
  • Third occurrence: Discontinue therapy

Coadministration with CYP3A inhibitors

• Moderate CYP3A4 inhibitor: Reduce ibrutinib to 420 mg once daily; modify dose as recommended
• Reduce ibrutinib dose to 280 mg once daily when coadministered with the following
  • Voriconazole 200 mg twice daily
  • Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily
  • Modify dose as recommended
• Reduce ibrutinib dose to 140 mg once daily when coadministered with the following
  • Posaconazole suspension 200 mg three times/day or 400 mg twice daily
  • Posaconazole intravenous (IV) injection 300 mg once daily
  • Posaconazole delayed-release tablets 300 mg once daily
• Avoid coadministration
  • Other strong CYP3A inhibitors (boceprevir, clarithromycin, cobicistat conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and [ombitasvir and/or dasabuvir], ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin)
  • If these inhibitors will be used short term (e.g., anti-infectives for less than 7 days), interrupt ibrutinib
  • After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib

Hepatic impairment

• Modify dose based on following upper limit of normal (ULN) unless of non-hepatic origin or due to Gilbert’s syndrome
• Total bilirubin (TB) level above 1.5 to 3 times ULN
  • Children 1 to below 12 years: Reduce to 80 mg/m2 orally once daily
  • Patients 12 years or above: Reduce to 140 mg orally once daily
  • TB above 3 times ULN: Avoid use

Renal impairment

• Mild-to-moderate (estimated creatinine clearance [eCrCl] 25 mL/minute or above): No dosage adjustment necessary
• Severe (eCrCl below 25 mL/minute) or patients on dialysis: Not studied

Dosing Considerations

• Available via a limited distributed system from specialty pharmacies

Pediatric:

Chronic Graft versus Host Disease

• Indicated for chronic graft versus host disease (cGVHD) in adult and pediatric patients aged 1 year or above who failed more than 1 line of systemic therapy
• Children 1 to 12 years: 240 mg/m2 orally once daily (not to exceed 420 mg/dose)  
• ≥12 years: 420 mg orally once daily
• Continue until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity
• If therapy is no longer required, consider discontinuing therapy based on medical assessment of individual patient

Dosage Modifications

Grade 2 cardiac failure

• Evaluate the benefit-risk before resuming treatment
• Children 1 to 12 years
  • First occurrence: Restart at 160 mg/m2 once daily
  • Second occurrence: Restart at 80 mg/m2 once daily
  • Third occurrence: Discontinue therapy
• Children 12 years or above
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Restart at 140 mg once daily
  • Third occurrence: Discontinue therapy

Grade 3 cardiac arrhythmias

• Children 1 to 12 years
  • First occurrence: Restart at 160 mg/m2 once daily
  • Second occurrence: Discontinue therapy
• Children 12 years or above
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Discontinue therapy

Grade 3 or above cardiac failure or Grade 4 cardiac arrhythmias

• First occurrence: Discontinue therapy

Nonhematological and hematologic toxicities

• Other Grade 3 or 4 nonhematological toxicities
• Grade 3 or 4 neutropenia with infection or fever
• Grade 4 hematological toxicities
• Children 1 to 12 years
  • First occurrence: Restart at 160 mg/m2 once daily
  • Second occurrence: Restart at 80 mg/m2 once daily
  • Third occurrence: Discontinue therapy
• Children 12 years or above
  • First occurrence: Restart at 280 mg once daily
  • Second occurrence: Restart at 140 mg once daily
  • Third occurrence: Discontinue therapy

CYP3A inducers

• Strong CYP3A inducers decrease ibrutinib plasma concentrations by 10-fold
• Avoid coadministration of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, St. John’s Wort, enzalutamide, mitotane)

Coadministration with CYP3A inhibitors for ≥1 to <12 years

• Moderate CYP3A4 inhibitor: Reduce ibrutinib 160 mg/m2 once daily; modify dose as recommended
• Posaconazole at any dosage: Reduce ibrutinib 80 mg/m2 once daily

Avoid coadministration

• Other strong CYP3A inhibitors (boceprevir, clarithromycin, cobicistat conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and [ombitasvir and/or dasabuvir], ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin)
• If these inhibitors will be used short term (e.g., anti-infectives for less than 7 days), interrupt ibrutinib
• After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib

