Bortezomib

Bortezomib is a reversible inhibitor of the 26S proteasome, the large protein complex that breaks down ubiquitin-tagged proteins inside cells. The ubiquitin–proteasome pathway regulates the turnover of many proteins that control growth and survival, and cancer cells are more sensitive than normal cells to its disruption.

Mechanism of Action

• Proteasome inhibition: bortezomib specifically inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells, acting at the β5 subunit of its 20S core. It dissociates from the proteasome with a half-life of about 20 minutes, so the inhibition is reversible. It is highly selective: more than 1,500-fold more selective for the proteasome than for the next most preferred enzyme.
• Downstream effects: blocking targeted protein breakdown alters regulatory proteins that control cell-cycle progression and the activation of nuclear factor kappa B (NF-κB), a transcription factor needed for cell growth and survival, angiogenesis, cell–cell interactions and metastasis. The result is cell-cycle arrest and apoptosis. Preventing the breakdown of IκB, the inhibitor of NF-κB, and induction of the pro-apoptotic protein NOXA are thought to contribute.
• Myeloma cells: bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
• Selective effect on cancer cells: cancer cells are more sensitive than normal cells to the pro-apoptotic effects of proteasome inhibition. In the laboratory bortezomib is cytotoxic to many cancer cell types and delays tumour growth in animal models.
• Dose dependence: proteasome inhibition rises with dose; in one study more than 75% inhibition was seen in whole blood within an hour of a dose.

Pharmacokinetics

• Absorption: after an intravenous bolus of 1.0 and 1.3 mg/m² in patients with multiple myeloma, mean first-dose peak plasma concentrations were 57 and 112 ng/mL; with later doses they ranged from 67 to 106 ng/mL (1.0 mg/m²) and 89 to 120 ng/mL (1.3 mg/m²). After subcutaneous injection the peak concentration is lower than after an intravenous dose, but total exposure is equivalent.
• Distribution: mean volume of distribution 1,659 to 3,294 L after single or repeated intravenous doses, indicating wide distribution to peripheral tissues. About 83% is bound to plasma proteins, independent of concentration.
• Metabolism: mainly oxidative, by CYP3A4, CYP2C19 and CYP1A2 (CYP2D6 contributes about 7%). The main route is deboronation to two metabolites that are then hydroxylated; the deboronated metabolites do not inhibit the proteasome.
• Elimination: mean elimination half-life after repeated dosing 40 to 193 hours. Elimination is faster after the first dose; mean total body clearance was 102 and 112 L/h after the first dose of 1.0 and 1.3 mg/m², and 15 to 32 L/h and 18 to 32 L/h after later doses.
• Special populations: mild hepatic impairment does not change dose-normalised exposure, but in moderate or severe impairment the average exposure (AUC) rises by about 60%, which is why the starting dose is reduced. Mild to moderate renal impairment (creatinine clearance above 20 mL/min/1.73 m²) does not change the pharmacokinetics; dialysis may lower concentrations, so doses are given after dialysis.

Bortezomib is used in adults.

• Progressive multiple myeloma: as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone, in patients who have received at least 1 prior therapy and have already undergone, or are unsuitable for, haematopoietic stem cell transplantation.
• Previously untreated multiple myeloma, not eligible for transplantation: in combination with melphalan and prednisone, in patients not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
• Previously untreated multiple myeloma, eligible for transplantation: as induction treatment in combination with dexamethasone, or with dexamethasone and thalidomide, in patients eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
• Previously untreated mantle cell lymphoma: in combination with rituximab, cyclophosphamide, doxorubicin and prednisone, in patients unsuitable for haematopoietic stem cell transplantation.

• Hypersensitivity to bortezomib, to boron or to any of the excipients.
• Acute diffuse infiltrative pulmonary and pericardial disease.
• When bortezomib is given with other medicines, their contraindications also apply (see their SmPCs).

The reactions below come from an integrated set of 5,476 patients with multiple myeloma, of whom 3,996 received bortezomib 1.3 mg/m², together with post-marketing reports. The most commonly reported are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia. Serious reactions reported uncommonly include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome and acute diffuse infiltrative pulmonary disorders; autonomic neuropathy has been reported rarely.

Very common (≥1/10): thrombocytopenia, neutropenia, anaemia, decreased appetite, neuropathies (including peripheral sensory neuropathy), dysaesthesia, neuralgia, nausea and vomiting, diarrhoea, constipation, musculoskeletal pain, pyrexia, fatigue, asthenia.

