Ogivri 440 mg Solution

Metastatic breast cancer (MBC)
OGIVRI is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2: u2022 As monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease. u2022 In combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease. u2022 In combination with an aromatase inhibitor for the treatment of patients with hormone-receptor positive metastatic breast cancer.
Early breast cancer (EBC)
OGIVRI is indicated for the treatment of patients with HER2 positive early breast cancer: u2022 Following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable). u2022 In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. u2022 In combination with neoadjuvant chemotherapy followed by adjuvant OGIVRI, for locally advanced (including inflammatory) breast cancer or tumours > 2 cm in diameter. OGIVRI should only be used in patients whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. OGIVRI should only be used in patients whose tumours have HER2 overexpression at a 3+ level as determined by immunohistochemistry.
Metastatic gastric-adenocarcinoma (MGC)
OGIVRI in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease. OGIVRI should only be used in patients with metastatic gastric-adenocarcinoma whose tumours have HER2 overexpression as defined by IHC 2+ and a confirmatory silver in situ hybridisation (SISH) or fluorescence in situ hybridisation (FISH) result, or by an IHC 3+ result. Accurate and validated assay methods should be used (see section 4.4). In a method comparison study a high degree of concordance (> 95 %) was observed for SISH and FISH techniques for the detection of HER2 gene amplification in gastric-adenocarcinoma patients.

Posology: HER2 testing is mandatory prior to initiation of OGIVRI therapy. OGIVRI should be administered as an intravenous infusion. Do not administer as an intravenous push or bolus.
Early breast cancer (EBC), Metastatic breast cancer (MBC) and Metastatic gastric-adenocarcinoma (MGC):
Weekly schedule
The following loading and subsequent doses are recommended for monotherapy and in combination with paclitaxel or docetaxel.
Loading dose
The recommended initial loading dose is 4 mg/kg body weight OGIVRI administered as a 90-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see section 4.8). Interruption of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.
Subsequent doses
The recommended weekly dose of OGIVRI is 2 mg/kg body weight, beginning one week after the loading dose. If the loading dose was well tolerated, the subsequent dose can be administered as a 30 [90]-minute intravenous infusion. Patients should be observed for fever and chills or other infusion-associated symptoms (see section 4.8). In clinical studies, patients were treated with OGIVRI until progression of disease.
Administration in combination with paclitaxel or docetaxel
Paclitaxel or docetaxel may be administered the day following the first dose of OGIVRI or immediately after the subsequent doses of OGIVRI if the preceding dose of OGIVRI was well tolerated.
Early and metastatic breast cancer
Alternative 3-weekly schedule
Initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dosage was well tolerated, the dose can be administered as a 30-minute infusion.
Duration of treatment
Patients with EBC should be treated for 1 year or until disease recurrence. If the patient misses a dose of OGIVRI by one week or less, then the usual dose of OGIVRI (6 mg/kg) should be given as soon as possible (do not wait until the next planned cycle). Subsequent maintenance OGIVRI doses of 6 mg/kg should then be given every 3 weeks, according to the previous schedule.
Missed doses
If the patient misses a dose of OGIVRI by more than one week, a re-loading dose of OGIVRI should be given (8 mg/kg over approximately 90 minutes). Subsequent maintenance OGIVRI doses of 6 mg/kg should then be given every 3 weeks from that point.
Dose reduction
No reductions in the dose of OGIVRI were made during clinical trials. Patients may continue OGIVRI therapy during periods of reversible, chemotherapy-induced, myelosuppression but they should be monitored carefully for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.
Special dosage instructions
Elderly
Data suggests that the disposition of trastuzumab, as in OGIVRI, is not altered based on age (see section 5.2). In clinical trials, elderly patients did not receive reduced doses of trastuzumab, as contained in OGIVRI.
Children
OGIVRI is not recommended for use in children below 18 years of age because the safety and efficacy in paediatric patients have not been established.
Method of administration
Handling and disposal
Appropriate aseptic technique should be used. OGIVRI 440: Each vial of OGIVRI 440 is reconstituted with 20 ml of bacteriostatic water for injection, containing 1,1 % benzyl alcohol. This yields a solution for multiple use, containing 21 mg/ml trastuzumab, at a pH of approximately 6,0. Use of other reconstitution diluents should be avoided.
OGIVRI should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted OGIVRI, may result in problems with the amount of OGIVRI that can be withdrawn from the vial.

u2022 Patients with known hypersensitivity to trastuzumab, murine proteins or to any of the excipients of OGIVRI (see section 6.1). (1, 2)
u2022 Patients with severe dyspnoea at rest due to complications of advanced malignancy or the requirement for supplementary oxygen therapy.
u2022 Pregnancy and lactation, as safety has not been demonstrated.

