Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

CD20-negative disease

There are limited data available on patients with CD20-negative DLBCL treated with Columvi and it is possible that patients with CD20-negative DLBCL may have less benefit compared to patients with CD20-positive DLBCL. The potential risks and benefits associated with treatment of patients with CD20-negative DLBCL with Columvi should be considered.

Cytokine release syndrome

CRS, including life-threatening reactions, has been reported in patients receiving Columvi (see section 4.8).

The most common manifestations of CRS were pyrexia, tachycardia, hypotension, chills and hypoxia.
Infusion-related reactions may be clinically indistinguishable from manifestations of CRS.

Most CRS events occurred following the first dose of Columvi. Elevated liver function tests (AST and alanine transaminase [ALT] > 3  ULN and/or total bilirubin > 2  ULN) concurrent with CRS have been reported after Columvi use (see section 4.8).

Patients in study NP30179 were pre-treated with obinutuzumab, 7 days prior to initiation of Columvi therapy, and patients should be premedicated with an anti-pyretic, antihistamine and a glucocorticoid (see section 4.2).


At least 1 dose of tocilizumab for use in the event of CRS must be available prior to Columvi infusion at Cycles 1 and 2. Access to an additional dose of tocilizumab within 8 hours of use of the previous tocilizumab dose must be ensured.
Patients must be monitored during all Columvi infusions and for at least 10 hours after completion of the first infusion. For complete information on monitoring, see section 4.2. Patients must be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time.
(See Patient information card in section 1)

Patients should be evaluated for other causes of fever, hypoxia and hypotension, such as infections or sepsis. CRS should be managed based on the patient’s clinical presentation and according to the CRS management guidance provided in Table 3 (section 4.2).

Neurologic Toxicity
Columvi can cause serious and fatal neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS) [see Undesirable effects (4.8)].
Coadministration of Columvi with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Optimize concomitant medications and hydration to avoid dizziness or mental status changes. Institute fall precautions as appropriate.
Monitor patients for signs and symptoms of neurologic toxicity, evaluate, and provide supportive therapy; withhold or permanently discontinue Columvi based on severity [see Posology and method of administration (4.2)].
Evaluate patients who experience neurologic toxicity such as tremors, dizziness, or adverse reactions that may impair cognition or consciousness promptly, including potential neurology evaluation.
Advise affected patients to refrain from driving and/or engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurologic toxicity fully resolves.

Interaction with CYP450 substrates

The initial release of cytokines associated with the start of Columvi treatment could suppress CYP450 enzymes and lead to fluctuations in concentrations of concomitantly administered drugs. On initiation of Columvi therapy, patients being treated with CYP450 substrates with a narrow therapeutic index should be monitored as fluctuations in the concentration of concomitant drugs may lead to toxicity, loss of effect or adverse events (see section 4.5).

Serious infections

Serious infections (such as sepsis and pneumonia) have occurred in patients treated with Columvi (see section 4.8).

Columvi must not be administered to patients with an active infection. Caution should be exercised when considering the use of Columvi in patients with a history of chronic or recurrent infection, those with underlying conditions that may predispose them to infections, or those who have had significant prior immunosuppressive treatment. Patients should be monitored before and during Columvi treatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections and treated appropriately.

Columvi should be temporarily withheld in the presence of an active infection until the infection has resolved. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur.

Febrile neutropenia has been reported during treatment with Columvi. Patients with febrile neutropenia should be evaluated for infection and treated promptly.

Tumour flare

Tumour flare has been reported in patients receiving Columvi (see section 4.8). Manifestations included localised pain and swelling.

Consistent with the mechanism of action of Columvi, tumour flare is likely due to the influx of T cells into tumour sites following Columvi administration and may mimic progression of disease. Tumour flare does not imply treatment failure or represent tumour progression.

Specific risk factors for tumour flare have not been identified, however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Monitoring and evaluation for tumour flare at critical anatomical sites is recommended in patients treated with Columvi and managed as clinically indicated. Corticosteroids and analgesics should be considered to treat tumour flare.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported in patients receiving Columvi (see section 4.8).
Patients with high tumour burden, rapidly proliferative tumours, renal dysfunction or dehydration are at greater risk of tumour lysis syndrome.

Patients at risk should be monitored closely by appropriate laboratory and clinical tests for electrolyte status, hydration and renal function. Appropriate prophylactic measures with anti-hyperuricaemics (e.g., allopurinol or rasburicase) and adequate hydration should be considered prior to obinutuzumab pre-treatment and prior to Columvi infusion.

Management of TLS may include aggressive hydration, correction of electrolyte abnormalities, anti-hyperuricaemic therapy and supportive care.

Immunisation

The safety of immunisation with live vaccines during or following Columvi therapy has not been studied. Immunisation with live vaccines is not recommended during Columvi therapy.

Effects on Driving

4.7    Effects on ability to drive and use machines

Columvi has minor influence on the ability to drive and use machines. Patients experiencing symptoms of neurological adverse events and/or CRS (pyrexia, tachycardia, hypotension, chills, hypoxia) should be advised not to drive or use machines until symptoms resolve (see sections 4.4 and 4.8).