Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 Herceptin (trastuzumab).
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 greater (<50,000/mm³), do not administer trastuzumab emtansine until platelet counts recover to Grade 1 (≥75,000/mm³) (see section 4.2).
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, 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 x ULN or total bilirubin >1.5 x ULN prior to initiation of treatment. Treatment in patients with serum transaminases >3 x ULN and concomitant total bilirubin >2 x ULN should be permanently discontinued. Treatment of patients with hepatic impairment should be undertaken with caution (see sections 4.2 and 5.2).
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.
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).
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 ³ 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.
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 infusionrelated reaction (see section 4.2).
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.
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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodiumfree’.
No formal interaction studies have been performed.
In vitro metabolism studies in human liver microsomes suggest that DM1, a component of trastuzumab emtansine, is metabolised mainly by CYP3A4 and, to a lesser extent, by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with trastuzumab emtansine should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medicinal product with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying trastuzumab emtansine treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and trastuzumab emtansine treatment cannot be delayed, patients should be closely monitored for adverse reactions.
Women of childbearing potential should use effective contraception while receiving trastuzumab emtansine and for 7 months following the last dose of trastuzumab emtansine. Male patients or their female partners should also use effective contraception.
There are no data from the use of trastuzumab emtansine in pregnant women. Trastuzumab, a component of trastuzumab emtansine, can cause foetal harm or death when administered to a pregnant woman. In the post-marketing setting, cases of oligohydramnios, some associated with fatal pulmonary hypoplasia, have been reported in pregnant women receiving trastuzumab. Animal studies of maytansine, a closely related chemical entity of the same maytansinoid class as DM1, suggest that DM1, the microtubule inhibiting cytotoxic component of trastuzumab emtansine, is expected to be teratogenic and potentially embryotoxic (see section 5.3).
Administration of trastuzumab emtansine to pregnant women is not recommended and women should be informed of the possibility of harm to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor. If a pregnant woman is treated with trastuzumab emtansine, close monitoring by a multidisciplinary team is recommended.
It is not known whether trastuzumab emtansine is excreted in human milk. Since many medicinal products are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants, women should discontinue breast-feeding prior to initiating treatment with trastuzumab emtansine. Women may begin breast-feeding 7 months after concluding treatment.
No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.
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.
The safety of trastuzumab emtansine has been evaluated in 2,611 breast cancer patients in clinical studies. In this patient population:
The ADRs in 2,611 patients treated with trastuzumab emtansine are presented in Table 3. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness. ADRs were reported using NCI-CTCAE for assessment of toxicity.
Table 3. Tabulated list of ADRs in patients treated with trastuzumab emtansine in clinical trials:
Very Common: Urinary tract infection
Very Common: Thrombocytopenia, Anaemia
Common: Neutropenia, Leucopoenia
Common: Drug hypersensitivity
Common: Hypokalaemia
Very Common: Insomnia
Very Common: Neuropathy peripheral, Headache
Common: Dizziness, Dysgeusia, Memory impairment
Common: Dry eye, Conjunctivitis, Vision blurred, Lacrimation increased
Common: Left ventricular dysfunction
Very Common: Haemorrhage
Common: Hypertension
Very Common: Epistaxis, Cough, Dyspnoea
Uncommon: Pneumonitis (ILD)
Very Common: Stomatitis, Diarrhoea, Vomiting, Nausea, Constipation, Dry mouth, Abdominal pain
Common: Dyspepsia, Gingival bleeding
Very Common: Transaminases increased
Common: Blood alkaline phosphatase increased, blood bilirubin increased
Uncommon: Hepatotoxicity, Hepatic failure, Nodular regenerative hyperplasia, Portal hypertension
Common: Rash, Pruritus, Alopecia, Nail disorder, Palmarplantar erythrodysaesthesia syndrome, Urticaria
Very Common: Musculoskeletal pain, Arthralgia, Myalgia
Very Common: Fatigue, Pyrexia, Asthenia
Common: Peripheral oedema, Chills
Uncommon: Injection site extravasation
Common: Infusion-related reactions
Uncommon: Radiation pneumonitis
Table 3 shows pooled data from the overall treatment period in the MBC studies (N= 1871; median number of cycles of trastuzumab emtansine was 10) and in KATHERINE (N=740; median number of cycles was 14).
Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in MBC clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (2.6%). Thrombocytopenia was reported in 28.5% of patients in EBC clinical studies with trastuzumab emtansine and was the most common reported adverse reaction for all grades and grades ≥3, as well as the most common adverse reaction leading to treatment discontinuation (4.2%), dose interruptions, and dose reductions. The majority of the patients had Grade 1 or 2 events (≥50,000/mm³), with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (≥75,000/mm³) by the next scheduled dose. In clinical studies, the incidence and severity of thrombocytopenia were higher in Asian patients. Independent of race, the incidence of Grade 3 or 4 events (<50,000/mm³) was 8.7% in patients with MBC treated with trastuzumab emtansine and 5.7% in patients with EBC. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4.
Haemorrhagic events were reported in 34.8% of patients in MBC clinical trials with trastuzumab emtansine and the incidence of severe haemorrhagic events (Grade ≥3) occurred in 2.2%. Haemorrhagic events were reported in 29% of patients with EBC and the incidence of severe haemorrhagic events (Grade ≥3) was 0.4%, including one Grade 5 event. 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. Cases of bleeding events with a fatal outcome have been observed in both MBC and EBC.
