Ibrutinib (Imbruvica) is a small molecule irreversible Bruton's Tyrosine Kinase Inhibitor. It inhibits the proliferation of B-lymphocytes and decreases their survival.

Ibrutinib (Imbruvica) Uses:

• Chronic graft-versus-host disease (refractory):

  • Second-line treatment of chronic graft-versus-host disease.

• Chronic lymphocytic leukemia/small lymphocytic lymphoma:

  • Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with 17p deletion.

• Mantle cell lymphoma, previously treated:

  • Second line therapy in the mantle cell lymphoma (MCL)

• Marginal zone lymphoma, relapsed/refractory:

  • Second-line therapy marginal zone lymphoma (MZL)

• Waldenström macroglobulinemia:

  • Treatment of Waldenström macroglobulinemia

Ibrutinib (Imbruvica) Dose in Adults:

Ibrutinib (Imbruvica) Dose in the treatment of refractory chronic graft-versus-host disease:

• Oral: 420 mg OD continue until chronic graft-versus-host disease (cGVHD) resolves, or relapse of underlying malignancy or toxic effects cannot be tolerated.

Ibrutinib (Imbruvica) Dose in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma:

• Oral: 420 mg OD as a single agent or with bendamustine and rituximab or obinutuzumab until tolerated.

Ibrutinib (Imbruvica) Dose in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma (off-label combination):

• Adults <70 years of age; previously untreated (IGHV-unmutated and without 17p deletion):

  • Oral: 420 mg OD (with rituximab [cycles 2 to 7]).

Ibrutinib (Imbruvica) Dose in the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion:

• Oral: 420 mg OD until tolerated.

Ibrutinib (Imbruvica) Dose in the treatment of previously treated Mantle cell lymphoma:

• Oral: 560 mg OD until tolerated.

Ibrutinib (Imbruvica) Dose in the treatment of Ibrutinib in combination with venetoclax (off-label combination):

• Oral: 560 mg once daily combined with venetoclax until tolerated.
• Start venetoclax 1 month after ibrutinib.

Ibrutinib (Imbruvica) Dose in the treatment of relapsed or refractory Marginal zone lymphoma:

• Oral: 560 mg OD until tolerated.

Ibrutinib (Imbruvica) Dose in the treatment of Waldenström macroglobulinemia:

• Oral: 420 mg OD as a single agent or combined with rituximab, until tolerated.
• Missed doses:
  • Take when remembered. Do not administer an additional dose to compensate for a missed dose

Ibrutinib (Imbruvica) Dosage adjustment for concomitant therapy:

Note:  Restart at previous dose after discontinuing CYP3A inhibitor

• B-cell malignancies:

  • Moderate CYP3A inhibitors:
    • Reduce ibrutinib dose to 280 mg OD.
    • Dose adjustment may be required according to adverse effects
  • Voriconazole 200 mg BD, posaconazole suspension 100 mg OD, 100 mg BD, or 200 mg BD:
    • Reduce ibrutinib dose to 140 mg OD.
    • Dose adjustment may be required according to adverse effects
  • Posaconazole suspension 200 mg TDS, posaconazole 300 mg IV OD, or posaconazole delayed-release tablets 300 mg OD:
    • Reduce ibrutinib dose to 70 mg OD. Dose adjustment may be required according to adverse effects
  • Other strong CYP3A inhibitors:
    • Do not use with ibrutinib. Hold ibrutinib if they must be used

• Chronic graft-versus-host disease:

  • Moderate CYP3A inhibitors:
    • Administer ibrutinib at 420 mg OD
  • Voriconazole 200 mg BD, posaconazole suspension 100 mg OD, 100 mg twice daily, or 200 mg BD:
    • decrease ibrutinib dose to 280 mg OD. Dose adjustment may be required according to adverse effects
  • Posaconazole suspension 200 mg TDS or 400 mg BD, posaconazole 300 mg IV OD, or posaconazole delayed-release tablets 300 mg OD:
    • Decrease ibrutinib dose to 140 mg OD. Dose adjustment may be required according to adverse effects
  • Strong CYP3A inhibitors:
    • Do not use with ibrutinib.
    • Hold ibrutinib if they must be used.