Coadministration with CYP3A inhibitors for children 12 years and above

• Moderate CYP3A4 inhibitor: Reduce ibrutinib to 420 mg once daily; modify dose as recommended
• Reduce ibrutinib dose to 280 mg once daily when coadministered with the following
  • Voriconazole 200 mg twice daily
  • Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily
  • Modify dose as recommended
• Reduce ibrutinib dose to 140 mg once daily when coadministered with the following
  • Posaconazole suspension 200 mg three times/day or 400 mg twice daily
  • Posaconazole IV injection 300 mg once daily
  • Posaconazole delayed-release tablets 300 mg once daily
• Avoid coadministration
  • Other strong CYP3A inhibitors (boceprevir, clarithromycin, cobicistat conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and [ombitasvir and/or dasabuvir], ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin)
  • If these inhibitors will be used short term (e.g., anti-infectives for less than 7 days), interrupt ibrutinib
  • After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib

Hepatic impairment

Modify dose based on following ULN unless of non-hepatic origin or due to Gilbert’s syndrome

• Total bilirubin (TB) level above 1.5 to 3 times ULN
  • Children 1 to 12 years: Reduce to 80 mg/m2 orally once daily
  • Children 12 years and above: Reduce to 140 mg orally once daily
  • TB above 3 times ULN: Avoid use

Renal impairment

• Mild-to-moderate (eCrCl 25 mL/minute or higher): No dosage adjustment necessary
• Severe (eCrCl below 25 mL/min) or patients on dialysis: Not studied

Overdose

• There is no experience with overdose of ibrutinib. A dosage of 1680 mg caused reversible Grade 4 liver enzyme (ALT and AST) increases in a healthy individual.
• Overdose may be treated with appropriate supportive and symptomatic treatment.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of ibrutinib include:
  • adenovirus types 4 and 7 live, oral
  • BCG vaccine live
  • cholera vaccine
  • influenza virus vaccine quadrivalent, intranasal
  • measles (rubeola) vaccine
  • measles mumps and rubella vaccine, live
  • measles, mumps, rubella and varicella vaccine, live
  • ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)
  • rotavirus oral vaccine, live
  • rubella vaccine
  • smallpox (vaccinia) vaccine, live
  • typhoid polysaccharide vaccine
  • typhoid vaccine live
  • varicella virus vaccine live
  • yellow fever vaccine
  • zoster vaccine live
• Ibrutinib has serious interactions with at least 73 different drugs.
• Ibrutinib has moderate interactions with at least i38 different drugs.
• Mild interactions of ibrutinib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • arotrectinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider about all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or healthcare provider if you have any questions about the medication.

• There are no data available on ibrutinib use in pregnant women, however, animal reproductive studies indicate ibrutinib can cause fetal harm if used during pregnancy.
• Women of pregnancy potential and men with female partners of pregnancy potential should use effective contraception during therapy and for 1 month after the last dose.
• There is no information on the presence of ibrutinib in breastmilk, or its effects on milk production or the breastfed infant. Avoid breastfeeding during treatment and for 1 week after the last dose, because of the potential for serious adverse reactions in the breastfed infant.

• Take ibrutinib exactly as prescribed. Swallow the tablet whole and do not break, chew or crush them before swallowing.
• Take the medication at appropriately the same time every day. If you miss a daily dose, take as soon as possible on the same day and return to the normal schedule on the next day. Do not take extra doses if you miss a dose.
• You may experience loose stools or diarrhea. Drink adequate fluids and contact your physician if diarrhea persists.
• Inform your physician immediately if you experience:
  • Signs and symptoms of hemorrhage, which may include blood in stool or urine, severe headache or unusual or uncontrolled bleeding
  • Heart-related symptoms such as palpitations, dizziness, lightheadedness, fainting, chest discomfort, shortness of breath or edema
  • Increase in blood pressure
  • Signs of infection such as fever, chills, weakness, and confusion
  • Abnormal changes in the skin
  • Signs of tumor lysis syndrome which can cause kidney failure, abnormal heart rhythm, or seizure
• You will need periodic tests, follow up with your physician, and do not miss your appointments.
• Store ibrutinib safely out of reach of children.
• In case of overdose, seek medical help immediately or call Poison Control.