Common (≥1/100 to <1/10): herpes zoster (including disseminated and ophthalmic), pneumonia, herpes simplex, fungal infection, leukopenia, lymphopenia, dehydration, low potassium, sodium or calcium, abnormal blood glucose, mood disorders, anxiety, sleep disorders, motor neuropathy, loss of consciousness (including syncope), dizziness, altered taste, lethargy, headache, eye swelling, vision disorders, conjunctivitis, vertigo, hypotension, orthostatic hypotension, hypertension, dyspnoea, nosebleed, respiratory tract infections, cough, gastrointestinal haemorrhage, dyspepsia, stomatitis, abdominal distension, abdominal pain, oral disorders, flatulence, abnormal liver enzymes, rash, pruritus, erythema, dry skin, muscle spasms, pain in extremity, muscular weakness, renal failure, oedema, chills, pain, malaise, weight loss.

Uncommon (≥1/1,000 to <1/100): sepsis (including septic shock), bronchopneumonia, bacterial and viral infections, herpetic meningoencephalitis, cellulitis; pancytopenia, febrile neutropenia, coagulopathy, haemolytic anaemia; angioedema, hypersensitivity; tumour lysis syndrome, fluid retention, diabetes mellitus, disturbed magnesium, phosphate, potassium, calcium or sodium levels; hallucinations, psychotic disorder, confusion; tremor, peripheral sensorimotor neuropathy, encephalopathy, posterior reversible encephalopathy syndrome, seizure disorders, memory loss, post-herpetic neuralgia; eye haemorrhage, double vision, dry eye; hearing disorders including tinnitus and hearing loss up to deafness; cardiac failure, atrial fibrillation and other arrhythmias, angina pectoris, pericarditis, cardiomyopathy, cardiorespiratory arrest; stroke, deep vein thrombosis, haemorrhage, thrombophlebitis, circulatory collapse; pulmonary embolism, pleural effusion, pulmonary oedema, alveolar haemorrhage, bronchospasm; pancreatitis, intestinal obstruction including ileus, colitis (including Clostridium difficile colitis), gastritis, dysphagia; hepatotoxicity, hepatitis, cholestasis; erythema multiforme, urticaria, toxic epidermal necrolysis, Stevens–Johnson syndrome; arthritis, myopathy; acute and chronic renal failure, haematuria, urinary retention, proteinuria; injection site reactions, facial oedema, extravasation; raised bilirubin; falls.

Rare (≥1/10,000 to <1/1,000): meningitis, Epstein–Barr virus infection, genital herpes; neoplasms (including plasma cell leukaemia and renal cell carcinoma); disseminated intravascular coagulation, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura), hyperviscosity syndrome, haemorrhagic diathesis; anaphylactic shock, amyloidosis, type III immune-complex-mediated reaction; hypothyroidism; suicidal ideation, delirium; autonomic neuropathy, cerebral and intracranial haemorrhage, cerebral oedema, transient ischaemic attack, coma, Guillain–Barré syndrome, demyelinating polyneuropathy, cranial nerve palsies; optic neuropathy, visual impairment up to blindness; torsade de pointes, myocardial infarction, atrioventricular block, atrial flutter; acute respiratory distress syndrome, respiratory failure, pulmonary hypertension, pneumonitis, interstitial lung disease, pulmonary fibrosis; acute pancreatitis, peritonitis, gastrointestinal ulcer and perforation; hepatic failure, hepatic haemorrhage, Budd–Chiari syndrome; photosensitivity reaction, palmar-plantar erythrodysaesthesia; rhabdomyolysis; multi-organ failure, death (including sudden death); QT prolongation; macrophage activation.

Further points from the SmPC:

• Mantle cell lymphoma (with rituximab, cyclophosphamide, doxorubicin and prednisone): the safety profile was broadly like that in myeloma. Blood-count reactions (neutropenia, thrombocytopenia, leukopenia, anaemia, lymphopenia), sensory peripheral neuropathy, hypertension, pyrexia, pneumonia, stomatitis and hair disorders were at least 5% more frequent. Hepatitis B infection (below 1%) and myocardial ischaemia (1.3%) were additional reactions seen with the combination.
• Peripheral neuropathy in combinations: in induction studies, any-grade peripheral neuropathy occurred in 15% with bortezomib and dexamethasone and 45% with bortezomib, thalidomide and dexamethasone; in the mantle cell lymphoma study it occurred in 30% (grade 3 or higher in 8%).
• Subcutaneous versus intravenous: in a phase III study of single-agent treatment, the subcutaneous route had 13% fewer grade 3 or higher reactions and 5% fewer discontinuations, and diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections and peripheral neuropathy were 12–15% less frequent. Grade 3 or higher neuropathy was 10% less frequent. A local reaction, mostly redness, occurred in 6% of patients and resolved in a median of 6 days.

