Ibrutinib (Imbruvia) belongs to a class of drugs called Bruton's tyrosine kinase (BTK) inhibitors, which work by blocking the activity of the BTK enzyme, which is involved in the growth and survival of cancer cells. By inhibiting this enzyme, Ibrutinib can help slow down or stop the growth of cancer cells. Imbruvica is used to treat various blood-related cancers.

Ibrutinib (Imbruvica) Uses:

• Ibrutinib is considered one of the second line treatments of refractory chronic GVH  (Graft-versus-host)disease):

• It is also indicated for the treatment of CLL and Small lymphocytic lymphoma (SLL) with 17p deletion.

• It is used as a second-line treatment of mantle cell lymphoma in patients who have failed previous treatments.

• In addition, Ibrutinib is indicated in the treatment of Waldenstrom macroglobulinemia and as a 2nd line treatment in patients with relapsed or refractory marginal zone lymphoma.

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Ibrutinib (Imbruvica) Dose in Adults:

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

• The recommended dose of Ibrutinib for treating Chronic graft-versus-host disease (refractory) is 420 mg once a day taken orally.
• Patient should continue taking it until your cGVHD gets worse, your cancer comes back, or you experience unacceptable side effects. Your doctor will assess your condition to determine when it's safe to stop taking the medicine.

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

• For the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma, the recommended dose of Ibrutinib is 420 mg taken orally once a day.
• Patients can take it as a single therapy or with bendamustine and rituximab, or with obinutuzumab.
• Patients should continue taking the medicine until their disease gets worse or they experience intolerable side effects. Your doctor will monitor your condition to decide when it's safe to stop the treatment.

Ibrutinib (Imbruvica) Dose in the treatment of CLL and SLL (off-label combination):

• In the treatment of CLL or SLL, there is an off-label combination treatment for adults under 70 years of age who have not been previously treated and who do not have the IGHV-unmutated and 17p deletion genetic mutations.
• The recommended dose of Ibrutinib for this combination therapy is 420 mg taken orally once a day in combination with rituximab (starting from the second cycle up to the seventh cycle).
• Patients should continue taking Ibrutinib until their disease gets worse or they experience intolerable side effects.

Ibrutinib (Imbruvica) Dose in the treatment of CLL and SLL with 17p deletion:

• For the treatment of Chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, the recommended dose of Ibrutinib is 420 mg taken orally once a day.
• Patients should continue taking the medicine until their disease gets worse or they experience intolerable side effects. 

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

• For the treatment of previously treated Mantle cell lymphoma, the recommended dose of Ibrutinib is 560 mg taken orally once a day.
• Patients should continue taking the medicine until their disease gets worse or they experience intolerable side effects. Your doctor will monitor your condition and decide when it's safe to stop the treatment.

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

• There is an off-label combination treatment of Ibrutinib with Venetoclax. For this combination therapy, the recommended dose of Ibrutinib is 560 mg taken orally once a day, in combination with venetoclax.
• Patients should continue taking the medication until their disease gets worse or they experience intolerable side effects.
• The treatment starts with taking Ibrutinib, and venetoclax is initiated with ramp-up dosing four weeks after starting Ibrutinib.
• Your doctor will monitor your condition and decide when it's safe to stop the treatment.
• The dosing regimen is based on a study conducted by Tam in 2018.

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

• For the treatment of Marginal zone lymphoma that has relapsed or is refractory, the recommended dose of Ibrutinib is 560 mg taken orally once a day.
• Patients should keep taking the medicine until their disease gets worse or they experience intolerable side effects. Your doctor will monitor your condition and decide when it's safe to stop the treatment.
• The recommended dosing regimen is based on a study conducted by Noy in 2017.

