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Drug Details

VELCADE 3.5mg powder Solution for Injection

• Drug Class Description
  Antineoplastic agent
• Generic Name
  Bortezomib
• Presentation
  VELCADE 3.5 mg powder for solution for injection. Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester). After reconstitution, 1 ml of solution for injection contains 1 mg bortezomib.
• Description
  Powder for solution for injection. White to off-white cake or powder.
• Indications
  VELCADE is indicated as mono-therapy for the treatment of progressive multiple myeloma in patients who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.
• Adult Dosage
  

  Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

  Monotherapy

  Recommended dosage

  The recommended starting dose of bortezomib is 1.3 mg/m² body surface area twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.

  It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELCADE beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy.

  Currently there are limited data concerning retreatment with VELCADE.

  Recommended dosage adjustments during treatment and re-initiation of treatment

  VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4). Once the symptoms of the toxicity have resolved, VELCADE treatment may be re-initiated at a 25% reduced dose (1.3 mg/m² reduced to 1.0 mg/m²; 1.0 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of VELCADE must be considered unless the benefit of treatment clearly outweighs the risk.

  Patients who experience VELCADE related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1. Patients with pre-existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.

  Table 1: Recommended* dose modifications for VELCADE related neuropathy.

  Severity of neuropathy	Modification of dose and regimen
  Grade 1 (paraesthesia, weakness and/or loss of reflexes) with no pain or loss of function	No action
  Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living)	Reduce to 1.0 mg/m2
  Grade 2 with pain or Grade 3 (interfering with activities of daily living)	Withhold VELCADE treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate VELCADE treatment and reduce dose to 0.7 mg/m2 and change treatment schedule to once per week.
  Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life threatening or leads to paralysis)And/or severe autonomic neuropathy	Discontinue VELCADE

  *Based on dose modifications in phase II & III multiple myeloma studies and post-marketing experience.

• Child Dosage
  The experience in children and adolescents is limited. Therefore, it should not be used in the paediatric age group until further data become available.
• Elderly Dosage
  There is no evidence to suggest that dose adjustments are necessary in the elderly (See Adverse Reactions).
• Contra Indications
  Hypersensitivity to bortezomib, boron or to any of the excipients. Severe hepatic impairment.
• Special Precautions
  

  Gastrointestinal

  Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been reported, therefore patients who experience constipation should be closely monitored.

  Haematological

  VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). The most common haematologic toxicity is transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of VELCADE treatment. There was no evidence of cumulative thrombocytopenia, including in the phase II extension study. The mean platelet count nadir measured was approximately 40% of baseline. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts <75,000/μl, 90% of 21 patients had a count 25,000/μl during the study, including 14% <10,000/μl; in contrast, with a baseline platelet count>75,000/μl, only 14% of 309 patients had a count 25×10⁹/l during the study. Platelet counts should be monitored prior to each dose of VELCADE. Therapy should be held when the platelet count is <25,000/μl and re-initiated at a reduced dose after resolution. Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.

  Therefore, complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with VELCADE.

  Peripheral Neuropathy

  Treatment with VELCADE is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.

  It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require the dose and schedule of VELCADE to be modified. Neuropathy has been managed with supportive care and other therapies. Improvement in, or resolution of, peripheral neuropathy was reported in 51% of patients with Grade 2 peripheral neuropathy in the single agent phase III multiple myeloma study and 71% of patients with grade 3 or 4 peripheral neuropathy or peripheral neuropathy leading to discontinuation of treatment in phase II studies, respectively.

  In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.

  Seizures

  Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

  Hypotension

  VELCADE treatment is commonly associated with orthostatic/postural hypotension. Most undesirable effects are mild to moderate in nature and are observed throughout treatment. Patients developing orthostatic hypotension on VELCADE did not have evidence of orthostatic hypotension prior to treatment with VELCADE. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELCADE. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.

  Heart failure

  Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. In a single agent phase III randomized, comparative study the incidence of heart failure in the VELCADE group was similar to that in the dexamethasone group. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.

  ECG Investigations

  There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.

  Pulmonary Disorders

  There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A pretreatment chest radiograph is recommended to determine if any additional diagnostic measures are necessary and to serve as a baseline for potential post-treatment pulmonary changes.

  In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing VELCADE therapy.

  In a clinical trial, two patients given high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2g/m² per day) by continuous infusion over 24 hours is not recommended.

  Renal Impairment

  Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely.

  Hepatic Impairment

  Patients with hepatic impairment should be treated with extreme caution and a dose reduction should be considered.

