Kadcyla 160 Mg Solution

Breast cancer:

Early Breast Cancer (EBC)

Kadcyla is indicated for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease, after pre-operative systemic treatment.

Metastatic Breast Cancer (MBC)

Kadcyla is indicated as monotherapy for the treatment of patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who have received prior treatment with trastuzumab and a taxane.

In order to prevent medication errors it is important to check the vial labels to ensure that the medicine being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab. Kadcyla therapy should only be administered as an intravenous infusion under the supervision of a healthcare professional experienced in the treatment of cancer patients (prepared to manage allergic/anaphylactic infusion reactions and in an environment where full resuscitation facilities are immediately available (see section 4.4). Patients treated with Kadcyla should have HER2 positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) or a ratio of u2265 2,0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a validated test.

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. Substitution by any other biological medicinal product requires the consent of the prescribing medical practitioner. Kadcyla must be reconstituted and diluted by a healthcare professional and administrated as an intravenous infusion (see section 6.6). Do not administer as an intravenous push or bolus.

Posology

The recommended dose of Kadcyla is 3,6 mg/kg given as an intravenous infusion every 3 weeks (21-day cycle) Administer the initial dose as a 90 minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial dose for fever, chills, or other infusion-related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during administration (see section 4.8). If prior infusions were well tolerated, subsequent doses of Kadcyla may be administered as 30 minute infusions and patients should be observed during the infusions and for at least 30 minutes after infusion. The infusion rate of Kadcyla should be slowed or interrupted if the patient develops infusion-related symptoms (see sections 4.4 and 4.8). Discontinue Kadcyla for life-threatening infusion reactions.

Duration of treatment:

Early breast cancer (EBC) Patients with EBC should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.

Metastatic breast cancer (MBC) Patients with MBC should receive treatment until disease progression or unmanageable toxicity.

Dose modification Management of symptomatic adverse events may require temporary interruption, dose reduction, or treatment discontinuation of Kadcyla as per guidelines provided in Tables 1 and 2. Kadcyla dose should not be re-escalated after a dose reduction is made.

Table 1 Dose Reduction Schedule

Dose reduction Schedule

Dose Level Starting Dose 3,6 mg/kg First dose reduction 3 mg/kg Second dose reduction 2,4 mg/kg Requirement for further dose reduction Discontinue treatment

Table 2 Dose Modification Guidelines Dose modifications for patients with EBC

Adverse reaction Severity Treatment modification Thrombocytopenia Grade 2-3 on day of scheduled treatment (25,000 to < 75,000/mm3) Do not administer Kadcyla until platelet count recovers to u2264 Grade 1 (u2265 75,000/mm3), and then treat at the same dose level. If a patient requires 2 delays due to thrombocytopenia, consider reducing dose by one level. Grade 4 at any time 3,0 to u2264 20 u00b4 ULN on day of scheduled treatment) Do not administer Kadcyla until ALT recovers to Grade u2264 1, and then reduce one dose level Grade 4 (> 20 u00b4 ULN at any time) Discontinue Kadcyla Increased Aspartate Transaminase ((AST) Grade 2 (> 3,0 to u2264 5 u00b4 ULN on day of scheduled treatment) Do not administer Kadcyla until AST recovers to Grade u2264 1, and then treat at the same dose level Grade 3 (> 5 to u2264 20 u00b4 ULN on day of scheduled treatment) Do not administer Kadcyla until AST recovers to Grade u2264 1, and then reduce one dose level Grade 4 (> 20 u00b4 ULN at any time) Discontinue Kadcyla Hyperbilirubinaemia TBILI > 1.0 to u2264 2.0 u00b4 the ULN on day of scheduled treatment Do not administer Kadcyla until total bilirubin recovers to u2264 1.0 u00b4 ULN, and then reduce one dose level TBILI > 2 u00b4 ULN at any time Discontinue Kadcyla Drug Induced Liver Injury (DILI) Serum transaminases >3 u00b4 ULN and Permanently discontinue Kadcyla in the absence of concomitant total bilirubin >2 u00b4 ULN another likely cause for the elevation of liver enzymes and bilirubin, e.g. liver metastasis or concomitant medication Nodular Regenerative Hyperplasia (NRH) All Grades Permanently discontinue Kadcyla Peripheral Neuropathy Grade 3-4 Do not administer Kadcyla until resolution u2264 Grade 2 Left Ventricular Dysfunction LVEF < 45% Do not administer Kadcyla Repeat LVEF assessment within 3 weeks. If LVEF < 45 % is confirmed, discontinue Kadcyla. LVEF 45 % to < 50 % and decrease is u2265 10 % points from baseline* Do not administer Kadcyla Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50 % and has not recovered to < 10 % points from baseline, discontinue Kadcyla. LVEF 45 % to < 50 % and decrease is < 10 % points from baseline* Continue treatment with Kadcyla. Repeat LVEF assessment within 3 weeks. LVEF u2265 50 % Continue treatment with Kadcyla.