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

• For the treatment of Waldenström macroglobulinemia, the recommended dose of Ibrutinib is 420 mg taken orally once a day.
• Patients can take it either as a single therapy or in combination with rituximab.
• Continue taking the medicine until your disease worsens, or you experience intolerable side effects.
• Missed doses:
  • If the dose is missed, take it as soon as you remember it on the same day and return to the regular dosing schedule the next day. Don't take extra doses to compensate for the missed one.

Ibrutinib (Imbruvica) Dosage adjustment for concomitant therapy:

Note:  Restart at the previous dose after discontinuing the CYP3A inhibitor

For B-cell malignancies:

• Moderate CYP3A inhibitors:
  • Take 280 mg of ibrutinib once a day and monitor closely for any side effects.
• Voriconazole (200 mg twice a day) and posaconazole suspension (100-200 mg once or twice a day):
  • Take 140 mg of ibrutinib once a day and monitor closely for any side effects.
• Stronger posaconazole suspension (200 mg three times a day or 400 mg twice a day), Posaconazole 300 mg IV once daily, or posaconazole delayed-release tablets 300 mg once daily:
  • Take 70 mg of ibrutinib once a day and monitor closely for any side effects.
• Other strong CYP3A inhibitors:
  • Avoid using it concurrently with ibrutinib. If necessary, interrupt ibrutinib treatment if using these inhibitors short-term (for example, anti-infectives for up to 7 days).

For chronic graft-versus-host disease:

• Moderate CYP3A inhibitors:
  • Take 420 mg of ibrutinib once a day and monitor closely for any side effects.
• Voriconazole (200 mg twice a day) and posaconazole suspension (100-200 mg once or twice a day):
  • Take 280 mg of ibrutinib once a day and monitor closely for any side effects.
• Stronger posaconazole suspension (200 mg three times a day or 400 mg twice a day), Posaconazole 300 mg IV once daily, or posaconazole delayed-release tablets 300 mg once daily:
  • Take 140 mg of ibrutinib once a day and monitor closely for any side effects.
• Other strong CYP3A inhibitors:
  • Avoid using it concurrently with ibrutinib. If necessary, interrupt ibrutinib treatment if using these inhibitors short-term (for example, anti-infectives for up to 7 days). After discontinuing the CYP3A inhibitor, resume the previous dose of ibrutinib.

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Use in Children:

Not indicated.

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Ibrutinib Pregnancy Category: X

• Ibrutinib has the potential to cause harm to a developing fetus if taken during pregnancy, based on its mechanism of action and findings from animal studies.
• Therefore, it is important to confirm the pregnancy status of female patients before starting ibrutinib treatment.
• Women of childbearing potential are advised to use effective contraception during therapy and for one month after stopping the treatment.
• Men are also advised to use contraception during treatment and for one month after the last dose, to avoid fathering a child.

Ibrutinib can be used during breastfeeding

• It is currently unknown whether ibrutinib is excreted in breast milk.
• Therefore, it is important for nursing mothers to consider the potential risks of exposure to their infant when deciding whether to breastfeed during treatment with ibrutinib.
• The decision to breastfeed should be made in consultation with a healthcare provider, taking into account the benefits of treatment to the mother and the potential risks to the infant.

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Ibrutinib (Imbruvica) Dose in Kidney Disease:

For patients with a kidney function of Creatinine Clearance less than or equal to 25 mL/minute:

• No dose adjustments are needed for ibrutinib.
• This is because the drug is eliminated from the body mostly through the liver, not the kidneys, and its levels in the blood are not affected by mild to moderate kidney impairment.

For patients with severe kidney impairment Creatinine Clearance less than 25 mL/minute or end-stage renal disease requiring dialysis:

• There is no information available on whether dose adjustments are necessary.

Ibrutinib (Imbruvica) Dose in Liver Disease:

The recommended dosing of ibrutinib in patients with hepatic impairment (Child-Pugh class A, B, or C) is as follows:

• Mild impairment (Child-Pugh class A): Reduce the dose to 140 mg once daily. Close monitoring for toxicities is necessary, and treatment interruption may be required.
• Moderate impairment (Child-Pugh class B): Reduce the dose to 70 mg once daily. Close monitoring for toxicities is necessary, and treatment interruption may be required.
• Severe impairment (Child-Pugh class C): Ibrutinib use is not recommended in patients with severe hepatic impairment.

