Bortezomib Equity 3.5mg Injection

Bortezomib Equity for injection is indicated for:

• Multiple Myeloma - as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone for the treatment of adult patients with progressive multiple myeloma who have received at least one prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation;
• - in combination with dexamethasone, or with dexamethasone and thalidomide, for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high dose chemotherapy with haematopoietic stem cell transplantation;
• - in combination with melphalan and prednisone for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high dose chemotherapy with haematopoietic stem cell transplantation.
• Mantle Cell Lymphoma - treatment of relapsed or refractory mantle cell lymphoma for patients who have received at least 1 prior line of therapy, one of which should have included an anthracycline (or mitoxantrone) and/or rituximab as part of their chemotherapy regimen.
• - treatment for newly diagnosed mantle cell lymphoma (MCL) in adults, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone who are unsuitable for haematopoietic stem cell transplantation.

Posology

Bortezomib Equity 3,5 mg powder for solution for injection is available for:

• intravenous administration at a concentration of 1 mg/mL (as a 3-5 second bolus injection) or
• subcutaneous administration at a concentration 2,5 mg/mL.

Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. BORTEZOMIB EQUITY IS FOR INTRAVENOUS AND SUBCUTANEOUS USE ONLY and should not be given by other routes. Intrathecal administration has resulted in death.

Bortezomib Equity retreatment may be considered for multiple myeloma patients who had previously responded to treatment with Bortezomib Equity (see below).

Monotherapy

Relapsed multiple myeloma and relapsed mantle cell lymphoma

Recommended dosage

The recommended starting dose of Bortezomib Equity is 1,3 mg/mu00b2 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 Bortezomib Equity. It is recommended that patients with a confirmed complete response receive 2 additional cycles of Bortezomib Equity beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of Bortezomib Equity therapy.

Dose modification and re-initiation of treatment

Bortezomib Equity 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 section 4.4). Once the symptoms of the toxicity have resolved, Bortezomib Equity treatment may be re-initiated at a 25 % reduced dose (1,3 mg/mu00b2 reduced to 1,0 mg/mu00b2; 1,0 mg/mu00b2 reduced to 0,7 mg/mu00b2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of Bortezomib Equity must be considered. Patients who experience Bortezomib Equity related neuropathic pain and/or peripheral sensory neuropathy are to be managed as presented in Table 1. Severe autonomic neuropathy resulting in treatment interruption or discontinuation has been reported. Caution should be used with Bortezomib Equity in patients with pre-existing severe neuropathy.

Hypersensitivity to bortezomib, to boron or to any of the excipients listed in section 6.1. Acute diffuse infiltrative pulmonary and pericardial disease. When Bortezomib Equity is given in combination with other medicines, refer to their Professional Information for additional contraindications.

There have been fatal cases of inadvertent intrathecal administration of Bortezomib Equity. Bortezomib Equity 3,5 mg is for IV or SC use. DO NOT ADMINISTER BORTEZOMIB EQUITY INTRATHECALLY. When Bortezomib Equity is given in combination with other medicines, the Professional Information of these other medicines must be consulted prior to initiation of treatment with bortezomib. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed.

Gastrointestinal toxicity

Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are frequently associated with bortezomib treatment. Reactions usually occur early in treatment (Cycles 1 and 2) and may persist for several cycles. Patients experiencing treatment emergent gastrointestinal toxicity may benefit from administration of anti-emetics and anti-diarrhetic medicine Fluid and electrolyte replacement should be administered to prevent or treat dehydration. Cases of ileus have been reported (see section 4.8). Therefore, patients who experience constipation should be closely monitored.

Haematological toxicity

Bortezomib treatment is frequently associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). However, febrile neutropenia is a less frequent undesirable effect. The most frequent haematologic toxicity is transient thrombocytopenia, which generally resolves between treatment cycles. Platelets were lowest at Day 11 of each cycle of bortezomib treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease and recovery remained consistent in studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied. The mean platelet count nadir measured was approximately 40 % of baseline. Severe bleeding, including CNS and gastrointestinal bleeding, associated with thrombocytopenia, have been reported in association with bortezomib treatment. Therefore, platelet counts should be monitored prior to each dose of bortezomib. Bortezomib Equity therapy should be withheld when the platelet count is < 25 000/u03bcL or, in the case of combination with melphalan and prednisone, when the platelet count is u2264 30 000/u03bcL (see section 4.2 and 4.8). Bortezomib Equity should be used with caution particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding. Full blood counts (FBC) with differential and including platelet counts should be frequently monitored throughout treatment with Bortezomib Equity. Platelet transfusions, red blood cell (RBC) transfusions and administration of growth factors may be utilised in the management of haematologic toxicities. Prophylactic platelet transfusions should be considered in thrombocytopenic patients at high risk of bleeding.

