4.1. Therapeutic indications

Early Breast Cancer (EBC)

Kadcyla, as a single agent, is indicated for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease, in the breast and/or lymph nodes, after neoadjuvant taxane-based and HER2-targeted therapy.

Metastatic Breast Cancer (MBC)

Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

• Received prior therapy for locally advanced or metastatic disease, or

• Developed disease recurrence during or within six months of completing adjuvant therapy.

4.2. Posology and method of administration

Kadcyla should only be prescribed by a physician and administered as an intravenous infusion under the supervision of a healthcare professional who is experienced in the treatment of cancer patients (i.e. 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 trastuzumab emtansine should have HER2 positive tumour status, defined as a score of 3 + by immunohistochemistry (IHC) or a ratio of ≥ 2.0 by in situ hybridization (ISH) or by fluorescence in situ hybridization (FISH) assessed by a CE-marked In Vitro Diagnostic (IVD) medical device. If a CE-marked IVD is not available, the HER2-status should be assessed by an alternate validated test.

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).

Posology

The recommended dose of trastuzumab emtansine is 3.6 mg/kg bodyweight administered as an intravenous infusion every 3 weeks (21‑day cycle).

The initial dose should be administered as a 90 minute intravenous infusion. Patients should be observed during the infusion and for at least 90 minutes following the initial infusion for fever, chills, or other infusion‑related reactions. The infusion site should be closely monitored for possible subcutaneous infiltration during administration. Cases of delayed epidermal injury or necrosis following extravasation have been observed in the post-marketing setting (see section 4.4 and 4.8).

If the prior infusion was well tolerated, subsequent doses of trastuzumab emtansine may be administered as 30 minute infusions. Patients should be observed during the infusion and for at least 30 minutes after infusion.

The infusion rate of trastuzumab emtansine should be slowed or interrupted if the patient develops infusion‑related symptoms (see sections 4.4 and 4.8). Trastuzumab emtansine should be discontinued in case of life‑threatening infusion reactions.

Duration of treatment

Early Breast Cancer (EBC)

Patients should receive treatment for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.

Metastatic Breast Cancer (MBC)

Patients should receive treatment until disease progression or unmanageable toxicity.

Dose modification

Management of symptomatic adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of trastuzumab emtansine as per guidelines provided in text and Tables 1 and 2.

Trastuzumab emtansine dose should not be re‑escalated after a dose reduction is made.

Table 1 Dose reduction schedule

Dose reduction schedule

(Starting dose is 3.6 mg/kg)

Dose to be administered

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 trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥ 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< 25,000/mm3

Do not administer trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥ 75,000/mm3), and then reduce one dose level.

Increased Alanine Transaminase (ALT)

Grade 2-3(> 3.0 to ≤ 20× ULN on day of scheduled treatment)

Do not administer trastuzumab emtansine until ALT recovers to Grade ≤ 1, and then reduce one dose level

Grade 4(> 20 × ULN at any time)

Discontinue trastuzumab emtansine

Increased Aspartate Transaminase (AST)

Grade 2 (> 3.0 to ≤ 5× ULN on day of scheduled treatment)

Do not administer trastuzumab emtansine until AST recovers to Grade ≤ 1, and then treat at the same dose level

Grade 3 (> 5 to ≤ 20× ULN on day of scheduled treatment)

Do not administer trastuzumab emtansine until AST recovers to Grade ≤ 1, and then reduce one dose level

Grade 4 (> 20 × ULN at any time)

Discontinue trastuzumab emtansine

Hyperbilirubinaemia

TBILI > 1.0 to ≤ 2.0× the ULN on day of scheduled treatment

Do not administer trastuzumab emtansine until total bilirubin recovers to ≤ 1.0× ULN, and then reduce one dose level

TBILI > 2× ULN at any time

Discontinue trastuzumab emtansine

Drug Induced Liver Injury (DILI)

Serum transaminases > 3 x ULN and concomitant total bilirubin > 2× ULN

Permanently discontinue trastuzumab emtansine in the absence of 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 trastuzumab emtansine

Peripheral Neuropathy

Grade 3-4

Do not administer trastuzumab emtansine until resolution ≤ Grade 2

Left Ventricular Dysfunction

LVEF < 45%

Do not administer trastuzumab emtansine.Repeat LVEF assessment within 3 weeks. If LVEF < 45% is confirmed, discontinue trastuzumab emtansine.

LVEF 45% to < 50% and decrease is ≥ 10% points from baseline*

Do not administer trastuzumab emtansine.Repeat LVEF assessment within 3 weeks. If the LVEF remains < 50% and has not recovered to < 10% points from baseline, discontinue trastuzumab emtansine.

LVEF 45% to < 50% and decrease is < 10% points from baseline*

Continue treatment with trastuzumab emtansine. Repeat LVEF assessment within 3 weeks.

LVEF ≥ 50%

Continue treatment with trastuzumab emtansine

Heart Failure

Symptomatic CHF,

Grade 3-4 LVSD or Grade 3-4 heart failure, or

Grade 2 heart failure accompanied by LVEF < 45%

Discontinue trastuzumab emtansine

Pulmonary Toxicity

Interstitial lung disease (ILD) or pneumonitis

Permanently discontinue trastuzumab emtansine

Radiotherapy-Related Pneumonitis

Grade 2

Discontinue trastuzumab emtansine if not resolving with standard treatment

Grade 3-4

Discontinue trastuzumab emtansine

Dose modifications for patients with MBC

Adverse reaction

Severity

Treatment modification

Thrombocytopenia

Grade 3

(25,000 to < 50,000/mm3)

Do not administer trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥ 75,000/mm3), and then treat at the same dose level

Grade 4

(< 25,000/mm3)

Do not administer trastuzumab emtansine until platelet count recovers to ≤ Grade 1 (≥ 75,000/mm3), and then reduce one dose level

Increased Transaminase (AST/ALT)

Grade 2(> 2.5 to ≤ 5× the ULN)

Treat at the same dose level

Grade 3(> 5 to ≤ 20× the ULN)

Do not administer trastuzumab emtansine until AST/ALT recovers to Grade ≤ 2, and then reduce one dose level

Grade 4(> 20× the ULN)

Discontinue trastuzumab emtansine

Hyperbilirubinaemia

Grade 2(> 1.5 to ≤ 3× the ULN)

Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤ 1, and then treat at the same dose level.