It is important to note that the safety and efficacy of ibrutinib in patients with hepatic impairment have not been established in clinical studies, and caution should be exercised when administering the drug in this population.

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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

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Contraindications to Ibrutinib (Imbruvica):

Ibrutinib is approved by the FDA in the United States for use in multiple indications, and there are no contraindications listed in the current US labeling.

However, patients with known hypersensitivity to ibrutinib and any component of the formulation should avoid it.

Warnings and precautions

• Cardiovascular effects

Ibrutinib has been associated with serious and potentially fatal cardiac arrhythmias, including atrial fibrillation, atrial flutter, and ventricular tachyarrhythmias.

The drug is also linked with a higher incidence of cardiovascular adverse events such as ventricular arrhythmia, supraventricular arrhythmia, heart failure, hypertension, conduction disorders, and CNS hemorrhagic or ischemic events.

These events are more likely to occur in patients with cardiac risk factors, hypertension, acute infections, or a history of arrhythmias.

Patients should be monitored periodically for clinical symptoms of cardiac arrhythmias, such as palpitations, light-headedness, syncope, and chest pain.

An ECG should be performed if symptoms or new-onset dyspneal develop.

Arrhythmias should be managed appropriately, and for persistent events, the risks and benefits of continuing ibrutinib treatment and dose modification should be evaluated.

• CNS effects

Ibrutinib may cause CNS (central nervous system) effects, such as dizziness, fatigue, and weakness.

These effects can impair physical or mental abilities, so patients should be cautioned about performing tasks that require mental alertness, such as operating machinery or driving.

• Toxicity to the GI:

Diarrhea is a common side effect of ibrutinib.

Patients should be advised to maintain adequate hydration to prevent dehydration.

• Hematologic effects

Anaemia, 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.

Lymphocytosis 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.

• Bleeding:

Ibrutinib may cause major hemorrhage, including intracranial hemorrhage, gastrointestinal bleeding, hematuria, and postprocedural bleeding.

Bleeding events of any grade have been reported in almost 40% of patients.

Monitor for signs and symptoms of bleeding and consider the risks and benefits of concurrent antiplatelet or anticoagulant therapy.

Prior to and after surgery, evaluate the risks and benefits of withholding ibrutinib for 3 to 7 days based on the procedure type and bleeding risk.

• Hypertension

Ibrutinib therapy may cause hypertension (high blood pressure), which usually occurs about 5 months after starting treatment.

Monitor blood pressure regularly and inform the healthcare provider if there are any new or uncontrolled hypertension symptoms.

In some cases, the use of antihypertensive medications may be necessary.

It is important to note that new or worsening hypertension may increase the risk of major adverse cardiovascular events, and the initiation of antihypertensive therapy may lower this risk.

• Infections

Patients treated with ibrutinib are at risk of serious infections, including bacterial, viral, and fungal infections, some of which can be fatal.

Pneumocystis jirovecii pneumonia, a type of fungal infection, has also been reported. Patients should be monitored for signs of infection such as fever and managed appropriately.

Patients at an increased risk of opportunistic infections should be considered for prophylaxis according to standard of care.

• Progressive multifocal Encephalopathy

Progressive multifocal encephalopathy (PML) is a rare but serious brain infection that has been observed in patients receiving ibrutinib.

Symptoms may include progressive weakness on one side of the body, clumsiness of limbs, vision disturbances, and confusion.

Patients should be monitored for signs and symptoms of PML and managed appropriately if suspected.

• Second primary malignancy:

Patients receiving ibrutinib have developed second primary malignancies, including skin cancers and other carcinomas.