Kadcyla is contraindicated in patients with a known hypersensitivity to trastuzumab emtansine or any of the excipients of Kadcyla (see section 6.1). Pregnancy and Lactation (see section 4.6).

General Patients treated with Kadcyla must have confirmed HER2-positive tumour status as assessed by either HER2 protein over-expression or gene amplification.

Immunogenicity A total of 1 243 patients from seven clinical studies were tested at multiple time points for anti-drug antibody (ADA) responses to Kadcyla. Following Kadcyla dosing, 5,1 % (63/1 243) 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 MBC study, 5,2 % (24/466) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 13 were also positive for neutralising antibodies. In the EBC study, 3,7 % (15/401) of patients tested positive for anti-trastuzumab emtansine antibodies, of which 5 of were also positive for neutralising 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 Kadcyla.

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 Kadcyla (see section 4.8). Signs and symptoms include dyspnoea, cough, fatigue, and pulmonary infiltrates. It is recommended that treatment with Kadcyla be permanently discontinued in patients who are diagnosed with ILD or pneumonitis, except for radiation pneumonitis in the adjuvant setting, where Kadcyla should be permanently discontinued for u2265 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.

Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic increases in the concentrations of serum transaminases (Grade 1-4 transaminitis), has been observed while on treatment with Kadcyla in clinical trials (see section 4.8). Transaminase elevations were generally transient with peak elevation at day 8 after therapy and subsequent recovery to Grade 1 or less prior to the next cycle. A cumulative effect of Kadcyla 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 Kadcyla in the majority of the cases. 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 Kadcyla. Observed cases have been confounded by comorbidities and/or concomitant medicines with known hepatotoxic potential. Liver function should be monitored prior to initiation of treatment and each Kadcyla dose. Patients with baseline elevation of ALT (e.g. due to liver metastasis) 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. Kadcyla 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. Kadcyla treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN should be permanently discontinued. Cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies in patients treated with Kadcyla. NRH is a 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, Kadcyla treatment must be permanently discontinued. Treatment of patients with hepatic impairment should be undertaken with caution (see sections 4.2 and 5.2).

Left Ventricular Dysfunction Patients treated with Kadcyla are at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) < 40 % has been observed commonly in patients treated with Kadcyla, and therefore symptomatic congestive heart failure (CHF) is a potential risk. Standard cardiac function testing (echocardiogram or multigated acquisition (MUGA) scanning) should be performed prior to initiation and at regular intervals (e.g. every three months) during treatment with Kadcyla. Events of LVEF drop of u02c310% from baseline and/or CHF were observed in approximately 22% of patients with MBC in an observational study (BO39807) with baseline LVEF of 40-49% in a real world setting. Most of these patients had other cardiovascular risk factors. The decision to administer Kadcyla in patients with MBC with low LVEF must be made only after careful benefit risk assessment and cardiac function should be closely monitored in these patients. The dose should be delayed or treatment discontinued as necessary in cases of left ventricular dysfunction (see section 4.2).

Infusion-Related Reactions (IRR) Treatment with Kadcyla has not been studied in patients who had trastuzumab permanently discontinued due to IRR; treatment with Kadcyla is not recommended for these patients. Patients should be observed carefully for infusion-related reactions, especially during the first infusion. IRR, characterised by one or more of the following symptoms - flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm and tachycardia have been reported. These reactions resolved over the course of several hours to a day after the infusion was terminated. Kadcyla treatment should be interrupted in patients with severe IRR until signs and symptoms resolve. Consideration for re-treatment should be based on clinical assessment of the severity of the reaction. Kadcyla treatment must be permanently discontinued in the event of a life threatening IRR (see section 4.2).