• Potent CYP3A4 inhibitors (for example ketoconazole, ritonavir): ketoconazole raised bortezomib exposure (AUC) by 35% in 12 patients. Patients should be monitored closely when the two are combined.
• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort): rifampicin cut bortezomib exposure by 45% in 6 patients. The combination is not recommended because efficacy may be reduced.
• No relevant effect: omeprazole (a potent CYP2C19 inhibitor) and dexamethasone (a weaker CYP3A4 inducer) did not significantly change bortezomib exposure. Melphalan with prednisone raised exposure by 17%, which is not considered clinically relevant.
• Effect of bortezomib on other medicines: in laboratory tests it is a weak inhibitor of CYP1A2, 2C9, 2C19, 2D6 and 3A4. Because CYP2D6 contributes only about 7% of its metabolism, CYP2D6 poor metabolisers are not expected to handle it differently.
• Oral antidiabetic medicines: caution is advised in patients taking them.
• Food and herbal products: avoid St John’s wort, which induces CYP3A4 and may lower bortezomib levels. Grapefruit products inhibit CYP3A4 and call for caution. DrugBank also advises limiting foods and supplements high in flavonoids (such as green tea) or vitamin C, which may interfere with the effect of the medicine; the SmPC gives no food restriction.

Treatment must be started under the supervision of a physician experienced in treating cancer patients. Velcade may be given by a healthcare professional experienced in the use of chemotherapeutic agents, and the vial must be reconstituted by a healthcare professional.

Route of Administration

• Velcade 1 mg: intravenous use only. The reconstituted solution is given as a 3–5 second bolus injection through a peripheral or central venous catheter, followed by a flush with sodium chloride 9 mg/mL (0.9%) solution for injection.
• Velcade 3.5 mg: intravenous or subcutaneous use. The subcutaneous technique is described in the SmPC for this presentation.
• Never intrathecal: bortezomib must not be given by any other route. Intrathecal administration has resulted in death.
• At least 72 hours must pass between consecutive doses.

Progressive Multiple Myeloma (After at Least One Prior Therapy)

• Monotherapy: 1.3 mg/m² body surface area twice weekly for two weeks, on days 1, 4, 8 and 11 of a 21-day treatment cycle. Two cycles are recommended after a complete response is confirmed; responding patients who do not reach complete remission should receive a total of 8 cycles.
• With pegylated liposomal doxorubicin: the same bortezomib schedule, with pegylated liposomal doxorubicin 30 mg/m² on day 4 as a 1-hour intravenous infusion after the bortezomib injection. Up to 8 cycles can be given while the disease has not progressed and treatment is tolerated. Patients with a complete response can continue for at least 2 cycles after the first evidence of complete response, even beyond 8 cycles, and those whose paraprotein keeps falling after 8 cycles can continue while they respond and tolerate it.
• With dexamethasone: the same bortezomib schedule, with dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle. Patients with a response or stable disease after 4 cycles can receive a maximum of 4 further cycles.

Previously Untreated Multiple Myeloma, Not Eligible for Transplantation

• With melphalan and prednisone: 9 treatment cycles of 6 weeks each. In cycles 1 to 4, bortezomib 1.3 mg/m² is given twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In cycles 5 to 9 it is given once weekly on days 1, 8, 22 and 29. Melphalan 9 mg/m² and prednisone 60 mg/m² are both given orally on days 1 to 4 of the first week of each cycle.
• Before each new cycle, platelets should be at least 70 × 10⁹/L, the absolute neutrophil count at least 1.0 × 10⁹/L, and non-haematological toxicities back to grade 1 or baseline.

Previously Untreated Multiple Myeloma, Eligible for Transplantation (Induction)

• With dexamethasone: 4 cycles of 21 days. Bortezomib 1.3 mg/m² twice weekly on days 1, 4, 8 and 11; dexamethasone 40 mg orally on days 1 to 4 and 8 to 11.
• With dexamethasone and thalidomide: 4 cycles of 28 days. Bortezomib 1.3 mg/m² twice weekly on days 1, 4, 8 and 11; dexamethasone 40 mg orally on days 1 to 4 and 8 to 11; thalidomide orally 50 mg daily on days 1 to 14, raised to 100 mg on days 15 to 28 if tolerated and to 200 mg daily from cycle 2 if 100 mg is tolerated. Patients with at least a partial response should receive 2 additional cycles (up to 6 cycles in total).