Nonmelanoma skin cancer is the most frequent second primary malignancy.

During treatment, monitor for signs and symptoms of secondary malignancy.

• Tumor lysis syndrome

Rare cases of tumor lysis syndrome have been reported with the use of ibrutinib.

Patients with high tumor burden are at increased risk and may experience elevated levels of uric acid, including severe (grade 4) elevations.

It is important to assess the risk of tumor lysis syndrome in each patient and monitor closely, managing appropriately as needed.

• Hepatic impairment

Ibrutinib is processed by the liver, and patients with liver dysfunction may have higher exposure to the drug.

If a patient has a mild or moderate liver impairment (Child-Pugh class A or B), the dosage of ibrutinib may need to be adjusted.

However, the use of ibrutinib is not recommended for patients with severe liver impairment (Child-Pugh class C).

• Renal impairment

Kidney problems, including kidney failure, have been reported with the use of Ibrutinib.

The patient's kidney function should be regularly monitored and they should stay hydrated.

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Ibrutinib: Drug Interaction

Risk Category C Drugs: Monitor for side effects

Ibrutinib may increase the side effects of these drugs:

Antiplatelets and drugs with antiplatelet properties (NSAIDs, SSRIs, and Clopidogrel), Flaxseed Oil, Omega-3 Fatty Acids, Vitamin E (Systemic), and anticoagulants (Dabigatran Etexilate)

Ibrutinib levels are decreased with	CYP3A4 Inducers (Moderate) Bosentan Defarasirox Erdafitinib Ivosidenib Sarilumab Siltuximab Tocilizumab
Ibrutinib levels are increased with	Clofazimine Fosaprepitant Larotrectinib Palbociclib Simeprevir
Bone marrow suppression and immunosuppression may occur more frequently with concomitant	Chloramphenicol Clozapine Denosumab Mesalamine Ocrelizumab Promazine Siponimod Trastuzumab
Ibrutinib may reduce the diagnostic efficacy of these tests	Coccidioides immitis Skin Test
Ibrutinib may decrease the therapeutic effects of these drugs	Pidotimod Tertomotide Smallpox and Monkeypox Vaccine (Live)
Ibrutinib may increase the levels of these drugs	Digoxin Methotrexate

Risk Category D Drugs: Avoid combining but if not possible, then monitor closely for drug interactions

Ibrutinib may increase the immunosuppressive effects of these drugs	Baricitinib	Avoid combining with potent immunosuppressants. If one can not avoid combining these, very strict monitoring is necessary
Ibrutinib levels are decreased with	Dabrafenib Echinacea Lorlatinib	Seek alternative medicines if possible. Monitor closely if not
Ibrutinib levels are increased with	CYP3A4 Inhibitors (Moderate) Posaconazole Stiripentol Voriconazole	Decrease Ibrutinib dose and monitor closely
Bone marrow suppression and immunosuppression may occur more frequently with concomitant	Baricitinib Deferiprone Fingolimod Leflunomide Nivolumab Roflumilast Tofacitinib	Avoid concomitant use if possible; Monitor absolute neutrophil count closely if combined usage is necessary
Ibrutinib may decrease the therapeutic effects of these drugs	Sipuleucel-T Inactivated vaccines	Consider reducing the dose of Ibrutinib or discontinuing it before starting Sipuleucel-T therapy
Ibrutinib may reduce the therapeutic effects of inactivated vaccines	Inactivated vacccines	Administer age-appropriate vaccinations prior to immunosuppressant therapy; Consider revaccination after therapy

Risk Category X: Avoid Combining these drugs with Ibrutinib:

Ibrutinib may increase the side effects of these drugs:	Natalizumab
Ibrutinib levels are decreased with	Strong CYP3A4 Inducers St John's Wort Live vaccines
Ibrutinib levels are increased with	Strong CYP3A4 Inhibitors Bitter orange Conivaptan Fusidic Acid (Systemic) Grapefruit Juice Idelalisib
Bone marrow suppression and immunosuppression may occur more frequently with concomitant	Cladribine Dipyrone Pimecrolimus Tacrolimus (Topical) Upadacitinib
Ibrutinib may decrease the therapeutic effects of these drugs	Intravesical BCG Live Vaccines (Live vaccines except for monkey pox and smallpox vaccines can be given after 3 months of the last dose.

