Bortezomib

Parenteral
Multiple myeloma
Adult: Previously untreated patient not eligible for haematopoietic stem cell transplant: W/ melphalan, prednisone: Initial: 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, 32 of a 42-day cycle for 4 cycles then 1.3 mg/m² on days 1, 8, 22, 29 for 5 cycles. Previously untreated patient eligible for haematopoietic stem cell transplant: W/ dexamethasone: 1.3 mg/m² on days 1, 4, 8, 11 of a 21-day cycle for 4 cycles. W/ dexamethasone, thalidomide: 1.3 mg/m² on days 1, 4, 8, 11 in a 28-day cycle for 4 cycles. Patient w/ progressive case who have received at least 1 prior therapy: Monotherapy: 1.3 mg/m² on days 1, 4, 8, 11 of a 21-day cycle. W/ pegylated liposomal doxorubicin: 1.3 mg/m² on days 1, 4, 8, 11 of a 21-day cycle. W/ dexamethasone: 1.3 mg/m² on days 1, 4, 8, 11 of a 21-day cycle. Given via SC inj or as a 3-5 second bolus IV inj. Refer to country- or product-specific recommendations as treatment guidelines may vary.
Hepatic impairment: Moderate to severe: Reduce dose in the 1st cycle to 0.7 mg/m²; subsequent cycles may be increased up to 1 mg/m² or reduced to 0.5 mg/m² based on tolerability.
Reconstitution: IV: Reconstitute each vial containing 3.5 mg with 3.5 mL of NaCl 0.9% to a concentration of 1 mg/mL. SC: Reconstitute each vial containing 3.5 mg with 1.4 mL of NaCl 0.9% to a concentration of 2.5 mg/mL; if inj site reaction occurs, 1 mg/mL concentration may be used.

Parenteral
Mantle cell lymphoma
Adult: Previously untreated patients who are not eligible for haematopoietic stem cell transplantation, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone: Initial bolus doses of 1.3 mg/m² on days 1, 4, 8 and 11 of a 21-day cycle for 6 cycles; additional 2 cycles may be given in patients with a response 1st documented at cycle 6. Doses may be given via SC inj or (after dilution) as a 3-5 second bolus IV inj. Observe at least 72-hour interval between consecutive doses. Dose reduction or dosing interruption may be required according to individual safety or tolerability. Treatment guidelines may vary among countries or individual products. Refer to country- or product-specific recommendations.
Hepatic impairment: Moderate to severe: Reduce dose in the 1st cycle to 0.7 mg/m²; subsequent cycles may be increased up to 1 mg/m² or reduced to 0.5 mg/m² based on tolerability.
Reconstitution: IV: Reconstitute each vial containing 3.5 mg with 3.5 mL of NaCl 0.9% to a concentration of 1 mg/mL. SC: Reconstitute each vial containing 3.5 mg with 1.4 mL of NaCl 0.9% to a concentration of 2.5 mg/mL; if inj site reaction occurs, 1 mg/mL concentration may be used.

Acute diffuse infiltrative pulmonary disease and pericardial disease. Pregnancy and lactation.

Patient with hypotension, cardiac disease, peripheral neuropathy, diabetes, dehydration. Not intended for intrathecal administration. Moderate to severe hepatic impairment (bilirubin >1.5 times the upper limit of normal with any AST concentration). Patient Counselling This drug may cause, dizziness, fatigue, orthostatic/postural hypotension, syncope or blurred vision, if affected, do not drive or operate machinery. Monitoring Parameters Monitor CBC, blood glucose levels. Assess for signs/symptoms of peripheral neuropathy.

Significant: Neutropenia, thrombocytopenia, anaemia, peripheral neuropathy, seizures, hypotension (including orthostatic or postural hypotension), congestive heart failure, tumour lysis syndrome, decreased LVEF, diarrhoea or constipation, nausea, vomiting, herpes zoster virus reactivation, gastrointestinal or intracerebral haemorrhage, serum-sickness-type reaction, polyarthritis with rash, proliferative glomerulonephritis. Rarely, acute hepatic failure, posterior reversible leucoencephalopathy syndrome. Blood and lymphatic system disorders: Leucopenia, lymphopenia, febrile neutropenia. Cardiac disorders: Arrhythmia, cardiac fibrillation, myocardial ischaemia. Ear and labyrinth disorders: Dysacusis. Eye disorders: Abnormal vision, conjunctivitis, eye swelling. Gastrointestinal disorders: Dyspepsia, dysphagia, abdominal pain or distension, flatulence, gastritis, stomatitis, dysgeusia, oropharyngeal pain, oral ulceration. General disorders and administration site conditions: Asthenia, chills, lethargy, pain, pyrexia, fatigue, malaise, inj site reaction. Hepatobiliary disorders: Hepatitis, hyperbilirubinaemia. Immune system disorders: Hypersensitivity. Infections and infestations: Herpes simplex, bacterial or fungal infection. Investigations: Abnormal glucose and hepatic enzyme levels, decreased or increased weight. Metabolism and nutrition disorders: Decreased appetite, dehydration, diabetes mellitus, fluid retention, hypocalcaemia, hypokalaemia, hyponatraemia. Musculoskeletal and connective tissue disorders: Myalgia, musculoskeletal pain, muscle weakness or spasm, pain in extremities. Nervous system disorders: Headache, vertigo, paraesthesia, dysaesthesia, neuralgia, motor neuropathy, loss of consciousness. Psychiatric disorders: Anxiety, sleep or mood disorders. Renal and urinary disorders: Renal impairment, UTI. Respiratory, thoracic and mediastinal disorders: Dyspnoea, epistaxis, cough, hiccups, respiratory tract infection. Skin and subcutaneous tissue disorders: Rash, dry skin, dermatitis, erythema, hair disorder, pruritus. Vascular disorders: Hypertension.
Potentially Fatal: Acute respiratory distress syndrome, interstitial pneumonia, pneumonitis, lung infiltrates, thrombotic microangiopathy, progressive multifocal leucoencephalopathy.

Increased exposure with potent CYP3A4 inhibitors (e.g. ritonavir, ketoconazole). Decreased exposure with potent CYP3A4 inducers (e.g. carbamazepine, rifampicin). May alter the effects of oral hypoglycaemics.

Decreased exposure with St. John's wort.

Bortezomib reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, a large protein complex in cells that is responsible for maintaining homeostasis within cells. This results in the disruption of normal homeostatic mechanisms leading to cell cycle arrest, and apoptosis.
Distribution: Widely distributed to peripheral tissues. Volume of distribution: Approx 498-1,884 L/m². Plasma protein binding: Approx 83%.
Metabolism: Metabolised in the liver via oxidation mainly by CYP3A4, CYP2C19, and CYP1A2, with minor metabolism by CYP2D6 and CYP2C9; forms inactive metabolites via deboronation followed by hydroxylation.
Excretion: Elimination half-life: IV: Single dose: 9-15 hours; Multiple dosing: 1 mg/m²: 40-193 hours; 1.3 mg/m²: 76-108 hours.

Parenteral: Store between 20-25°C or between 2-8°C. Storage recommendations vary among countries or individual products. Refer to specific product guidelines. Protect from light. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.

Targeted Cancer Therapy

L01XG01 - bortezomib