Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Kadcyla

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HOS-125639 · Präparat HOS-096111

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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Wechselwirkungen · Kadcyla

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HOS-125640 · Präparat HOS-096111

No formal interaction studies have been performed.

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Wechselwirkungen · Kadcyla

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HOS-125641 · Präparat HOS-096111

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 co-administered and trastuzumab emtansine treatment cannot be delayed, patients should be closely monitored for adverse reactions.

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RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): indinavir (HOS-084518) nefazodone (HOS-084519) atazanavir (HOS-086180) nelfinavir (HOS-084520) ketoconazole (HOS-084513) voriconazole (HOS-084524) telithromycin (HOS-084523) itraconazole (HOS-084516) saquinavir (HOS-084522) clarithromycin (HOS-084517) ritonavir (HOS-084521)

Nebenwirkungen · Kadcyla

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HOS-125642 · Präparat HOS-096111

Summary of the safety profile

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Nebenwirkungen · Kadcyla

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HOS-125643 · Präparat HOS-096111

The safety of trastuzumab emtansine has been evaluated in 2 611 breast cancer patients in clinical studies. In this patient population:

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Nebenwirkungen · Kadcyla

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HOS-125644 · Präparat HOS-096111

 the most common serious adverse drug reactions (ADRs) (> 0.5% of patients) were haemorrhage, pyrexia, thrombocytopenia, dyspnoea, abdominal pain, musculoskeletal pain, and vomiting.  the most common ADRs (≥ 25%) with trastuzumab emtansine were nausea, fatigue, musculoskeletal pain, haemorrhage, headache, transaminases increased, thrombocytopenia, and peripheral neuropathy. The majority of ADRs reported were of Grade 1 or 2 severity.  the most common National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≥ 3 ADRs (> 2%) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue and hypokalaemia.

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Nebenwirkungen · Kadcyla

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HOS-125645 · Präparat HOS-096111

Tabulated list of adverse reactions

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Nebenwirkungen · Kadcyla

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HOS-125646 · Präparat HOS-096111

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.

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Nebenwirkungen · Kadcyla

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HOS-125647 · Präparat HOS-096111

11 Table 3 Tabulated list of ADRs in patients treated with trastuzumab emtansine in clinical studies System Organ Class Frequency Adverse reactions Infections and infestations Very common Urinary tract infection Blood and lymphatic system Very common Thrombocytopenia, Anaemia disorders Common Neutropenia, Leukopenia Immune system disorders Common Drug hypersensitivity Metabolism and nutrition Common Hypokalaemia disorders Psychiatric disorders Very common Insomnia Nervous system disorders Very common Neuropathy peripheral, Headache Common Dizziness, Dysgeusia, Memory impairment Eye disorders Common Dry eye, Conjunctivitis, Vision blurred, Lacrimation increased Cardiac disorders Common Left ventricular dysfunction Vascular disorders Very common Haemorrhage Common Hypertension Respiratory, thoracic and Very common Epistaxis, Cough, Dyspnoea mediastinal disorders Uncommon Pneumonitis (ILD)

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Nebenwirkungen · Kadcyla

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HOS-125648 · Präparat HOS-096111

Gastrointestinal disorders Very common Stomatitis, Diarrhoea, Vomiting, Nausea, Constipation, Dry mouth, Abdominal pain Common Dyspepsia, Gingival bleeding Hepatobiliary disorders Very common Transaminases increased Common Blood alkaline phosphatase increased, Blood bilirubin increased Uncommon Hepatotoxicity, Nodular regenerative hyperplasia, Portal hypertension Rare Hepatic failure Skin and subcutaneous tissue Common Rash, Pruritus, Alopecia, Nail disorders disorder, Palmar-plantar erythrodysaesthesia syndrome, Urticaria Musculoskeletal and Very common Musculoskeletal pain, connective tissue disorders Arthralgia, Myalgia General disorders and Very common Fatigue, Pyrexia, Asthenia administration site conditions Common Peripheral oedema, Chills Uncommon Injection site extravasation Injury, poisoning and Common Infusion related reactions procedural complications Uncommon Radiation pneumonitis

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Nebenwirkungen · Kadcyla

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HOS-125649 · Präparat HOS-096111

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).

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Nebenwirkungen · Kadcyla

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HOS-125650 · Präparat HOS-096111

12 Description of selected adverse reactions

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Nebenwirkungen · Kadcyla

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HOS-125651 · Präparat HOS-096111

Thrombocytopenia 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 28.6% 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.

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Nebenwirkungen · Kadcyla

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HOS-125652 · Präparat HOS-096111

Haemorrhage Haemorrhagic events were reported in 34.8% of patients in MBC clinical studies with trastuzumab emtansine and the incidence of severe haemorrhagic events (Grade ≥ 3) occurred in 2.2%. Haemorrhagic events were reported in 29.2% 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.

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Nebenwirkungen · Kadcyla

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HOS-125653 · Präparat HOS-096111

Transaminases increased (AST/ALT) 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 32.6% of patients with EBC. Grade 3 and 4 increased transaminases were reported in 1.6% 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.

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Nebenwirkungen · Kadcyla

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HOS-125654 · Präparat HOS-096111

Left ventricular dysfunction 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 in 0.5% of patients, and no events of higher grade. For dose modifications in the event of LVEF decrease, see Table 2 in section 4.2 and section 4.4.

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Nebenwirkungen · Kadcyla

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HOS-125655 · Präparat HOS-096111

Peripheral neuropathy Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical studies 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 32.0% and 10.1% for Grade ≥ 2.

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Nebenwirkungen · Kadcyla

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HOS-125656 · Präparat HOS-096111

13 Infusion-related reactions 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.

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Nebenwirkungen · Kadcyla

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HOS-125657 · Präparat HOS-096111

Hypersensitivity reactions 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 in 0.4% of patients and no events of higher grade. 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.

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Nebenwirkungen · Kadcyla

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HOS-125658 · Präparat HOS-096111

Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. A total of 1 243 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% (64/1 243) 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 neutralising antibodies. In the KATHERINE (BO27938) study, 4.0% (16/401) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 were also positive for neutralizing antibodies. Due to the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of trastuzumab emtansine is unknown.

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