Cardiomyopathy
OGIVRI administration can result in the development of ventricular dysfunction and congestive heart failure. Left ventricular function should be evaluated in all patients prior to and during treatment with OGIVRI. Discontinuation of OGIVRI treatment should be strongly considered in patients who develop a clinically significant decrease in left ventricular function. The incidence and severity of cardiac dysfunction was particularly high in patients who received trastuzumab, as in OGIVRI, in combination with anthracyclines and cyclophosphamide.
Hypersensitivity reactions including anaphylaxis. Infusion reactions
Pulmonary events
OGIVRI administration can result in severe hypersensitivity reactions (including anaphylaxis), infusion reactions and pulmonary events. These may be fatal. In most cases, symptoms occurred during or within 24 hours of administration of OGIVRI. OGIVRI infusion should be interrupted for patients experiencing dyspnoea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of OGIVRI should be strongly considered for patients who develop anaphylaxis, angioedema interstitial pneumonitis or acute respiratory distress syndrome.
Embryo-foetal toxicity
Exposure to OGIVRI during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. OGIVRI therapy should only be initiated under supervision of a medical practitioner experienced in the treatment of cancer patients. Refer to blocked warning. The use of OGIVRI and anthracyclines in combination has been associated with a high risk of cardiotoxicity. OGIVRI and anthracyclines should not be used concurrently in combination except in a well-controlled clinical trial setting with cardiac monitoring.
Cardiotoxicity
Signs and symptoms of cardiac dysfunction, such as dyspnoea, increased cough, paroxysmal nocturnal dyspnoea, peripheral oedema, S3 gallop, or reduced ejection fraction, have been observed in patients treated with OGIVRI. Congestive heart failure associated with OGIVRI therapy may be severe and has been associated with disabling cardiac failure, death and mural thrombosis leading to stroke. Candidates for treatment with OGIVRI, should undergo thorough baseline cardiac assessment including history and physical exam and one or more of the following: ECG, echocardiogram and MUGA scan. There are no data regarding the most appropriate method of evaluation for the identification of patients at risk for developing cardiotoxicity. Monitoring may not identify all patients who will develop cardiac dysfunction. A careful risk-benefit assessment should be made before deciding to treat with OGIVRI.
In Early Breast Cancer, the following patients were excluded from the trial; there are no data regarding the benefit: risk balance, and therefore treatment cannot be recommended in such patients:
u2022 History of documented CHF
u2022 High-risk uncontrolled dysrhythmias
u2022 Angina pectoris requiring medication
u2022 Clinically significant valvular disease
u2022 Evidence of transmural infarction on ECG
u2022 Poorly controlled hypertension
Extreme caution should be exercised in treating patients with pre-existing cardiac dysfunction, such as symptomatic heart failure, a history of hypertension or documented coronary heart disease, and in EBC, in those patients with a LVEF of 55 % or less. If LVEF drops 10 ejection points from baseline AND to below 50 %, OGIVRI should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or has declined further, discontinuation of OGIVRI should be strongly considered, unless the benefits for the individual patients are deemed to outweigh the risks. Patients receiving OGIVRI should undergo frequent monitoring for deteriorating cardiac function. The probability of cardiac dysfunction was highest in patients who received OGIVRI concurrently with anthracyclines. The data suggest that advanced age may increase the probability of cardiac dysfunction. Pre-existing cardiac disease or prior cardiotoxicity therapy (e.g. anthracycline or radiation therapy to the chest) may decrease the ability to tolerate OGIVRI therapy: however, the data are not adequate to evaluate the correlation between OGIVRI-induced cardiotoxicity and these factors.
Discontinuation of OGIVRI therapy should be strongly considered in patients who develop clinically significant congestive heart failure. In clinical trials, most patients with cardiac dysfunction responded to appropriate medical therapy often including discontinuation of OGIVRI. The safety of continuation or resumption of OGIVRI, in patients who have previously experienced cardiac toxicity has not been studied. There are insufficient data regarding discontinuation of OGIVRI therapy in patients with asymptomatic decreases in ejection fraction; such patients should be closely monitored for evidence of clinical deterioration.
Hypersensitivity reactions including anaphylaxis