Use in Children:

Not indicated.

Ibrutinib Pregnancy Category: X

• Studies on animals have shown that fetuses are at risk
• Before starting treatment, it is important to rule out pregnancy. Prevent pregnancy in female patients, and in male partners, during and after treatment.

Ibrutinib can be used during breastfeeding

• Evaluate mother infant risk to benefit ratio

Ibrutinib (Imbruvica) Dose in Kidney Disease:

• CrCl ≥25 mL/minute: 
  • No dosage adjustment needed.
• CrCl <25 mL/minute:
  • No data available, no dose adjustment mentioned.
• End-stage renal disease (ESRD) requiring dialysis:
  • No data available, no dose adjustment mentioned.

Ibrutinib (Imbruvica) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):
  • Reduce to 140 mg OD.
  • Observe closely hold treatment if needed
• Moderate impairment (Child-Pugh class B):
  • Reduce dose to 70 mg OD.
  • Observe closely hold treatment if needed
• Severe impairment (Child-Pugh class C):
  • Contraindicated in severe renal impairment.

Common Side Effects of Ibrutinib (Imbruvica):

• Cardiovascular:

  • Peripheral Edema
  • Hypertension

• Central Nervous System:

  • Fatigue
  • Dizziness
  • Headache
  • Anxiety
  • Chills

• Dermatologic:

  • Skin Rash
  • Skin Infection
  • Pruritus

• Endocrine & Metabolic:

  • Hyperuricemia
  • Hypoalbuminemia
  • Hypokalemia
  • Dehydration

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Stomatitis
  • Constipation
  • Abdominal Pain
  • Vomiting
  • Decreased Appetite
  • Dyspepsia
  • Gastroesophageal Reflux Disease
  • Upper Abdominal Pain

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Thrombocytopenia
  • Neutropenia
  • Bruise
  • Hemorrhage
  • Decreased Hemoglobin
  • Petechia
  • Second Primary Malignant Neoplasm

• Infection:

  • Infection

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain
  • Muscle Spasm
  • Arthralgia
  • Asthenia
  • Arthropathy

• Ophthalmic:

  • Dry Eye Syndrome
  • Increased Lacrimation
  • Blurred Vision
  • Decreased Visual Acuity

• Respiratory:

  • Upper Respiratory Tract Infection
  • Dyspnea
  • Cough
  • Sinusitis
  • Pneumonia
  • Epistaxis
  • Oropharyngeal Pain
  • Bronchitis

• Miscellaneous:

  • Fever
  • Falling

Less Common Side Effects of Ibrutinib (Imbruvica):

• Cardiovascular:

  • Atrial Fibrillation
  • Atrial Flutter
  • Subdural Hematoma
  • Ventricular Tachycardia

• Central Nervous System:

  • Intracranial Hemorrhage

• Gastrointestinal:

  • Gastrointestinal Hemorrhage

• Genitourinary:

  • Hematuria

• Hematologic & Oncologic:

  • Skin Carcinoma
  • Anemia
  • Postprocedural Hemorrhage

• Infection:

  • Sepsis

• Renal:

  • Increased Serum Creatinine

Contraindications to Ibrutinib (Imbruvica):

Known hypersensitivity to ibrutinib and any component of the formulation.

Warnings and precautions

• Cardiovascular effects

  • Cardiac arrhythmias can cause grade 3 atrial fibrillation, atrial Flutter, and ventricular Tachyarrhythmias.
  • Other cardiovascular toxic effects include supraventricular arrhythmia and ventricular arrhythmia.
  • This is more common in patients with preexisting heart disease, hypertension, or arrhythmias. 
  • Consider the risk-benefit ratio, especially for recurring episodes that could require stopping treatment or decreasing the dose.