  Hepatic Reactions

  Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib.

  Tumour lysis syndrome

  Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

  Amyloidosis

  The impact of proteasome inhibition by bortezomib on disorders associated with protein accumulation such as amyloidosis is unknown. Caution is advised in these patients.

  Precautions with certain concomitant medicinal products

  Patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates.

  Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics.

  Potentially immunocomplex-mediated reactions

  Potentially immunocomplex-mediated reactions, such as serum-sickness –type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.

• Interactions
  

  In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.

  An interaction study based on data from 12 patients, assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, showed a bortezomib AUC mean increase of 35% (CI_90% [1.032 to 1.772]). Therefore patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

  In an interaction study based on data from 17 patients, assessing the effect of omeprazole, a potent CYP2C19 inhibitor, there was no significant effect on the pharmacokinetics of bortezomib.

  In the absence of interaction studies investigating the effect of CYP3A4 inducers on the pharmacokinetics of bortezomib, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inducers (e.g. rifampicin).

  An interaction study assessing the effect of melphalan-prednisone on bortezomib showed a 17% increase in mean bortezomib AUC based on data from 21 patients. This is not considered clinically relevant.

  During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

• Adverse Drug Reactions
  

  The following undesirable effects were considered to have at least a possible or probable causal relationship to VELCADE by the investigators during the conduct of 5 non-comparative Phase II studies and 1 comparative phase III trial VELCADE vs dexamethasone in 663 patients with relapsed or refractory multiple myeloma, of whom 331 received VELCADE as single agent. The safety database comprises data from patients with multiple myeloma or B-cell lymphocytic leukemia (CLL). Patients were treated with VELCADE as a single agent, or in combination with dexamethasone.

  Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (1/10); common (1/100, <1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data) including isolated reports.

  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

  Infections and infestations Very common: herpes zoster (including disseminated). Common: pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes simplex. Uncommon: sepsis, bacteraemia, pneumonia pneumococcal, bronchopneumonia, upper and lower respiratory tract infection, catheter related infection, pleural infection, haemophilus infection, cytomegalovirus infection, influenza, infectious mononucleosis, varicella, urinary tract infection, gastroenteritis, candidal infection, fungal infection, post herpetic neuralgia, oral candidiasis, blepharitis, infection.

  Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: tumour lysis syndrome

  Blood and lymphatic system disorders Very Common: thrombocytopenia, neutropenia, anaemia. Common: leukopenia, lymphopenia. Uncommon: pancytopenia, febrile neutropenia, haemolytic anaemia, thrombocytopenic purpura, lymphadenopathy.

  Immune system disorders Uncommon: hypersensitivity, immunocomplex mediated hypersensitivity, potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis

  Endocrine disorders Uncommon: Inappropriate antidiuretic hormone (ADH) secretion.

  Metabolism and nutrition disorders Very Common: appetite decreased. Common: dehydration, hypokalaemia, hyperglycaemia. Uncommon: hyperkalaemia, cachexia, hypercalcaemia, hypocalcaemia, hypernatraemia, hyponatraemia, hypoglycaemia, hyperuricaemia, vitamin B12 deficiency, appetite increased, hypomagnesaemia, hypophosphataemia

  Psychiatric disorders Common: confusion, depression, insomnia, anxiety. Uncommon: agitation, delirium, hallucinations, restlessness, mood swings, mental status changes, sleep disorder, irritability, abnormal dreams.

  Nervous system disorders Very Common: peripheral neuropathy, peripheral sensory neuropathy, paraesthesia, headache. Common: polyneuropathy, peripheral neuropathy aggravated, dizziness (excluding vertigo), dysgeusia, dysaesthesia, hypoaesthesia, tremor. Uncommon: paraplegia, intracranial haemorrhage, subarachnoid haemorrhage convulsions, peripheral motor neuropathy, syncope, paresis, disturbance in attention, increased activity, ageusia, somnolence, migraine, cognitive disorder, jerky movements, dizziness postural, sciatica, mononeuropathy, speech disorder, restless leg syndrome.

  Eye disorders Common: vision blurred, eye pain. Uncommon: eye haemorrhage, vision abnormal, dry eye, conjunctivitis, eye discharge, photophobia, eye irritation, lacrimation increased, conjunctival hyperaemia, eye swelling.

  Ear and labyrinth disorders Common: vertigo. Uncommon: deafness, tinnitus, hypoacusis, hearing impaired.

