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BORTEBIN contraindications, warnings and precautions for use

BORTEBIN (Bortezomib 3.5 mg powder for solution for injection)

Contraindications

  • Hypersensitivity to the active substance, to boron or to any of the excipients.
  • Acute diffuse infiltrative pulmonary and pericardial disease.

When Bortezomib is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.

BORTEBIN Special warnings and precautions for use

When Bortezomib is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with Bortezomib. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed.

Intrathecal administration: There have been fatal cases of inadvertent intrathecal administration of Bortezomib. Bortezomib 1 mg powder for solution for injection is for intravenous use only, while Bortezomib 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. Bortezomib should not be administered intrathecally.

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

Haematological toxicity: Bortezomib treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with Bortezomib and in patients with previously untreated MCL treated with Bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), one of the most common haematologic toxicity was transient thrombocytopenia.

Herpes zoster virus reactivation: Antiviral prophylaxis is recommended in patients being treated with Bortezomib.

In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with Bortezomib + Melphalan+ Prednisone compared with Melphalan+ Prednisone (14% versus 4% respectively).

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.

Hepatitis B Virus (HBV) reactivation and infection: When rituximab is used in combination with Bortezomib, 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. Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics of rituximab for more information.

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Progressive multifocal leukoencephalopathy (PML) Very rare 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 if PML is diagnosed.

Peripheral neuropathy: Treatment with Bortezomib 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.

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: Bortezomib treatment is commonly associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment.

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 should be discontinued.

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.

Electrocardiogram 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 Bortezomib. 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.

Renal impairment: Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely.

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 at reduced doses and closely monitored for toxicities.

Hepatic reactions: Rare cases of hepatic failure have been reported in patients receiving Bortezomib and concomitant medicinal products 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 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. These patients should be monitored closely and appropriate precautions taken.

Concomitant medicinal products: Patients should be closely monitored when given Bortezomib in combination with potent CYP3A4-inhibitors. 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.

BORTEBIN Interaction with other medicinal products and other forms of interaction

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.

BORTEBIN Fertility, pregnancy and lactation

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: No clinical data are available for Bortezomib with regard to exposure during pregnancy. The teratogenic potential of Bortezomib has not been fully investigated.

In non-clinical studies, Bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of Bortezomib on parturition and post-natal development were not conducted.

Bortezomib should not be used during pregnancy unless the clinical condition of the woman requires treatment with Bortezomib.

If Bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this medicinal product, the patient should be informed of potential for hazard to the foetus.

Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the thalidomide pregnancy prevention programme are met. Patients receiving Bortezomib in combination with thalidomide should adhere to the pregnancy prevention programme of thalidomide. Refer to the Summary of Product Characteristics of thalidomide for additional information.

Breast-feeding: It is not known whether Bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with Bortezomib.

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Fertility: Fertility studies were not conducted with Bortezomib.

BORTEBIN Effects on ability to drive and use machines

Bortezomib may have a moderate influence on the ability to drive and use machines.

Bortezomib 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.

BORTEBIN Undesirable effects

Serious adverse reactions uncommonly 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.

The most commonly 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.

BORTEBIN Overdose

In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical cardiovascular safety pharmacology studies.

There is no known specific antidote for Bortezomib overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature.

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