• CNS effects

  • Inform patients about dizziness, fatigue, weakness, impaired mental alertness, and other potential symptoms.

• Toxicity to the GI:

  • The treatment may cause diarrhea.

• Hematologic effects

  • Anemia, thrombocytopenia and neutropenia are all possible in Grades 3 and 4. When treatment began, lymphocytosis (>=50% rise from baseline) was common.
  • This usually resolves in 8 to 14 weeks.
  • Lympocytosis is a condition in which lymphocytes >400,000/MCL have caused intracranial bleeding, lethargy and headaches.
  • Some cases have also been linked to disease progression.

• Hemorrhage

  • Reports of minor hemorhage, such as bruising, to major hemorhage (>=grade 3, serious or any CNS event; eg intracranial hemorhage [including subdural hematoma], GI hemorhage, hematuria and postprocedural hemorhage] have been made.
  • Be on the lookout for bleeding symptoms.
  • Higher risk for those taking anticoagulant or antiplatelet medication.
  • If indicated, you may hold ibrutinib for up to 7 days prior and/or after surgery.
• Hypertension
  • Ibrutinib therapy has been shown to be effective in treating new-onset hypertension and worsening blood pressure control.
  • This is associated with an increased risk of major adverse cardiovascular events (MACE) in the future.

• Infections

  • There have been reports of serious infections (some fatal) caused by bacterial, viral and fungal infections.
  • Monitor for fever and other symptoms. Patients at high risk of opportunistic infection may be prescribed prophylaxis according to the standard.

• Progressive multifocal Encephalopathy

  • Reports of progressive multifocal Encephalopathy have been made.
  • Pay attention to neurological symptoms.

• Second primary malignancy:

  • Two primary malignancies have been reported, including cutaneous malignancy, and other types of carcinomas.
  • Pay attention to any signs of secondary malignancy.

• Tumor lysis syndrome

  • Rare cases of Tumor Lysis Syndrome have been reported. High-risk patients require close observation. Monitor your uric acid levels.

• Hepatic impairment

  • Avoid use in cases of severe hepatic dysfunction. Mild to moderate dysfunction may require a reduction of the dose. To minimize toxic effects, it is important to monitor the liver function closely.

• Renal impairment

  • It can cause renal failure and is considered nephrotoxic.
  • Patients with kidney dysfunction should be cautious.

Ibrutinib: Drug Interaction

Monitoring parameters:

• complete blood picture
• renal and hepatic function
• uric acid
• Rule out pregnancy
• monitorblood pressure
• monitor sign/symptoms of bleeding, infections, progressive multifocal encephalopathy, tumor lysis syndrome, second primary malignancies
• ECG for cardiac arrhythmias
• Compliance

How to administer Ibrutinib (Imbruvica)?

• Take per oral with plenty of water with or without food. Swallow whole do not chew or cut. 
• It may be given via nasogastric tube or PEG (percutaneous entero-gastrostomy tube) by breaking open the capsule.
• When given combined with rituximab or obinutuzumab, take ibrutinib first.

Mechanism of action of Ibrutinib (Imbruvica):

• Ibrutinib irreversibly inhibits Bruton’s tyrosine kinase. B cell activation plays a vital role in malignant B-cell proliferation.
• Inhibition of BTK stops B-cell activation, which decreases B-cell malignant cell division and survival.

Bioavailability:

• empty stomach: 2.9%. 2 to 4 times that when taken with food.

Protein binding:

• ~97%

Metabolism:

• Hepatic via CYP3A (major) and CYP2D6 (minor) to active metabolite PCI-45227

Half-life elimination: 4 to 6 hours Time to peak:

• 1 to 2 hours (4 hours under fed conditions.

Excretion:

• Feces (80%; 1% as unchanged drug);
• urine (<10%, as metabolites)

International Brand Names of Ibrutinib:

• Imbruvica

Ibrutinib Brand Names in Pakistan:

No Brands Available in Pakistan.