Previously Untreated Mantle Cell Lymphoma

• With rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP): 21-day cycles. Bortezomib 1.3 mg/m² twice weekly on days 1, 4, 8 and 11, followed by a 10-day rest period on days 12 to 21. Six cycles are recommended; two more may be given if a response is first documented at cycle 6.
• On day 1 of each cycle, rituximab 375 mg/m², cyclophosphamide 750 mg/m² and doxorubicin 50 mg/m² are given as intravenous infusions; prednisone 100 mg/m² is given orally on days 1 to 5.
• Before each new cycle, platelets should be at least 100,000/µL (75,000/µL with bone marrow infiltration or splenic sequestration), neutrophils at least 1,500/µL and haemoglobin at least 8 g/dL, with non-haematological toxicities back to grade 1 or baseline.

Dose Adjustments for Side Effects

• Monotherapy: treatment must be withheld at any grade 3 non-haematological or grade 4 haematological toxicity (neuropathy is handled separately). Once it resolves, bortezomib can be restarted at a 25% lower dose (1.3 to 1.0 mg/m², or 1.0 to 0.7 mg/m²). If the toxicity does not resolve or returns at the lowest dose, stopping must be considered unless the benefit clearly outweighs the risk. The same guidelines apply in combinations with doxorubicin or dexamethasone, and the doses of the partner medicines should also be reduced for toxicity according to their SmPCs.
• Peripheral neuropathy: grade 1 without pain or loss of function, no change. Grade 1 with pain, or grade 2: reduce to 1.0 mg/m² or change to 1.3 mg/m² once weekly. Grade 2 with pain, or grade 3: withhold until resolved, then restart at 0.7 mg/m² once weekly. Grade 4 and/or severe autonomic neuropathy: stop. Patients with pre-existing severe neuropathy may be treated only after a careful benefit–risk assessment.
• With melphalan and prednisone: withhold bortezomib if platelets are 30 × 10⁹/L or below, or neutrophils 0.75 × 10⁹/L or below, on a dosing day other than day 1. If several doses in a cycle are withheld (3 or more on the twice-weekly schedule, 2 or more on the weekly schedule), reduce by one dose level. For grade 3 or higher non-haematological toxicity, withhold until grade 1 or baseline, then restart one dose level lower. Reducing melphalan by 25% in the next cycle can be considered after prolonged grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding.
• Mantle cell lymphoma: withhold for up to 2 weeks for neutropenia of grade 3 or higher with fever, grade 4 neutropenia lasting more than 7 days, or platelets below 10,000/µL, until neutrophils are at least 750/µL and platelets at least 25,000/µL; if not resolved, stop, and if resolved restart one dose level lower. Withhold on any dosing day other than day 1 if platelets are below 25,000/µL or neutrophils below 750/µL. For grade 3 or higher non-haematological toxicity, withhold until grade 2 or better, then restart one dose level lower. Granulocyte colony-stimulating factors and platelet transfusion may be used.

Special Populations

• Elderly: no dose adjustment is needed over 65 years in myeloma or mantle cell lymphoma. No dose recommendation can be made for older patients with previously untreated myeloma who are eligible for transplantation. In mantle cell lymphoma, patients aged 75 years or more tolerated both the bortezomib and the comparison regimens less well.
• Hepatic impairment: no adjustment in mild impairment. In moderate or severe impairment, start at 0.7 mg/m² per injection in the first cycle, then consider raising to 1.0 mg/m² or lowering to 0.5 mg/m² according to tolerance.
• Renal impairment: no adjustment in mild to moderate impairment (creatinine clearance above 20 mL/min/1.73 m²). The effect of severe impairment without dialysis is unknown. Because dialysis may lower bortezomib levels, give the dose after dialysis.
• Children and adolescents: safety and efficacy below 18 years have not been established, and no dose can be recommended.

Never Intrathecal

There have been fatal cases of inadvertent intrathecal administration of bortezomib. The 1 mg vial is for intravenous use only and the 3.5 mg vial for intravenous or subcutaneous use. Bortezomib must not be given into the spinal canal or by any other route.