Increase in serum transaminases (Grade 1-4) has been observed during treatment with trastuzumab emtansine in clinical studies (see section 4.4). Transaminase elevations were generally transient. A cumulative effect of trastuzumab emtansine on transaminases has been observed, and generally recovered when treatment was discontinued. Increased transaminases were reported in 24.2% of patients in MBC clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.2% and 2.7% of patients with MBC respectively and usually occurred in the early treatment cycles (1-6). Increased transaminases were reported in 32.4% of patients with EBC. Grade 3 and 4 increased transaminases were reported in 1.5% of patients with EBC. In general, the Grade ≥3 hepatic events were not associated with poor clinical outcome; subsequent follow-up values tended to show improvement to ranges allowing the patient to remain on study and continue to receive study treatment at the same or reduced dose. No relationship was observed between trastuzumab emtansine exposure (AUC), trastuzumab emtansine maximum serum concentration (Cmax), total trastuzumab exposure (AUC), or Cmax of DM1 and increases in transaminase. For dose modifications in the event of increased transaminases, see sections 4.2 and 4.4.
Left ventricular dysfunction was reported in 2.2% of patients in MBC clinical studies with trastuzumab emtansine. The majority of events were asymptomatic Grade 1 or 2 decrease in LVEF. Grade 3 or 4 events were reported in 0.4% of patients with MBC. In an observational study (BO39807), approximately 22% (7 out of 32) of MBC patients initiating trastuzumab emtansine with LVEF of 40-49% at baseline, experienced a LVEF drop of >10% from baseline and/or CHF; most of these patients had other cardiovascular risk factors. Left ventricular dysfunction occurred in 3.0% of patients with EBC, with Grade 3 or 4 in 0.5% of patients. For dose modifications in the event of LVEF decrease, see Table 2 in section 4.2 and section 4.4.
Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of trastuzumab emtansine. In patients with MBC, the overall incidence of peripheral neuropathy was 29.0% and 8.6% for Grade ≥2. In patients with EBC, the overall incidence was 32.3% and 10.3% for Grade ≥2.
Infusion-related reactions are characterised by one or more of the following symptoms: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia. Infusion-related reactions were reported in 4.0% of patients in MBC clinical studies with trastuzumab emtansine, with six Grade 3 and no Grade 4 events reported. Infusion-related reactions were reported in 1.6% of patients with EBC, with no Grade 3 or 4 events reported. Infusion-related reactions resolved over the course of several hours to a day after the infusion was terminated. No dose relationship was observed in clinical studies. For dose modifications in the event of infusion-related reactions, see sections 4.2 and 4.4.
Hypersensitivity was reported in 2.6% of patients in MBC clinical studies with trastuzumab emtansine, with one Grade 3 and one Grade 4 events reported. Hypersensitivity was reported in 2.7% of patients with EBC, with Grade 3 or 4 in 0.4% of patients. Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolved upon treatment. For dose modifications in the event of hypersensitivity reactions, see sections 4.2 and 4.4.
As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. A total of 1243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to trastuzumab emtansine. Following trastuzumab emtansine dosing, 5.1% (63/1243) of patients tested positive for anti-trastuzumab emtansine antibodies at one or more post-dose time points. In the Phase I and Phase II studies, 6.4% (24/376) of patients tested positive for anti-trastuzumab emtansine antibodies. In the EMILIA study (TDM4370g/BO21977), 5.2% (24/466) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 13 were also positive for neutralizing antibodies. In the KATHERINE (BO27938) study, 3.7% (15/401) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive for neutralizing antibodies. Due to the low incidence of ADA, conclusions cannot be made on the impact of anti-trastuzumab emtansine antibodies on the pharmacokinetics, safety, and efficacy of trastuzumab emtansine.
Reactions secondary to extravasation have been observed in clinical studies with trastuzumab emtansine. These reactions were usually mild or moderate and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. These reactions have been observed more frequently within 24 hours of infusion. Specific treatment for trastuzumab emtansine extravasation is unknown at this time.
Tables 4 and 5 displays laboratory abnormalities observed in patients treated with trastuzumab emtansine in clinical study TDM4370g/BO21977/EMILIA and study BO27938/KATHERINE.
Table 4. Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study TDM4370g/BO21977/EMILIA:
| Trastuzumab emtansine (Ν=490) | |||
|---|---|---|---|
| Parameter | All Grades (%) | Grade 3 (%) | Grade 4 (%) |
| Hepatic | |||
| Increased bilirubin | 21 | <1 | 0 |
| Increased AST | 98 | 8 | <1 |
| Increased ALT | 82 | 5 | <1 |
| Haematologic | |||
| Decreased platelet count | 85 | 14 | 3 |
| Decreased haemoglobin | 63 | 5 | 1 |
| Decreased neutrophils | 41 | 4 | <1 |
| Potassium | |||
| Decreased potassium | 35 | 3 | <1 |
Table 5. Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study BO27938/KATHERINE:
| Trastuzumab emtansine (Ν=740) | |||
|---|---|---|---|
| Parameter | All Grades (%) | Grade 3 (%) | Grade 4 (%) |
| Hepatic | |||
| Increased bilirubin | 11 | 0 | 0 |
| Increased AST | 79 | <1 | 0 |
| Increased ALT | 55 | <1 | 0 |
| Haematologic | |||
| Decreased platelet count | 51 | 4 | 2 |
| Decreased haemoglobin | 31 | 1 | 0 |
| Decreased neutrophils | 24 | 1 | 0 |
| Potassium | |||
| Decreased potassium | 26 | 2 | <1 |
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed or diluted with other medicinal products except those mentioned in section 6.6.
Glucose (5%) solution should not be used for reconstitution or dilution since it causes aggregation of the protein.
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