Ibrutinib

Registered South African indications:

• Mantle cell lymphoma (MCL)
• Relapsed or previously untreated chronic lymphocytic leukaemia (CLL)
• Waldenström’s macroglobulinaemia (WM)

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Coadministration with strong CYP3A inhibitors
• Coadministration with St. John's wort

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with St. John's wort

Cautions

South African manufacturer recommendations

• Women of childbearing potential and for 3 months after ending treatment
• Males of reproductive potential and for 3 months after ending treatment
• Severe renal impairment/ on dialysis (CrCl<30ml/min)
• Hepatic impairment (Child-Pugh class A, B and C)
• Risk of bleeding related events
  - 3-7 days pre-and post-surgey
• Congenital bleeding diathesis
• Increased risk for opportunistic infections
• Cardiac risk factors
• Hypertension
• Acute infections
• History of atrial fibrillation
• High tumour burden
• Pre-existing non-melanoma skin cancer
• Spinal anaesthesia and epidural anaesthesia
• Coadministration with other anticoagulants or medications that inhibit platelet function
• Coadministration with fish oil and vitamin E
• Coadministration with vitamin K antagonists
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Women of childbearing potential and for 3 months after ending treatment
• Severe renal impairment/ on dialysis (CrCl<30ml/min)
• Hepatic impairment (Child-Pugh class A, B and C)
• Hepatitis
• Risk of bleeding related events
  - 3-7 days pre-and post-surgey
• Congenital bleeding diathesis
• Increased risk for opportunistic infections
• Cardiac risk factors
• Hypertension
• Acute infections
• History of atrial fibrillation
• Pre-existing neurological, cognitive or behavioural signs or symptoms
• High tumour burden
• Pre-existing non-melanoma skin cancer
• Prior or current coadministration with immunosuppressive therapy
• Coadministration with other anticoagulants or medications that inhibit platelet function
• Coadministration with fish oil and vitamin E
• Coadministration with vitamin K antagonists
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Used for the treatment of

• Mantle cell lymphoma (MCL)
  - Having received at least one prior therapy
• Relapsed chronic lymphocytic leukaemia (CLL)
• Previously untreated CLL (Additional agent(s) may be required)
  - In combination with bendamustine and rituximab
• Waldenström’s macroglobulinaemia (WM)

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Consult specialist for dosages and regimens

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International manufacturer recommendations

Used for the treatment of

• Mantle cell lymphoma (MCL)
  - As a single agent for the treatment of relapsed or refractory MCL
• Chronic lymphocytic leukaemia (CLL)
  - As a single agent or in combination with rituximab or obinutuzumab in those with previously untreated CLL
  - As a single agent or in combination with bendamustine and rituximab in those with CLL who have received at least one prior therapy
• Waldenström's macroglobulinaemia (WM) 
  - As a single agent in those who have received at least one prior therapy
  - First line treatment in those where it is unsuitable for chemo-immunotherapy
  - In combination with rituximab for the treatment of WM

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When administering ibrutinib in combination with anti-CD20 therapy for CLL and WM, it is recommended to administer ibrutinib prior to anti-CD20 therapy when given on the same day

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Ibrutinib should not be used during pregnancy
• Based on findings in animals, ibrutinib may cause foetal harm when administered to pregnant women
• Women of childbearing potential must use highly effective contraceptive measures while taking ibrutinib. Those using hormonal methods of birth control must add a barrier method
• Women should avoid becoming pregnant while taking ibrutinib and for up to 3 months after ending treatment. If this medicine is used during pregnancy or if the patient becomes pregnant while taking ibrutinib, the patient should be apprised of the potential hazard to a foetus. The time period following treatment with ibrutinib where it is safe to become pregnant is unknown. Men should be advised not to father a child or donate sperm while receiving ibrutinib, and for 3 months following completion of treatment

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• Ibrutinib should not be used during pregnancy
• There are no data from the use of ibrutinib in pregnant women. Studies in animals have shown reproductive toxicity
• Based on findings in animals, ibrutinib may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking ibrutinib and for up to 3 months after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking ibrutinib and for three months after stopping treatment
• In pregnant rats, ibrutinib at a dose of 80mg/kg/day was associated with increased post-implantation loss and increased visceral (heart and major vessels) malformations and skeletal variations with an exposure margin 14 times the AUC found in patients at a daily dose of 560mg. At a dose of ≥40mg/kg/day, ibrutinib was associated with decreased foetal weights (AUC ratio of ≥5.6 as compared to daily dose of 560mg in patients). Consequently, the foetal NOAEL (no observed adverse effect level) was 10mg/kg/day (approximately 1.3 times the AUC of ibrutinib at a dose of 560mg daily)
• In pregnant rabbits, ibrutinib at a dose of 15mg/kg/day or greater was associated with skeletal malformations (fused sternebrae) and ibrutinib at a dose of 45mg/kg/day was associated with increased post-implantation loss. Ibrutinib caused malformations in rabbits at a dose of 15mg/kg/day (approximately 2.0 times the exposure (AUC) in patients with MCL administered ibrutinib 560mg daily and 2.8 times the exposure in patients with CLL or WM receiving ibrutinib dose 420mg per day). Consequently, the foetal NOAEL was 5mg/kg/day (approximately 0.7 times the AUC of ibrutinib at a dose of 560mg daily)