Peripheral Neuropathy

Peripheral neuropathy, mostly sensory, is very common, and motor neuropathy also occurs. Patients should be asked about and examined for burning sensations, altered or reduced sensation, tingling, neuropathic pain and weakness, and the dose is reduced, delayed or stopped according to severity (see Dose Adjustments). Subcutaneous injection caused less peripheral neuropathy than intravenous injection in a phase III study.

Gastrointestinal Toxicity

Nausea, diarrhoea, vomiting and constipation are very common; ileus has been reported uncommonly. Patients who become constipated should be monitored closely.

Haematological Toxicity and Bleeding

Thrombocytopenia, neutropenia and anaemia are very common. Platelet counts are lowest around day 11 of each cycle and usually recover by the next one, with no evidence of cumulative thrombocytopenia; the mean nadir was about 40% of baseline in single-agent myeloma studies and 50% in the mantle cell lymphoma study. Gastrointestinal and intracerebral haemorrhage have been reported. Platelet counts should be checked before each dose, and a full blood count with differential monitored frequently. Treatment is withheld when platelets fall below 25,000/µL (30,000/µL or below in combination with melphalan and prednisone), after weighing the benefit against the risk, particularly in moderate to severe thrombocytopenia and with bleeding risk factors.

Infections, Herpes Zoster and Hepatitis B

Antiviral prophylaxis is recommended during treatment because of the risk of herpes zoster reactivation. In the melphalan–prednisone study, herpes zoster occurred in 17% of patients without antiviral prophylaxis and 3% with it; in the mantle cell lymphoma study, 10.7% and 3.6%. When rituximab is combined with bortezomib, patients at risk of hepatitis B should be screened before treatment and carriers monitored. Progressive multifocal leukoencephalopathy has been reported, so new or worsening neurological symptoms need prompt assessment.

Cardiac, Pulmonary, Blood-Pressure and Other Serious Reactions

• Heart failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome and acute diffuse infiltrative pulmonary disorders have been reported uncommonly. Patients with heart disease or risk factors should be monitored closely, and patients at risk of tumour lysis syndrome (high tumour burden) should be watched closely.
• Low blood pressure, including orthostatic hypotension, is common. Caution is needed in patients with a history of fainting, those taking blood pressure-lowering medicines, and those dehydrated by diarrhoea or vomiting.
• Hepatic reactions, including hepatitis, and, rarely, hepatic failure have been reported; seizures have been reported uncommonly.

Combination Treatments

The SmPC of every medicine used with bortezomib must be consulted before starting. With thalidomide, particular attention to pregnancy testing and the pregnancy prevention programme is needed.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: because bortezomib may damage genetic material, women of childbearing potential must use effective contraception and avoid becoming pregnant during treatment and for 8 months after it. Men should use effective contraception and not father a child during treatment and for 5 months after it.
• Pregnancy: there are no clinical data. The teratogenic potential has not been fully investigated; in rats and rabbits there were no effects on embryonal or foetal development at the highest maternally tolerated doses, and no studies of birth or postnatal development were done. Bortezomib should not be used in pregnancy unless the woman’s condition requires it, and a patient who becomes pregnant must be told of the potential hazard to the foetus. Thalidomide causes severe birth defects and must be used under its pregnancy prevention programme.
• Breastfeeding: it is not known whether bortezomib passes into human milk; breastfeeding should be stopped during treatment because of the potential for serious reactions in the infant.
• Fertility: fertility studies have not been done.

Effect on Driving

Bortezomib may have a moderate influence on the ability to drive and use machines. Fatigue is very common, dizziness common, syncope uncommon, and orthostatic hypotension or blurred vision common. Patients who have these symptoms should not drive or operate machinery.

Do not store above 30 °C. Keep the vial in the outer carton to protect it from light. Velcade does not need refrigeration, so it is not a cold-chain product. For storage after reconstitution, see Shelf Life.

• Unopened vial: 3 years.
• Reconstituted solution: use immediately after preparation. If it is not used immediately, in-use storage times and conditions are the responsibility of the user. In-use stability has been shown for 8 hours at 25 °C in the original vial and/or a syringe, and the total storage time of the reconstituted product must not exceed 8 hours before administration.

Prescription only (Rx), subject to restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in treating cancer patients. Bortezomib is reconstituted and injected by a healthcare professional, intravenously or (3.5 mg vial) subcutaneously, never intrathecally, so it is supplied to the hospital or clinic that administers it.