Severe hypersensitivity reactions have been infrequently reported in patients treated with OGIVRI. Signs and symptoms include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. In some cases, the reactions have been fatal. The onset of symptoms generally occurred during an infusion, but there have also been reports of symptom onset after the completion of an infusion. Reactions were most frequently reported in association with the initial infusion.
OGIVRI infusion should be interrupted in all patients with severe hypersensitivity reactions. In the event of a hypersensitivity reaction, appropriate medical therapy should be administered, which may include epinephrine (adrenaline), corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. There are no data regarding the most appropriate method of identification of patients who may safely be treated with OGIVRI after experiencing a severe hypersensitivity reaction. OGIVRI has been re-administered to some patients who fully recovered from a previous severe reaction. Prior to re-administration of OGIVRI, the majority of these patients were prophylactically treated with pre-medications including antihistamines and/or corticosteroids. While some of these patients tolerated re-treatment, others had severe reactions despite the use of prophylactic pre-medications.
Infusion reactions
In the post-marketing setting, rare occurrences of severe infusion reactions leading to a fatal outcome have been associated with the use of OGIVRI. In clinical trials, infusion reactions consisted of a symptom complex characterised by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumour sites), headache, dizziness, dyspnoea, hypotension, rash, and asthaenia. These reactions were usually mild to moderate in severity (see section 4.8). However, in post-marketing reports, more severe adverse reactions to OGIVRI infusion were observed and included bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension. These severe reactions were usually associated with the initial infusion of OGIVRI and generally occurred during or immediately following the infusion. However, the onset and clinical course were variable. For some patients, symptoms progressively worsened and led to further pulmonary complications. See u201cPulmonary eventsu201d below. In other patients with acute onset of signs and symptoms, initial improvement was followed by clinical deterioration. Delayed post-infusion events with rapid clinical deterioration have also been reported. Rarely, severe infusion reactions culminated in death within hours or up to one week following an infusion. Some severe reactions have been treated successfully with interruption of the trastuzumab, as in OGIVRI infusion and administration of supportive therapy included oxygen, intravenous fluids, beta- agonist, and corticosteroids. Interrupt OGIVRI infusion in all patients experiencing dyspnoea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
There are no data regarding the most appropriate methods of identification of patients who may safely be retreated with OGIVRI after experiencing a severe infusion reaction. Trastuzumab, as in OGIVRI, has been re-administered to some patients who fully recovered from the previous severe reaction. Prior to re- administration of trastuzumab, as in OGIVRI, the majority of these patients were prophylactically treated with pre-medications including antihistamines and/or corticosteroids. While some of these patients tolerated re-treatment, others had severe reactions again despite the use of prophylactic pre-medications.
Pulmonary events
Severe pulmonary events leading to death have been reported with the use of trastuzumab, as in OGIVRI, in the post-marketing setting. Signs, symptoms, and clinical findings include dyspnoea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary oedema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome and pulmonary fibrosis. These events may or may not occur as sequelae of infusion reactions. See u201cInfusion reactionsu201d above. Patients with symptomatic intrinsic lung disease or with extensive tumour involvement of the lungs, resulting in dyspnoea at rest, may be at greater risk of severe reactions.
Other severe events reported rarely in the post-marketing setting include pneumonitis and pulmonary fibrosis.
Benzyl alcohol
Benzyl alcohol, used as a preservative in bacteriostatic water for injection, has been associated with toxicity in neonates and children up to 3 years old. When administering OGIVRI to a patient with a known sensitivity to benzyl alcohol, OGIVRI should be reconstituted with water for injection, and only one dose per OGIVRI vial should be used. Any unused portion must be discarded.
Sorbitol
Contains sorbitol and may have a laxative effect. Patients with the rare hereditary condition of sorbitol intolerance should not take OGIVRI.