Hypersensitivity Reactions Patients should be observed closely for hypersensitivity/allergic reactions, Serious anaphylactic reactions, have been observed in clinical trials with Kadcyla. Medicines 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 the severity of the reaction increases with subsequent infusions), Kadcyla treatment must be permanently discontinued.

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

Thrombocytopenia Thrombocytopenia, or decreased platelet counts, was commonly reported with Kadcyla and was the most common adverse reaction leading to treatment discontinuation, dose reduction, and dose interruption (see section 4.8). In clinical trials, the incidence and severity of thrombocytopenia were higher in Asian patients. Patients with thrombocytopenia (< 100 000/mm3) and patients on anti-coagulant treatment should be monitored closely while on Kadcyla treatment. It is recommended that platelet counts are monitored prior to each Kadcyla dose. Rare cases of severe and prolonged thrombocytopenia (u2265 Grade 3 thrombocytopenia lasting for more than 90 days) have been reported with Kadcyla. In most of these cases, patients received concomitant recombinant human thrombopoietin (rhTPO). Kadcyla 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 Kadcyla until platelet counts recover to Grade 1 (u2265 75 000/mm3) (see section 4.2).

Neurotoxicity Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in clinical trials of Kadcyla. Treatment with Kadcyla should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until symptoms resolve or improve to u2264 Grade 2. Patients should be clinically monitored on an ongoing basis for signs/symptoms of neurotoxicity.

Extravasation In Kadcyla clinical studies, reactions secondary to extravasation have been observed. 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 Kadcyla extravasation is unknown at this time. The infusion site should be closely monitored for possible subcutaneous infiltration during administration.

Sucrose Kadcyla contains sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus. Contains sucrose: Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Kadcyla.

Sodium content in excipients Kadcyla contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially u201csodium freeu201d.

No formal medicine interaction studies with Kadcyla in humans have been conducted. In vitro metabolism studies in human liver microsomes suggest that DM1, a component of Kadcyla, 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, nefazadone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) with Kadcyla should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medicine with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying Kadcyla 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 inhhibitor is coadministered and Kadcyla treatment cannot be delayed, patients should be closely monitored for adverse reactions.

Safety and efficacy has not been established. Contraception: Women of childbearing potential should use effective contraception during treatment with Kadcyla and for at least 7 months following the last dose of Kadcyla. Male patients of their female partners should also receive effective contraception.

Pregnancy Kadcyla is contraindicated in pregnancy and lactation (see section 4.3). There are no data from the use of Kadcyla in pregnant women. Trastuzumab, a component of Kadcyla, 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 drug component of Kadcyla, is expected to be teratogenic and potentially embryotoxic.

Administration of Kadcyla to pregnant women is not recommended. Women who become pregnant must contact their doctor and should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Kadcyla, close monitoring by a multidisciplinary team is recommended.

Breastfeeding It is not known whether Kadcyla is excreted in human milk. Women should discontinue breastfeeding prior to initiating treatment with Kadcyla. Women may begin breastfeeding 7 months following the last dose of Kadcyla.

Fertility No reproductive and developmental toxicology studies have been conducted with Kadcyla.

Kadcyla can cause adverse reactions such as fatigue, headache, dizziness and blurred vision which may impair the ability to drive or use machines. Patients experiencing infusion-related reactions (flushing, shivering fits, fever, trouble breathing, low blood pressure or a rapid heart-beat) should be advised not to drive and use machines until symptoms abate.

a. Summary of the safety profile The safety of Kadcyla has been evaluated in 2 611 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.
• the most common adverse drug reactions (ADRs) (u2265 25 %) with Kadcyla were nausea, fatigue, headache, musculoskeletal pain, peripheral neuropathy, thrombocytopenia, haemorrhage and increased transaminases. 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 u2265 3 ADRs (> 2 %) were thrombocytopenia, increased transaminases, anaemia, neutropenia, fatigue, hypokalaemia, musculoskeletal pain and haemorrhage.