Grade 3(> 3 to ≤ 10× the ULN)

Do not administer trastuzumab emtansine until total bilirubin recovers to Grade ≤ 1 and then reduce one dose level.

Grade 4(> 10× the ULN)

Discontinue trastuzumab emtansine

Drug Induced Liver Injury (DILI)

Serum transaminases > 3 x ULN and concomitant total bilirubin > 2× ULN

Permanently discontinue trastuzumab emtansine in the absence of 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 trastuzumab emtansine

Left Ventricular Dysfunction

Symptomatic CHF

Discontinue trastuzumab emtansine

LVEF < 40%

Do not administer trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks. If LVEF < 40% is confirmed, discontinue trastuzumab emtansine

LVEF 40% to ≤ 45% and decrease is ≥ 10% points from baseline

Do not administer trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks. If the LVEF has not recovered to within 10% points from baseline, discontinue trastuzumab emtansine.

LVEF 40% to ≤ 45% and decrease is < 10% points from baseline

Continue treatment with trastuzumab emtansine.

Repeat LVEF assessment within 3 weeks.

LVEF > 45%

Continue treatment with trastuzumab emtansine.

Peripheral Neuropathy

Grade 3-4

Do not administer trastuzumab emtansine until resolution ≤ Grade 2

Pulmonary Toxicity

Interstitial lung disease (ILD) or pneumonitis

Permanently discontinue trastuzumab emtansine

ALT = alanine transaminase; AST = aspartate transaminase, CHF = congestive heart failure, LVEF = left ventricular ejection fraction, LVSD = left ventricular systolic dysfunction, TBILI = Total Bilirubin, ULN = upper limit of normal

* Prior to starting trastuzumab emtansine treatment.

Delayed or missed dose

If a planned dose is missed, it should be administered as soon as possible; without waiting until the next planned cycle. The schedule of administration should be adjusted to maintain a 3‑week interval between doses. The next dose should be administered in accordance with the dosing recommendations above.

Peripheral neuropathy

Trastuzumab emtansine should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. At retreatment a dose reduction may be considered according to the dose reduction schedule (see Table 1).

Special populations

Elderly patients

No dose adjustment is required in patients aged ≥ 65 years. There are insufficient data to establish the safety and efficacy in patients ≥ 75 years due to limited data in this subgroup. However, for patients ≥ 65 years, subgroup analysis of 345 patients from study MO28231 shows a tendency of higher incidences of Grade 3, 4 and 5 AE's, SAE's and AE's leading to treatment discontinuation/interruption, but with a similar incidence of AEs of Grade 3 and above classified as treatment related.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of trastuzumab emtansine (see sections 5.1 and 5.2).

Renal 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.

Hepatic impairment

No adjustment to the starting dose is required for patients with mild or moderate hepatic impairment. Trastuzumab emtansine has not been 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 for the indication of breast cancer.

Method of administration

Kadcyla is for intravenous use. Trastuzumab emtansine must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. It must not be administered as an intravenous push or bolus.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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 anticoagulant 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).

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.

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 randomisation, 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), characterised 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.

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.

Excipients with known effect

This medicine contains 1.1 mg of polysorbate 20 in each 100 mg vial and 1.7 mg of polysorbate 20 in each 160 mg vial. Polysorbates may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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

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 7 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 7 months after concluding treatment.

Fertility

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

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.

4.8. Undesirable effects

Summary of the safety profile

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

• 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.

Tabulated list of adverse reactions

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 studies

System Organ Class

Frequency

Adverse reactions

Infections and infestations

Very common

Urinary tract infection

Blood and lymphatic system disorders

Very common

Thrombocytopenia, Anaemia

Common

Neutropenia, Leukopoenia

Immune system disorders

Common

Drug hypersensitivity

Metabolism and nutrition disorders

Common

Hypokalaemia

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 mediastinal disorders

Very common

Epistaxis, Cough, Dyspnoea

Uncommon

Pneumonitis (ILD)

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 disorders

Common

Rash, Pruritus, Alopecia, Nail disorder, Palmar-plantar erythrodysaesthesia syndrome, Urticaria

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain, Arthralgia, Myalgia

General disorders and administration site conditions

Very common

Fatigue, Pyrexia, Asthenia

Common

Peripheral oedema, Chills

Uncommon

Injection site extravasation

Injury, poisoning and procedural complications

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).

Description of selected adverse reactions

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.

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.

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.

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.

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.

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.

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.

Immunogenicity

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% (64/1243) 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 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.

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. In the post-marketing setting, cases of epidermal injury or necrosis following extravasation have been exceptionally observed within days to weeks after infusion. Specific treatment for trastuzumab emtansine extravasation is unknown at this time (see section 4.4).

Laboratory abnormalities

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

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 trastuzumab emtansine in study BO27938/KATHERINE

Parameter

Trastuzumab emtansine (N = 740)

All Grade %

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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known antidote for trastuzumab emtansine overdose. In case of overdose, the patient should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. Cases of overdose have been reported with trastuzumab emtansine 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 causal relationship to trastuzumab emtansine was not established.