There has been no formal medicine interaction study performed with OGIVRI in humans. Clinically significant interactions with the concomitant medication used in clinical trials have not been observed. See also section 6.2. Patients who receive anthracycline after stopping OGIVRI may be at increased risk of cardiac dysfunction because of OGIVRI u2019s long washout period. If possible, medical practitioners should avoid anthracycline based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, the patientu2019s cardiac function should be monitored carefully.

OGIVRI crosses the placenta and appears in the breast milk (see section 4.3).
OGIVRI can cause foetal harm when administered to a pregnant woman. In post- marketing reports, use of OGIVRI during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.

It is not known whether OGIVRI can affect your ability to drive a car or operate machines. However, if during treatment you experience symptoms, such as chills or fever, you should not drive or use machines until these symptoms disappear.

a) Summary of adverse effects
Metastatic breast cancer
OGIVRI can be used at the recommended dose regimen, either as monotherapy, or in combination with paclitaxel. Approximately 65 % of the patients can be expected to experience grade 3 or greater severity adverse reactions. The most common adverse reactions are infusion-related symptoms, such as fever and chills, usually following the first infusion of OGIVRI, nausea, vomiting, diarrhoea, infections, increased cough, headache, fatigue, dyspnoea, rash, neutropenia, anaemia and myalgia. Adverse reactions that have been reported in association with the use of intravenous trastuzumab, as in OGIVRI, alone or in combination with chemotherapy in pivotal clinical trials and in the post-marketing setting are presented in the table below.
b) Tabulated summary of adverse reactions
System organ class Adverse reaction Frequency Infection Frequent
System organ class Adverse reaction Frequency Infections and infestations Nasopharyngitis Frequent Neutropenic sepsis Frequent Cystitis Frequent Herpes zoster Frequent Influenza Frequent Sinusitis Frequent Skin infection Frequent Rhinitis Frequent Upper respiratory tract infection Frequent Urinary tract infection Frequent Erysipelas Frequent Cellulitis Bronchitis Frequent Frequent Pharyngitis Frequent Sepsis less frequent Neoplasms benign, malignant and unspecified (incl. Cysts and polyps) Malignant neoplasm progression frequency unknown Neoplasm progression frequency unknown Blood and lymphatic system disorders Febrile neutropenia Frequent Anaemia Frequent Neutropenia Frequent
System organ class Adverse reaction Frequency White blood cell count decreased/leukopenia Frequent Thrombocytopenia frequent Hypoprothrombinaemia frequent Immune thrombocytopenia frequent Immune system disorders Hypersensitivity frequent + Anaphylactic reaction frequency unknown + Anaphylactic shock frequency unknown Metabolism and nutrition disorders Weight decreased/Weight loss frequent Anorexia frequent Hyperkalaemia frequency unknown Psychiatric disorders Insomnia frequent Anxiety frequent Depression frequent Thinking abnormal frequent Nervous system disorders 1 Tremor frequent Dizziness frequent Headache frequent Hypoaesthesia, paraesthesia frequent Dysgeusia frequent Peripheral neuropathy frequent Hypertonia frequent Somnolence frequent
System organ class Adverse reaction Frequency Ataxia Lethargy frequent frequent Paresis less frequent Brain oedema frequency unknown Eye disorders Conjunctivitis frequent Lacrimation increased frequent Dry eye frequent Papilloedema frequency unknown Retinal haemorrhage frequency unknown Ear and labyrinth disorders Vertigo Deafness frequent less frequent Cardiac disorders 1 Blood pressure decreased frequent 1 Blood pressure increased frequent 1 Heart beat irregular frequent 1 Palpitation frequent 1 Cardiac flutter frequent Ejection fraction decreased* frequent + Cardiac failure (congestive) frequent +1 Supraventricular tachyarrhythmia frequent Cardiomyopathy Chest discomfort frequent frequent Pericardial effusion less frequent
System organ class Adverse reaction Frequency Cardiogenic shock frequency unknown Pericarditis frequency unknown Bradycardia frequency unknown Gallop rhythm present frequency unknown Vascular disorders Hot flush Lymphoedema frequent frequent +1 Hypotension frequent Vasodilatation Hypertension frequent frequent Respiratory, thoracic and mediastinal disorders +1 Wheezing frequent + Dyspnoea Oropharyngeal pain frequent frequent Cough frequent Epistaxis frequent Rhinorrhoea frequent + Pneumonia frequent Asthma frequent Lung disorder Pharyngitis Hiccups Exertional dyspnoea frequent frequent frequent frequent + Pleural effusion frequent Pneumonitis less frequent + Pulmonary fibrosis frequency unknown