Herpes zoster virus reactivation

Antiviral prophylaxis is recommended in patients being treated with Bortezomib Equity. In patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation has been reported as more frequent in patients treated with bortezomib in combination with melphalan and prednisone, compared with when this medicine combination was given without bortezomib. It has also been reported that the incidence of herpes zoster infection was higher when bortezomib was given in combination with rituximab, cyclophosphamide, doxorubicin and prednisone, compared with when this medicine combination was given without bortezomib.

Hepatitis B Virus (HBV) reactivation and infection

When rituximab is used in combination with Bortezomib Equity, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with bortezomib, as in Bortezomib Equity. Antiviral prophylaxis should be considered. Refer to the Professional Information of rituximab for more information.

Laboratory tests

Complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with Bortezomib Equity.

Progressive multifocal leukoencephalopathy (PML)

Cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue Bortezomib Equity if PML is diagnosed.

Peripheral neuropathy

Treatment with bortezomib causes a peripheral neuropathy which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy are likely to experience worsening peripheral neuropathy (including u2265 Grade 3) during treatment with Bortezomib Equity. 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. The incidence of Grade u2265 2 and Grade u2265 3 peripheral neuropathy events was reported to be higher when bortezomib was given intravenously compared to being given subcutaneously. Therefore, patients with pre-existing peripheral neuropathy or at high risk of peripheral neuropathy may benefit from starting Bortezomib Equity subcutaneously. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to subcutaneous (see section 4.2). Neuropathy has been managed with supportive care and other therapies. Peripheral neuropathy may not be reversible. Improvement in, or resolution of, peripheral neuropathy has been reported in some patients with u2265 Grade 2 peripheral neuropathy. Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological evaluation should be considered in patients receiving Bortezomib Equity in combination with medicines known to be associated with neuropathy (e.g., thalidomide) and appropriate dose reduction or treatment discontinuation should be considered. 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 less frequently reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Hypotension

Bortezomib treatment is frequently associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on bortezomib (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with bortezomib. 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 bortezomib. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to Bortezomib Equity or Bortezomib Equity may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicines 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 medicines, 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.

Posterior Reversible Encephalopathy Syndrome (PRES)

There have been reports of PRES in patients receiving bortezomib. PRES is a rare, often reversible, rapidly evolving neurological condition, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patients developing PRES, Bortezomib Equity should be discontinued. The safety of reinitiating Bortezomib Equity therapy in patients previously experiencing PRES is not known.

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. 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. Patients using angiotensin inhibitors, beta-blockers, antihypertensives, calcium channel blockers, angiotensin receptor blockers and diuretics may have a higher incidence of cardiac failure during Bortezomib Equity treatment.

Electrocardiogram investigations

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

Pulmonary disorders

There have been 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 bortezomib (see section 4.8). Some of these events have been fatal. A pre-treatment chest radiograph is recommended 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. Caution should be used prior to continuing Bortezomib Equity therapy.

In a clinical trial, two patients (out of 2) given high-dose cytarabine (2 g/mu00b2 per day) by continuous infusion over 24 hours with daunorubicin and bortezomib for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, administration with high doses cytarabine (2 g/mu00b2 per day) by continuous infusion over 24 hours in combination with daunorubicin and bortezomib is not recommended.

Renal impairment

Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).

Hepatic impairment

Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with Bortezomib Equity at reduced doses and closely monitored for toxicities (see sections 4.2 and 5.2).

Hepatic reactions

Cases of acute hepatic failure have been reported in patients receiving bortezomib and concomitant medicines and with serious underlying medical conditions. Other reported hepatic reactions include asymptomatic increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of Bortezomib Equity (see section 4.8).

