Kadcyla 100mg & 160mg powder for concentrate for solution for infusion

The Healthcare Professional Brochure was updated to include reference to Enhertu (trastuzumab deruxtecan), a non-Roche recently approved trastuzumab-containing medicine in the context of information on the potential for medication error due to a risk of confusion between different trastuzumab-containing medicines. 

KADCYLA, EMEA/H/C/002389/II/0048/G.

Grouped type II variation related to submission of final CSR for BO28408 (KRISTINE) study in accordance with PV activities listed in the EU RMP approved on 15 Nov 2013 (at the time of the MAA approval) [MEA 017] and the submission of the final CSR for BO39807 study in accordance with PV activities listed in RMP v7.0 (approved 28 Sep 2017) [MEA 019].

PI updates as requested by EMA as part of renewal application assessment to align with SmPC guidelines and QRD template and formatting updates throught the PI. Removal of black triangle.

16 March 2018

4.4     Special warnings and precautions for use

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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.

Thrombocytopenia

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

Cases of bleeding events with a fatal outcome have been observed. Severe cases of haemorrhagic events, including central nervous system haemorrhage, have been reported in clinical studies; these events were independent of ethnicity. In some of the observed cases the patients were also receiving anti-coagulation therapy.

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4.8     Undesirable effects

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Haemorrhage

The incidence of severe haemorrhagic events (Grade ≥3) occurred in 2.2% of the overall trastuzumab emtansine treated patients in clinical studies. 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.

Thrombocytopenia

Thrombocytopenia or decreased platelet counts were reported in 24.9% of patients in clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (2.6%). 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 treated with trastuzumab emtansine. The incidence of severe haemorrhagic events (Grade ≥3) occurred in 2.2% of the overall trastuzumab emtansine treated patients and 1.8% of Asian trastuzumab emtansine treated patients. In some of the observed cases the patients were also receiving anti-coagulation therapy. Cases of bleeding events with a fatal outcome have been observed. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4. 

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10.     DATE OF REVISION OF THE TEXT

11 May 2017

4.8     Undesirable effects

Summary of the safety profile

The safety of trastuzumab emtansine has been evaluated in 1871884 breast cancer patients in clinical studies. In this patient population:

·    the most common serious ADRs (> 0.5% of patients) were haemorrhage, pyrexia, dyspnoea, musculoskeletal pain, thrombocytopenia, abdominal pain and vomiting., abdominal pain, nausea, constipation, diarrhoea, dyspnoea and pneumonitis.

·    the most common adverse drug reactions (ADRs) (≥25%) with trastuzumab emtansine were nausea, haemorrhage (including epistaxis), increased transaminases, fatigue, musculoskeletal pain, and headache. 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 or 4 ADRs (> 2%) were thrombocytopenia, fatigue, increased transaminases, anaemia, neutropenia, fatigue, hypokalaemia, musculoskeletal pain and haemorrhage,neutropenia.

Tabulated list of adverse reactions

The ADRs in 1871884 patients treated with trastuzumab emtansine are presented in Table 6.  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 6            Tabulated list of ADRs in patients treated with trastuzumab emtansine

Description of selected adverse reactions

The selected adverse reaction in 882 patients treated with trastuzumab emtansine is presented below.

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 2824.2% of patients in clinical studies. Grade 3 or 4 increased AST and ALT were reported in 4.14.2% and 2.82.7% of patients respectively and usually occurred in the early treatment cycles (1‑6). 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 (C_max), total trastuzumab exposure (AUC), or C_max 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

Left ventricular dysfunction was reported in 2.02.2% of patients in 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 0.30.4% of patients. These uncommon Grade 3 or 4 events usually occurred in the early treatment cycles (1‑2). Additional LVEF monitoring is recommended for patients with LVEF ≤ 45% (See Table 5 in section 4.2 for specific dose modifications).

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 4.54.0% of patients in clinical studies with trastuzumab emtansine, with one six Grade 3 and no Grade 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 reactions

Hypersensitivity was reported in 2.6% of patients in clinical studies with trastuzumab emtansine, with no one Grade 3 or and one Grade  4 events reported. 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.

Thrombocytopenia

Thrombocytopenia or decreased platelet counts were reported in 31.424.9% of patients in clinical studies with trastuzumab emtansine and was the most common adverse reaction leading to treatment discontinuation (1.42.6%). 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 11.38.7% in patients treated with trastuzumab emtansine. The incidence of severe haemorrhagic events (Grade ≥3) occurred in 1.72.2% of the overall trastuzumab emtansine treated patients and 11.8% of Asian trastuzumab emtansine treated patients. In some of the observed cases the patients were also receiving anti-coagulation therapy. Cases of bleeding events with a fatal outcome have been observed. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4. 

Immunogenicity

As with all therapeutic proteins, there is the potential for an immune response to trastuzumab emtansine. A total of 836 patients from six clinical studies were tested at multiple time points for anti‑therapeutic antibody (ATA) responses to trastuzumab emtansine. Following dosing, 5.3% (44/836) of patients tested positive for anti‑trastuzumab emtansine antibodies at one or more post‑dose time points. The clinical significance of anti-trastuzumab emtansine antibodies is not yet known.

Extravasation

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.

Laboratory abnormalities

Table 7 displays laboratory abnormalities observed in patients treated with trastuzumab emtansine in clinical study TDM4370g/BO21977.