  Cardiac disorders Uncommon: cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, angina unstable, development or exacerbation of congestive heart failure (see section 4.4), cardiac failure, ventricular hypokinesia, pulmonary oedema and acute pulmonary oedema, sinus arrest, atrioventricular block complete, tachycardia, sinus tachycardia, supraventricular tachycardia, arrhythmia, atrial fibrillation, palpitations. Rare: New onset of decreased left ventricular ejection fraction.

  Vascular disorders Common: hypotension, orthostatic and postural hypotension, phlebitis, haematoma, hypertension. Uncommon: cerebral hemorrhage, vasculitis, cerebrovascular accident, pulmonary hypertension, petechiae, ecchymosis, purpura, vein discolouration, vein distended, wound hemorrhage, flushing, hot flushes.

  Respiratory, thoracic and mediastinal disorders Very Common: dyspnoea. Common: dyspnoea exertional, epistaxis, cough, rhinorrhoea. Uncommon: respiratory arrest, hypoxia, pulmonary congestion, pleural effusion, asthma, respiratory alkalosis, tachypnoea, wheezing, nasal congestion,hoarseness, rhinitis, hyperventilation, orthopnoea, chest wall pain, sinus pain, throat tightness, productive cough.

  Gastrointestinal disorders Very Common: vomiting, diarrhoea, nausea, constipation. Common: abdominal pain, stomatitis, dyspepsia, loose stools, abdominal pain upper, flatulence, abdominal distension, hiccups, mouth ulceration, pharyngolaryngeal pain, dry mouth. Uncommon: acute pancreatitis, ileus paralytic, antibiotic associated colitis, colitis, haematemesis, diarrhoea haemorrhagic, gastrointestinal haemorrhage, rectal haemorrhage, enteritis, dysphagia, abdominal discomfort, eructation, gastrointestinal motility disorder, oral pain, retching, change in bowel habit, spleen pain, oesophagitis, gastritis, gastro-oesophageal reflux disease, gastrointestinal pain, gingival bleeding, gingival pain, hiatus hernia, irritable bowel syndrome, oral mucosal petechiae, salivary hypersecretion, tongue coated, tongue discolouration, faecal impaction.

  Hepatobiliary disorders Uncommon: hepatitis, hepatic haemorrhage, hypoproteinaemia, hyperbilirubinaemia

  Skin and subcutaneous tissue disorders Very Common: rash. Common: periorbital oedema, urticaria, rash pruritic, pruritus, erythema, sweating increased, dry skin, eczema. Uncommon: vasculitic rash, rash erythematous, photosensitivity reaction, contusion, pruritus generalised, rash macular, rash papular, psoriasis, rash generalized, eyelid oedema, face oedema, dermatitis, alopecia, nail disorder, skin discolouration, dermatitis atopic, hair texture abnormal, heat rash, night sweats, pressure sore, ichthyosis, skin nodule.

  Musculoskeletal and connective tissue disorders Very Common: myalgia. Common: muscle weakness, musculoskeletal pain, pain in limb, muscle cramps, arthralgia, bone pain, back pain, peripheral swelling. Uncommon: muscle spasms, muscle twitching or sensation of heaviness, muscle stiffness, joint swelling, joint stiffness, buttock pain, swelling, pain in jaw.

  Renal and urinary disorders Common: renal impairment, dysuria. Uncommon: renal failure acute, renal failure, oliguria, renal colic, haematuria, proteinuria, urinary retention, urinary frequency, difficulty in micturition, loin pain, urinary incontinence, micturition urgency.

  Reproductive system and breast disorders Uncommon: testicular pain, erectile dysfunction

  General disorders and administration site conditions Very Common: fatigue, pyrexia. Common: asthenia, weakness, lethargy, rigors, malaise, influenza like illness, oedema peripheral, chest pain, pain, oedema. Uncommon: fall, mucosal haemorrhage, mucosal inflammation, neuralgia, injection site phlebitis, extravasation inflammation tenderness, injection site erythema, feeling cold, chest pressure sensation, chest discomfort, groin pain, chest tightness.

  Investigations Common: weight decreased, blood lactate dehydrogenase increased. Uncommon: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, blood creatinine increased, blood urea increased, gamma-glutamyltransferase increased, blood amylase increased, liver function tests abnormal, red blood cell count decreased, white blood cell count decreased, blood bicarbonate decreased, heart rate irregular, C-reactive protein increased, blood phosphate decreased, weight increased.

  Injury, poisoning and procedural complications Uncommon: catheter related complications, post procedural pain, post procedural haemorrhage, burns.