Velcade Intravenous 1,0 mg/ 3,5 mg Injection, powder

VELCADE 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 1 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

VELCADE 1 mg powder for solution for injection is available for:

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

VELCADE 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. VELCADE IS FOR INTRAVENOUS AND SUBCUTANEOUS USE ONLY and should not be given by other routes. Intrathecal administration has resulted in death. See section 6.6 for Reconstitution Instructions.

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

Monotherapy

Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

Recommended dosage

The recommended starting dose of VELCADE is 1,3 mg/mu00b2 body surface area administered 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. It is recommended that patients receive 2 cycles of VELCADE following a confirmation of a complete response. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of therapy. At least 72 hours should elapse between consecutive doses of VELCADE.

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Hypersensitivity to VELCADE, boron or to any of the excipients (see section 6.1).

Acute diffuse infiltrative pulmonary and pericardial disease.

There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mg is for IV use only. VELCADE 3,5 mg is for IV or SC use. DO NOT ADMINISTER VELCADE INTRATHECALLY.

Herpes Zoster Virus Reactivation

Medical practitioners should consider the need for antiviral prophylaxis in patients being treated with VELCADE. In the phase 3 study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was very common in patients treated with Velcade, Melphalan and Prednisone (VcMP). In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6,7 % in the VcR-CAP arm and 1,2 % in the R-CHOP arm (see section 4.8).

Hepatitis B Virus (HBV) reactivation and infection

When rituximab is used in combination with VELCADE, 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 VELCADE. 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 VELCADE.

Gastrointestinal toxicity

Gastrointestinal toxicity, including diarrhoea, constipation, nausea and vomiting are very common with VELCADE treatment (see section 4.8). 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-diarrhoeals. Fluid and electrolyte replacement should be administered to prevent or treat dehydration. Cases of ileus have been reported therefore patients who experience constipation should be closely monitored.

Haematological toxicity

VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). However, febrile neutropenia is an uncommon undesirable effect. The most common haematologic toxicity is transient thrombocytopenia, which generally resolves between treatment cycles. Platelets were lowest at Day 11 of each cycle of VELCADE treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease, and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied.

In vitro studies indicate that VELCADE 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 VELCADE, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of VELCADE.

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

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

In an interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of VELCADE (injected intravenously), showed a mean bortezomib AUC reduction of 45 % based on data from 6 patients. The concomitant use of VELCADE 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, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics 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 VELCADE (injected intravenously), showed a 17 % increase in mean bortezomib AUC 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 agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. 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.

Contraception in males and females

Males and females of childbearing capacity must use effective contraceptive measures during treatment and for 3 months following VELCADE therapy.

Pregnancy

Safety in pregnancy has not been established. If VELCADE is used during pregnancy, alone or in combination with other medicines, or if the patient becomes pregnant while receiving VELCADE, the patient needs to be informed of the potential hazards to the foetus.

Breastfeeding

Safety in lactation has not been established. It is not known whether VELCADE is excreted in human milk. Because of the potential for serious undesirable effects in breastfed infants from mothers on VELCADE, women should not breastfeed their infants while receiving VELCADE.

VELCADE may have a moderate influence on the ability to drive and use machines. VELCADE may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly, and orthostatic/postural hypotension or blurred vision commonly. 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).

Clinical trial data

Summary of the safety profile

Serious adverse reactions uncommonly reported during treatment with VELCADE include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy. The most commonly reported adverse reactions during treatment with VELCADE 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

Multiple Myeloma

The undesirable effects in Table 7 were considered by the investigators to have at least a possible or probable causal relationship to VELCADE. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with VELCADE at 1,3 mg/mu00b2 and included in Table 7. Overall, VELCADE was administered for the treatment of multiple myeloma in 3,974 patients.

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (u2265 1/10); common (u2265 1/100, < 1/10); uncommon (u2265 1/1,000, < 1/100); rare (u2265 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

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One case of overdosage (more than twice the recommended dose) in the setting of concurrent sepsis has been reported with VELCADE. Overdosage was associated with acute onset of symptomatic hypotension and the patient subsequently died. It is recommended that in the event of overdosage, patients should undergo careful haemodynamic monitoring, and hypotension should be treated aggressively with intravenous hydration and other clinically appropriate measures.