Table 7    Laboratory abnormalities observed in patients treated with trastuzumab emtansine in study TDM4370g/BO21977

Reporting of suspected adverse reactions

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 (see details below).

Ireland

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5.1     Pharmacodynamic properties

In the descriptive follow-up overall survival analysis, the hazard ratio was 0.75 (95% CI 0.64, 0.88). The median duration of overall survival was 29.9 months in the trastuzumab emtansine arm compared with 25.9 months in the lapatinib plus capecitabine arm. At the time of the descriptive follow-up overall survival analysis, a total of 27.4% of the patients had crossed over from the lapatinib plus capecitabine arm to the trastuzumab emtansine arm. In a sensitivity analysis censoring patients at the time of cross-over, the hazard ratio was 0.69 (95% CI 0.59, 0.82). The results of this descriptive follow-up analysis are consistent with the confirmatory OS analysis.

6.3     Shelf life

3 years.

Shelf-life of the reconstituted solution

Chemical and physical in‑use stability of the reconstituted solution has been demonstrated for up to 24 hours at 2°C to 8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the reconstituted vials can be stored for up to 24 hours at 2°C to 8°C, provided it was reconstituted under controlled and validated aseptic conditions, and must be discarded thereafter.

Shelf-life of the diluted solution

The reconstituted Kadcyla solution diluted in infusion bags containing sodium chloride 9 mg/ml (0.9%) solution for infusion, or sodium chloride 4.5 mg/ml (0.45%) solution for infusion, is stable for up to 24 hours at 2°C to 8°C, provided it was prepared under controlled and validated aseptic conditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride (see section 6.6).

4.2     Posology and method of administration

Patients with Rrenal impairment

No adjustment to the starting dose is needed in patients with mild or moderate renal impairment (see section 5.2). The potential need for dose adjustment in patients with severe renal impairment cannot be determined due to insufficient data and therefore patients with severe renal impairment should be monitored carefully.

Patients with Hhepatic impairment

The safety and efficacy have not been studied in patients with hepatic impairment. No specific dose recommendations can be made (see section 4.4).

No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment.  Trastuzumab emtansine was not studied in patients with severe hepatic impairment.  Treatment of patients with hepatic impairment should be undertaken with caution due to known hepatotoxicity observed with trastuzumab emtansine (see section 4.4 and 5.2).

Paediatric population

The safety and efficacy in children and adolescents below 18 years of age have not been established as there is no relevant use in the paediatric population in for the indication of metastatic breast cancer (MBC). 

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.

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).

5.2       Pharmacokinetic properties

Patients with hHepatic impairment

No formal PK study has been conducted in patients with hepatic impairment.

The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtansine and DM1-containing catabolites were evaluated after the administration of 3.6 mg/kg of trastuzumab emtansine to metastatic HER2+ breast cancer patients with normal hepatic function (n=10), mild (Child-Pugh A; n=10) and moderate (Child-Pugh B; n=8) hepatic impairment.

-           Plasma concentrations of DM1 and DM1-containing catabolites (Lys-MCC-DM1 and MCC-DM1) were low and comparable between patients with and without hepatic impairment.

-           Systemic exposures (AUC) of trastuzumab emtansine at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively. Trastuzumab emtansine exposure (AUC) at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function. 

Trastuzumab emtansine has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

10.     DATE OF REVISION OF THE TEXT

22 January 2016

6.3     Shelf life

Shelf-life of the diluted solution

The reconstituted Kadcyla solution diluted in infusion bags containing sodium chloride 9 mg/ml (0.9%) solution for infusion, or sodium chloride 4.5 mg/ml (0.45%) solution for infusion, is stable for up to 24 hours at 2°C to 8°C, provided it was prepared under controlled and validated aseptic conditions. Particulates may be observed on storage if diluted in 0.9% sodium chloride (see section 6.6).

6.6     Special precautions for disposal and other handling

The reconstituted Kadcyla solution should be diluted in polyvinyl chloride (PVC) or latex‑free PVC‑free polyolefin infusion bags.

The use of 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion when the concentrate for infusion is diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion.

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of sodium chloride 4.5 mg/ml (0.45%) solution for infusion or sodium chloride 9 mg/ml (0.9%) solution for infusion. Glucose (5%) solution should not be used (see section 6.2). Sodium chloride 4.5 mg/ml (0.45%) solution for infusion may be used without a polyethersulfone (PES) 0.20 or 0.22‑μm in‑line filter. If sodium chloride 9 mg/ml (0.9%) solution for infusion is used for infusion, a 0.20 or 0.22 micron in-line polyethersulfone (PES) filter is required. Once the infusion is prepared it should be administered immediately. Do not freeze or shake the infusion during storage.

10.     DATE OF REVISION OF THE TEXT

4.6     Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential should use effective contraception while receiving trastuzumab emtansine and for 67 months following the last dose of trastuzumab emtansine. Male patients or their female partners should also use effective contraception.

Pregnancy

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.

Breast‑feeding

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 67 months after concluding treatment.

Fertility

No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.

4.6     Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential should use effective contraception while receiving trastuzumab emtansine and for 67 months following the last dose of trastuzumab emtansine. Male patients or their female partners should also use effective contraception.

Pregnancy

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.

Breast‑feeding

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 67 months after concluding treatment.

Fertility

No reproductive and developmental toxicology studies have been conducted with trastuzumab emtansine.

10.     DATE OF REVISION OF THE TEXT

23 October 2014