System organ class Adverse reaction Frequency + Respiratory distress frequency unknown + Respiratory failure frequency unknown + Lung infiltration frequency unknown + Acute pulmonary oedema frequency unknown + Acute respiratory distress syndrome frequency unknown + Bronchospasm frequency unknown + Hypoxia frequency unknown + Oxygen saturation decreased frequency unknown Laryngeal oedema frequency unknown Orthopnoea frequency unknown Pulmonary oedema frequency unknown Interstitial lung disease frequency unknown Gastrointestinal disorders Diarrhoea frequent Vomiting frequent Nausea frequent 1 Lip swelling frequent Abdominal pain frequent Dyspepsia frequent Constipation frequent Stomatitis frequent Pancreatitis frequent Haemorrhoids frequent
System organ class Adverse reaction Frequency Dry mouth Gastritis frequent frequent Hepatobiliary disorders Hepatocellular injury frequent Hepatitis frequent Liver tenderness Abnormal liver function frequent frequent Jaundice less frequent Hepatic failure frequency unknown Skin and subcutaneous tissue disorders Erythema frequent Rash frequent 1 Swelling face frequent Alopecia frequent Nail disorder frequent Palmar-plantar erythrodysaesthesia syndrome frequent Acne frequent Dry skin frequent Ecchymosis frequent Hyperhydrosis frequent Maculopapular rash frequent Pruritus Onychorrhexis frequent frequent Onychoclasis frequent
System organ class Adverse reaction Frequency Dermatitis frequent Urticaria frequent Angioedema frequency unknown Musculoskeletal and connective tissue disorders Arthralgia frequent 1 Muscle tightness frequent Myalgia frequent Arthritis frequent Back pain frequent Bone pain frequent Muscle spasms frequent Neck Pain frequent Pain in extremity Musculoskeletal pain frequent frequent Renal and urinary disorders Renal disorder Dysuria frequent frequent Glomerulonephritis membranous frequency unknown Glomerulonephropathy frequency unknown Renal failure frequency unknown Pregnancy, puerperium and perinatal conditions Oligohydramnios frequency unknown Renal hypoplasia frequency unknown Pulmonary hypoplasia frequency unknown Reproductive system and breast disorders Breast inflammation/mastitis Breast pain frequent frequent
General disorders and administration site conditions Asthenia frequent Chest pain frequent Chills frequent Fatigue frequent Influenza-like symptoms frequent Infusion related reaction frequent Pain frequent Pyrexia frequent Mucosal inflammation frequent Peripheral oedema Mucosal inflammation frequent frequent Malaise frequent Oedema frequent Injury, poisoning and procedural complications Nail toxicity Contusion frequent frequent + Denotes adverse reactions that have been reported in association with a fatal outcome 1 Denotes adverse reactions that are reported largely in association with Infusion- related reactions. Specific percentages for these are not available * Observed with combination therapy following anthracyclines and combined with taxanes The following information is relevant to all indications: Infusion-related symptoms
During the first infusion with trastuzumab as in OGIVRI, chills and/or fever is frequently observed. Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, dizziness, rash, asthenia and hypertension. These symptoms occur infrequently with subsequent OGIVRI infusions. These symptoms can be treated with an analgesic/antipyretic such as pethidine or paracetamol or an antihistamine such as diphenhydramine. See section 4.2. Some adverse reactions to OGIVRI infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress can be serious and potentially fatal. See section 4.4.
Hypersensitivity reaction
Anaphylactic reactions were observed less frequently.
Cardiac dysfunction
Congestive heart failure (NYHA Class II u2013 IV) is a common adverse reaction associated with the use of OGIVRI and has been associated with a fatal outcome (see WARNINGS AND SPECIAL PRECAUTIONS). Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop or reduced ejection fraction, have been frequently observed in patients treated with trastuzumab as in OGIVRI. See section 4.4.
Haematotoxicity
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred frequently. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly increased when trastuzumab is administered with docetaxel following anthracycline therapy.
Infection
An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, has been observed, in patients treated with OGIVRI.

There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.