Tumour lysis syndrome

Because Bortezomib Equity is a cytotoxic medicine and can rapidly kill malignant plasma cells and MCL 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. Symptoms of tumour lysis syndrome are weakness, vomiting, cramps, seizure, oedema and fluid overload, congestive heart failure, dysrhythmias and syncope. These patients should be monitored closely, and appropriate precautions taken.

Concomitant medicines

Patients should be closely monitored when given Bortezomib Equity in combination with potent CYP3A4- inhibitors. Caution should be exercised when Bortezomib Equity is combined with CYP3A4- or CYP2C19 substrates (see section 4.5). Normal liver function should be confirmed, and caution should be exercised in patients receiving oral hypoglycaemics (see section 4.5).

Amyloidosis

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

Potentially immunocomplex-mediated reactions

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

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 metaboliser phenotype is not expected to affect the overall disposition of bortezomib. An interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 35 % (CI 90 % [1,032 to 1,772]) based on data from 12 patients. Therefore, patients should be closely monitored when given Bortezomib Equity in combination with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). In an interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 17 patients. An interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45 % based on data from 6 patients. The concomitant use of Bortezomib Equity with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. Johnu2019s Wort. In the same interaction study assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 7 patients. Concomitant exposure to narcotics may increase the incidence of constipation, nausea and vomiting. An interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17 % based on data from 21 patients. This is not considered clinically relevant. During clinical trials, hypoglycaemia and hyperglycaemia were reported in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic medicines receiving Bortezomib Equity treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medicines. Normal liver function should be confirmed, and caution should be exercised in patients receiving oral hypoglycaemics. Patients should be cautioned about the use of concomitant medications that may be associated with peripheral neuropathy (such as amiodarone, anti-virals, isoniazid, nitrofurantoin, or statins), or with a decrease in blood pressure.

Women of childbearing potential / Contraception in males and females

Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.

Pregnancy

Safety in pregnancy has not been established. If Bortezomib Equity is used during pregnancy, or if the patient becomes pregnant while receiving Bortezomib Equity, the patient needs to be informed of potential for hazards to the foetus.

Breastfeeding

Safety in lactation has not been established. It is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with Bortezomib Equity.

Fertility

Fertility studies were not conducted with Bortezomib Equity.

Bortezomib Equity may be associated with fatigue, dizziness, syncope and orthostatic/postural hypotension or blurred vision. Therefore, patients must be cautious when driving or using machines and should be advised not to drive or operate machinery if they experience these symptoms (see section 4.8).

Summary of the safety profile

Serious adverse reactions less frequently reported during treatment with bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy. Frequently reported adverse reactions during treatment with bortezomib are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

Tabulated summary of adverse reactions

Table 6: Adverse reactions in patients with Multiple Myeloma treated with bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication

# MedDRA System Organ Class Frequency Adverse Reaction Infections and infestations Frequent Herpes zoster (inc. disseminated & ophthalmic), pneumonia*, herpes simplex*, fungal infection* Less frequent Infection*, bacterial infections*, viral infections*, sepsis (inc. septic shock)*, bronchopneumonia, herpes virus infection*, meningoencephalitis herpetic # , bacteraemia (inc. staphylococcal), hordeolum, influenza, cellulitis, device related infection, skin infection*, ear infection*, staphylococcal infection, tooth infection*, meningitis (inc. bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post viral fatigue syndrome Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Less frequent Neoplasm malignant, leukaemia plasmacytic, renal cell carcinoma, mass, mycosis fungoides, neoplasm benign* Blood and lymphatic system disorders Frequent Thrombocytopenia*, neutropenia*, anaemia*, leukopenia*, lymphopenia* Less frequent Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, haemolytic anaemia # , disseminated intravascular coagulation, thrombocytosis*, hyperviscosity syndrome, platelet disorder NOS, thrombotic microangiopathy (inc. thrombocytopenic purpura) # , blood disorder NOS, haemorrhagic diathesis, lymphocytic infiltration

In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for Bortezomib Equity overdose. In the event of an overdose, patients should undergo careful haemodynamic monitoring. Vital signs should be monitored, and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic medicines) and body temperature (see sections 4.2 and 4.4).