a) Tabulated list of adverse reactions The ADRs in 2 611 patients treated with Kadcyla are presented in Table 3. The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency. In this section, the following categories of frequency have been used: very common (u00b3 1/10), common (u00b3 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 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 Summary of ADRu2019s in patients treated with Kadcyla in clinical trials System Organ Class Very Common Common Uncommon Infections and infestations Urinary tract infection Blood and lymphatic system disorders Thrombocytopenia Anaemia Neutropenia Leucopenia Immune system disorders Drug hypersensitivity Metabolism and nutrition disorders Hypokalaemia Psychiatric disorders Insomnia Nervous system disorders Peripheral neuropathy, Headache Dizziness, Dysgeusia, Memory impairment Eye disorders Dry eye, Conjunctivitis, Blurred vision, Increased lacrimation Cardiac disorders Left ventricular dysfunction Vascular disorders Haemorrhage Hypertension Respiratory, thoracic and mediastinal disorders Epistaxis, Cough, Dyspnoea Pneumonitis (ILD) Gastrointestinal disorders Stomatitis, Diarrhoea, Vomiting, Nausea, Constipation, Dry mouth, Abdominal pain Dyspepsia, Gingival bleeding Hepatobiliary disorders Increased transaminases Increased blood alkaline phosphatase, Increased blood bilirubin Hepatotoxicity, Hepatic failure, Nodular regenerative hyperplasia, Portal hypertension Skin and subcutaneous disorders Rash, Pruritis, Alopecia, Nail disorder, Palmar-plantar erythrodysaethesia syndrome, Urticaria Musculoskeletal and connective tissue disorders Musculoskeletal pain, Arthralgia, Myalgia General disorders and administration site conditions Fatigue, Pyrxia, Asthenia Peripheral oedema, Chills Injection site extravasation Injury, poisoning and procedural complications Infusion-related reactions, radiation pneumonitis

Table 3 shows pooled data from the overall treatment period in the MBC studies (N=1 871; median number of cycles of Kadcyla was 10) and in EBC studies (N=740; median number of cycles was 14).

c. Description of selected adverse reactions from clinical trials Thrombocytopenia Thrombocytopenia or decreased platelet counts were reported in 24,9 % of patients in MBC clinical studies with Kadcyla 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 Kadcyla and was the most common reported adverse reaction for all grades and u22653, as well as the most common adverse reaction leading to discontinuation (4,2 %), dose interruptions, and dose reductions. The majority of the patients had Grade 1 or 2 events (u2265 50 000/mm3), with the nadir occurring by day 8 and generally improving to Grade 0 or 1 (u2265 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 Kadcyla and 18,8 % in patients with EBC. For dose modifications for thrombocytopenia, see sections 4.2 and 4.4.

Haemorrhage Haemorrhagic events were reported in 34,8 % of patients in MBC clinical trials with Kadcyla and the incidence of severe haemorrhagic events (Grade u22653) occurred in 2,2 %. Haemorrhagic events were reported in 29 % of patients with EBC and the incidence of severe haemorrhagic events (Grade u22653) 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.

Increased transaminases (AST/ALT) Increase in serum transaminases (Grade 1-4) has been observed during treatment with Kadcyla in clinical studies (see section 4.4). Transaminase elevations were generally transient. A cumulative effect of Kadcyla 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 u2265 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 Kadcyla exposure (AUC), Kadcyla 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 2,2 % of patients in clinical studies with Kadcyla. 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 the EBC study, left ventricular dysfunction was reported in 3,0 % of patients, with Grade 3 or 4 in 0,5 % of patients. Additional LVEF monitoring is recommended for patients with LVEF u2264 45 % (See Table 5 in section 4.2 for specific dose modifications).

Peripheral neuropathy Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of Kadcyla. In patients with MBC, the overall incidence of peripheral neuropathy was 29,0 % and 8,6 % for Grade u2265 2. In patients with EBC, the overall incidence was 32,3 % and 10,3 % for Grade u2265 2.

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 Kadcyla, 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 reactions Hypersensitivity was reported in 2,6 % of patients in MBC clinical studies with Kadcyla, 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.

Laboratory abnormalities Tables 4 and 5 displays laboratory abnormalities observed in patients treated with Kadcyla in the metastatic and early breast cancer clinical studies.

Table 4 Laboratory abnormalities observed in patients treated with Kadcyla in the Metastatic Breast Cancer studies Parameter Trastuzumab emtansine (N=490) 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 Kadcyla in the Early Breast Cancer study Parameter Trastuzumab emtansine (N=740) 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 of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Report Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored for signs and symptoms of adverse reactions and appropriate symptomatic treatment instituted. Cases of overdose have been reported with Kadcyla treatment, most associated with thrombocytopenia, and there was one death. In the fatal case, the patient incorrectly received trastuzumab emtansine 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to Kadcyla was not established.