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Because of the potential for serious adverse reactions in breastfeeding infants from ibrutinib, breastfeeding should be discontinued during ibrutinib treatment

International manufacturer recommendations

• Caution; not recommended 
• It is not known whether ibrutinib or its metabolites are excreted in human milk. A risk to breastfed children cannot be excluded. Breastfeeding should be discontinued during treatment with ibrutinib

Fertility

South African manufacturer recommendations

• No information available

International manufacturer recommendations

• No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100mg/kg/day (Human Equivalent Dose [HED] 16mg/kg/day)
• No human data on the effects of ibrutinib on fertility are available

Renal Impairment

South African manufacturer recommendations

• CrCl≥30ml/min: No dose adjustment recommended 
  Hydration should be maintained and serum creatinine levels monitored periodically
• CrCl<30ml/min/On dialysis: Caution; no information available 

International manufacturer recommendations

• CrCl≥30ml/min: No dose adjustment recommended 
  Hydration should be maintained and serum creatinine levels monitored periodically
• CrCl<30ml/min/On dialysis: Caution; no information available 
  Administer ibrutinib to patients with severe renal impairment (CrCl<30ml/min) only if the benefit outweighs the risk and monitor patients closely for signs of toxicity

Hepatic Impairment

• Mild to moderate (Child-Pugh class A and B): Caution; dose adjustment recommended 
  Monitor patients for signs of ibrutinib toxicity and follow dose modification guidance as needed
  Consult specialist for dosages and regimens
• Severe (Child-Pugh class C): Caution; not recommended 

Elderly

• No dose adjustment recommended 
  Population pharmacokinetics indicated that age does not significantly influence ibrutinib clearance from the circulation

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Peripheral neuropathy
• Cerebrovascular accident
• Transient ischaemic attack
• Ischaemic stroke
• Subdural haematoma
• Progressive multifocal leukoencephalopathy (PML)
• Intracranial bleeding

Cardiovascular Disorders

• Cardiac arrythmia
• Cardiac failure
• Atrial fibrillation
• Atrial flutter
• Ventricular tachyarrhythmia
• Haemorrhage
• Bruising
• Hypertension
• Epistaxis
• Petechiae
• Haematuria

Respiratory Disorders

• Pneumonia
• Upper respiratory tract infection
• Sinusitis
• Pneumocystis infections
  - Pneumocystis jiroveci infections
• Aspergillus infections
• Cryptococcal infections
  - Cryptococcosis
• Interstitial lung disease

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Stomatitis
• Constipation
• Gastrointestinal bleeding

Hepatobiliary Disorders

• Hepatitis B reactivation
• Hepatic failure

Genitourinary Disorders

• Urinary tract infection
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Hyperuricaemia
• Tumour lysis syndrome

Musculoskeletal Disorders

• Arthralgia
• Muscle spasms
• Musculoskeletal pain

Skin and Subcutaneous Tissue Disorders

• Skin infection
• Rash
• Urticaria
• Erythema
• Onychoclasis
• Panniculitis
• Neutrophilic dermatoses
• Stevens-Johnson syndrome
• Non-melanoma skin cancer
• Contusion

Immune, Blood and Lymphatic System Disorders

• Sepsis
• Infections
  - Neutropenic sepsis
  - Bacterial
  - Viral
• Invasive fungal infection
• Neutropenia
  - Febrile neutropenia
• Thrombocytopenia
• Lymphocytosis
• Leukocytosis
• Leukostasis syndrome
• Fever
• Oedema
  - Angioedema
  - Peripheral oedema
• Splenic rupture
• Haemophagocytic lymphohistiocytosis (HLH)
  - Fever
  - Hepatosplenomegaly
  - Hypertriglyceridaemia
  - High serum ferritin
  - Cytopenias

Sensory Disorders

• Blurred vision
• Eye haemorrhage

Others

• Basal cell carcinoma
• Squamous cell carcinoma

• Moderate and strong CYP3A4 inhibitors
• Ketoconazole
• Clarithromycin
• Voriconazole
• Posaconazole
• Indinavir
• Nefinavir
• Ritonavir
• Saquinavir
• Telithromycin
• Itraconazole
• Nefazodone
• Cobicistat
• Erythromycin
• Fluconazole
• Amprenavir
• Aprepitant
• Atazanavir
• Ciprofloxacin
• Crizotinib
• Diltiazem
• Fosamprenavir
• Imatinib
• Verapamil
• Amiodarone
• Dronedarone
• Mild CYP3A4 inhibitors
• Azithromycin
• Fluvoxamine
• Moderate or strong CYP3A4 inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• P-glycoprotein (P-gp)  substrates
• Breast cancer resistant protein (BCRP) substrates
• Rosuvastatin
• Digoxin
• Methotrexate
• Vitamin K antagonists
• Warfarin