Monitoring parameters:

Monitoring Recommendations:

• Blood counts (monthly or as necessary)
• Renal and hepatic function (periodically)
• Uric acid levels (as necessary)
• Pregnancy status (prior to treatment initiation in females of reproductive potential)
• Blood pressure (monitor for new onset hypertension or hypertension not adequately controlled)
• Bleeding (monitor for signs and symptoms)
• Infections (monitor and evaluate for fever and other signs/symptoms)
• Progressive multifocal encephalopathy (evaluate for symptoms)
• Tumor lysis syndrome (assess risk and monitor closely)
• Second primary malignancies (evaluate for signs/symptoms)
• Cardiac arrhythmias (monitor for signs/symptoms and perform ECG prior to initiation in patients with cardiac risk factors or history of cardiac arrhythmias, and during therapy if clinically indicated)
• Adherence (monitor)

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How to administer Ibrutinib (Imbruvica)?

• Administer orally with a glass of water at approximately the same time every day.
• Swallow capsules and tablets whole; do not open, break, or chew the capsules; do not cut, crush, or chew the tablets.
• Maintain adequate hydration during treatment.
• When administering in combination with rituximab or obinutuzumab, consider giving ibrutinib first.
• May be administered without regard to food.
• For patients who cannot swallow capsules or tablets, the contents can be opened and flushed down an NG or PEG tube with water.

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Mechanism of action of Ibrutinib (Imbruvica):

• Ibrutinib works by irreversibly inhibiting Bruton's tyrosine kinase (BTK), which is a crucial component of the B-cell receptor (BCR) signaling pathway.
• Inhibition of BTK leads to disruption of the BCR signaling cascade, ultimately resulting in decreased survival and proliferation of malignant B-cells.
• Additionally, ibrutinib has been shown to inhibit other kinases, such as interleukin-2-inducible T-cell kinase (ITK), which is important for T-cell signaling and activation.

Distribution:

• Ibrutinib has a large distribution volume of approximately 10,000 liters, according to a study (Marostica 2015).

Bioavailability:

• The absolute bioavailability of ibrutinib when taken in a fasted state was found to be 2.9%, but this doubled when it was taken with a meal.
• Taking ibrutinib with food resulted in a 2- to 4-fold increase in maximum concentration (Cmax) and a 2-fold increase in area under the curve (AUC) compared to taking it in a fasted state.
• The drug exposure was approximately 60% lower when taken in a fasted state than when taken 30 minutes before or after a meal or 2 hours after a high-fat meal (de Jong 2015).

Protein binding:

• Ibrutinib is highly bound to plasma proteins, with approximately 97% bound, according to available data.

Metabolism:

• Ibrutinib is primarily metabolized in the liver through the CYP3A enzyme system, with a minor contribution from CYP2D6.
• The active metabolite of ibrutinib is called PCI-45227.

Half-life elimination:

• The half-life of ibrutinib elimination is relatively short, ranging from 4 to 6 hours.

Time to peak:

• It takes approximately 1 to 2 hours for ibrutinib to reach its peak concentration in the blood, but this is delayed to 4 hours when it is taken with food (de Jong 2015).

Excretion:

• The majority of ibrutinib and its metabolites are eliminated through the feces (80%), with less than 10% eliminated through the urine in the form of metabolites.

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International Brand Names of Ibrutinib:

• Imbruvica

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Ibrutinib Brand Names in Pakistan:

No Brands are Available in Pakistan.