Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

In order to prevent medicinal product errors it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not another trastuzumab-containing product (e.g. trastuzumab or trastuzumab deruxtecan).

Thrombocytopenia
Thrombocytopenia, or decreased platelet counts, was commonly reported with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation, dose reduction, and dose interruption (see section 4.8). In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients (see section 4.8).

It is recommended that platelet counts are monitored prior to each trastuzumab emtansine dose.
Patients with thrombocytopenia (≤ 100,000/mm3) and patients on anti-coagulant treatment (e.g.
warfarin, heparin, low molecular weight heparins) should be monitored closely while on trastuzumab emtansine treatment. Trastuzumab emtansine has not been studied in patients with platelet counts ≤ 100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or 
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greater (< 50,000/mm3), do not administer trastuzumab emtansine until platelet counts recover to Grade 1 (≥ 75,000/mm3) (see section 4.2).

Haemorrhage
Cases of haemorrhagic events, including central nervous system, respiratory and gastrointestinal haemorrhage, have been reported with trastuzumab emtansine treatment. Some of these bleeding events resulted in fatal outcomes. In some of the observed cases the patients had thrombocytopenia, or were also receiving anti-coagulant therapy or antiplatelet therapy; in others there were no known additional risk factors. Use caution with these agents and consider additional monitoring when concomitant use is medically necessary.

Hepatotoxicity
Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (Grade 1-4 transaminitis), has been observed during treatment with trastuzumab emtansine in clinical studies (see section 4.8). Transaminase elevations were generally transient with peak elevation at day 8 after administration of therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect on transaminases has also been observed (the proportion of patients with Grade 1-2 ALT/AST abnormalities increases with successive cycles).

Patients with elevated transaminases improved to Grade 1 or normal within 30 days of the last dose of trastuzumab emtansine in the majority of the cases (see section 4.8).

Serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver and some with a fatal outcome due to drug-induced liver injury have been observed in patients treated with trastuzumab emtansine. Observed cases may have been confounded by comorbidities and/or concomitant medicinal products with known hepatotoxic potential.

Liver function should be monitored prior to initiation of treatment and each dose. Patients with baseline elevation of ALT (e.g. due to liver metastases) may be predisposed to liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase. Dose reductions or discontinuation for increased serum transaminases and total bilirubin are specified in section 4.2.

Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated with trastuzumab emtansine. NRH is a rare liver condition characterised by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. Diagnosis of NRH can be confirmed only by histopathology.
NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, trastuzumab emtansine treatment must be permanently discontinued.

Trastuzumab emtansine has not been studied in patients with serum transaminases > 2.5  ULN or total bilirubin > 1.5  ULN prior to initiation of treatment. Treatment in patients with serum transaminases > 3  ULN and concomitant total bilirubin > 2  ULN should be permanently discontinued. Treatment of patients with hepatic impairment should be undertaken with caution (see sections 4.2 and 5.2).

Neurotoxicity
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical studies with trastuzumab emtansine. MBC patients with Grade  3 and EBC patients with Grade  2 peripheral neuropathy at baseline were excluded from clinical studies. Treatment with trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.


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Left ventricular dysfunction
Patients treated with trastuzumab emtansine are at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with trastuzumab emtansine, and therefore symptomatic congestive heart failure (CHF) is a potential risk (see section 4.8). General risk factors for a cardiac event and those identified in adjuvant breast cancer studies with trastuzumab therapy include advancing age (> 50 years), low baseline LVEF values (< 55%), low LVEF levels prior to or following the use of paclitaxel in the adjuvant setting, prior or concomitant use of antihypertensive medicinal products, previous therapy with an anthracycline and high BMI (> 25 kg/m2).

Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation of treatment and also at regular intervals (e.g. every three months) during treatment. The dosing should be delayed, or treatment discontinued as necessary in cases of left ventricular dysfunction (see section 4.2). In clinical studies, patients had a LVEF  50% at baseline. Patients with a history of congestive heart failure (CHF), serious cardiac arrhythmia requiring treatment, history of myocardial infarction or unstable angina within 6 months of randomization, or current dyspnoea at rest due to advanced malignancy were excluded from clinical studies. Events of LVEF drop of >10% from baseline and/or CHF were observed in an observational study (BO39807) of MBC patients with baseline LVEF of 40-49% in a real world setting. The decision to administer trastuzumab emtansine in MBC patients with low LVEF must be made only after careful benefit risk assessment and cardiac function should be closely monitored in these patients (see section 4.8).

Pulmonary toxicity
Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or a fatal outcome, have been reported in clinical studies with trastuzumab emtansine (see section 4.8). Signs and symptoms include dyspnoea, cough, fatigue, and pulmonary infiltrates.

It is recommended that treatment with trastuzumab emtansine be permanently discontinued in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where trastuzumab emtansine should be permanently discontinued for  Grade 3 or for Grade 2 not responding to standard treatment (see section 4.2).

Patients with dyspnoea at rest due to complications of advanced malignancy, co-morbidities, and receiving concurrent pulmonary radiation therapy may be at increased risk of pulmonary events.

Infusion-related reactions
Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR); treatment is not recommended for these patients.
Patients should be observed closely for infusion-related reactions, especially during the first infusion.

Infusion-related reactions (due to cytokine release), characterized by one or more of the following symptoms have been reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia. In general, these symptoms were not severe (see section 4.8). In most patients, these reactions resolved over the course of several hours to a day after the infusion was terminated. Treatment should be interrupted in patients with a severe IRR until signs and symptoms resolve. Consideration for re-treatment should be based on clinical assessment of the severity of the reaction. Treatment must be permanently discontinued in the event of a life threatening infusion- related reaction (see section 4.2).

Hypersensitivity reactions
Trastuzumab emtansine treatment has not been studied in patients who had trastuzumab permanently discontinued due to hypersensitivity; treatment with trastuzumab emtansine is not recommended for these patients.


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Patients should be observed closely for hypersensitivity/allergic reactions, which may have the same clinical presentation as an IRR. Serious, anaphylactic reactions have been observed in clinical studies with trastuzumab emtansine. Medicinal products to treat such reactions, as well as emergency equipment, should be available for immediate use. In the event of a true hypersensitivity reaction (in which severity of reaction increases with subsequent infusions), trastuzumab emtansine treatment must be permanently discontinued.

Injection-site reactions
Extravasation of trastuzumab emtansine during intravenous injection may produce local pain.
Exceptionally, cases of severe tissue lesions and epidermal necrosis may occur. If extravasation occurs, the infusion should be terminated immediately and the patient should be examined regularly as necrosis may occur within days to weeks after infusion.

Sodium content in excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

Effects on Driving

4.7     Effects on ability to drive and use machines

Trastuzumab emtansine has minor influence on the ability to drive and use machines.
The significance of reported adverse reactions such as fatigue, headache, dizziness and blurred vision on the ability to drive or use machines is unknown. Patients experiencing infusion-related reactions (flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia) should be advised not to drive and use machines until symptoms abate.