Others

• St John's wort
• Grapefruit
• Grapefruit juice
• Seville oranges

• Full blood count
• Renal function
• Hepatic function
• Uric acid levels
• Blood pressure

Specific cases may require

• Pregnancy test
• Cardiac function
  - Electrocardiogram (ECG)
• Hepatitis B virus screening
  - Hepatitis B surface antigen (HBsAg)
  - Hepatitis B core antibody (anti-HBc)
  -  Total Ig or IgG
  - Antibody to hepatitis B surface antigen (anti-HBs)

Additional observations

• Signs/ symptoms of
  - Bleeding
  - Infections
  - Progressive multifocal encephalopathy
  - Tumor lysis syndrome 
  - Second primary malignancies
  - Cardiac arrhythmias
  - Heart failure
  - Appearance of non-melanoma skin cancer 
  - Interstitial lung disease 
  - Worsening neurological, cognitive or behavioural symptoms
• Clinical examination and ultrasound of spleen
• Neurological assessment
  - Magnetic resonance imaging (MRI)
• Monitor adherence

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Lymphocytosis

• Upon initiation of treatment, a reversible increase in lymphocyte counts (i.e., ≥50% increase from baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, has been observed in most patients (75%) with chronic lymphocytic leukaemia (CLL) treated with ibrutinib
• This effect has also been observed in some patients (35%) with mantle cell lymphoma (MCL) treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings
• In both disease types, lymphocytosis typically occurs during the first few weeks of ibrutinib therapy (median time 1,1 weeks) and typically resolves within a median of 8,0 weeks in patients with MCL and 18,7 weeks in patients with CLL. A large increase in the number of circulating lymphocytes (e.g., >400 000/µL) has been observed in some patients
• Lymphocytosis was not observed in patients with Waldenström’s macroglobulinaemia (WM) treated with ibrutinib

Splenic rupture

• Cases of splenic rupture have been reported following discontinuation of ibrutinib treatment 
• Disease status and spleen size should be carefully monitored (e.g. clinical examination, ultrasound) when ibrutinib treatment is interrupted or ceased
• Patients who develop left upper abdominal or shoulder tip pain should be evaluated and a diagnosis of splenic rupture should be considered

Infections

• Infections (including sepsis, neutropenic sepsis, bacterial, viral, or fungal infections) were observed in patients treated with ibrutinib
• Some of these infections have been associated with hospitalisation and death
• Most patients with fatal infections also had neutropenia
• Patients should be monitored for fever, abnormal hepatic function tests, neutropenia and infections and appropriate anti-infective therapy should be instituted as indicated
• Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections

Progressive multifocal leukoencephalopathy (PML)

• Cases of PML, including fatal ones have been reported following the use of ibrutinib within the context of a prior or concomitant immunosuppressive therapy
• Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms
• If PML is suspected then appropriate diagnostic evaluations should be undertaken and treatment suspended until PML is excluded
• If any doubt exists, referral to a neurologist and appropriate diagnostic measures for PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments should be considered

Interstitial Lung Disease (ILD)

• Cases of ILD have been reported in patients treated with ibrutinib
• Monitor patients for pulmonary symptoms indicative of ILD
• If symptoms develop, interrupt ibrutinib and manage ILD appropriately
• If symptoms persist, consider the risks and benefits of ibrutinib treatment and follow the dose modification guidelines

Cardiac arrhythmia and cardiac failure

• Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia and cardiac failure have been reported in patients treated with ibrutinib
• Cases of atrial fibrillation and atrial flutter have been reported particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation
• Periodically monitor all patients clinically for cardiac manifestations, including cardiac arrhythmia and cardiac failure
• Patients who develop arrhythmic symptoms or new onset of dyspnoea, dizziness or fainting should be evaluated clinically and if indicated have an electrocardiogram (ECG) performed
• In patients who develop signs and/or symptoms of ventricular tachyarrhythmia, ibrutinib should be temporarily discontinued and a thorough clinical benefit/risk assessment should be performed before possibly restarting therapy
• In patients with pre-existing atrial fibrillation requiring anticoagulant therapy, alternative treatment options to ibrutinib should be considered
• In patients who develop atrial fibrillation on therapy with ibrutinib, a thorough assessment of the risk for thromboembolic disease should be undertaken
• In patients at high risk and where alternatives to ibrutinib are non-suitable, tightly controlled treatment with anticoagulants should be considered
• In some of these cases, cardiac failure resolved or improved after ibrutinib withdrawal or dose reduction

Ibrutinib is a potent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK, a member of the Tec kinase family, is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and chronic lymphocytic leukaemia (CLL). BTK's pivotal role in signalling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

Capsule 140mg

• Imbruvica 140mg (Janssen Pharmaceuticals) originator