Ogivri 150 mg Solution

Metastatic breast cancer (MBC)
OGIVRI is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2:

• As monotherapy for the treatment of those patients who have received at least two chemotherapy regimens for their metastatic disease.
• In combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease.
• 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:

• Following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable).
• In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin.
• 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-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 150: Each vial of OGIVRI 150 is reconstituted with 7,2 ml of sterile water for injection (not supplied). This yields a solution for single-dose use, containing approximately 21 mg/ml trastuzumab at a pH of approximately 6.0. Use of other reconstitution diluents should be avoided.

• Patients with known hypersensitivity to trastuzumab, murine proteins or to any of the excipients of OGIVRI (see section 6.1).
• Patients with severe dyspnoea at rest due to complications of advanced malignancy or the requirement for supplementary oxygen therapy.
• 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
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:

• History of documented CHF
• High-risk uncontrolled dysrhythmias
• Angina pectoris requiring medication
• Clinically significant valvular disease
• Evidence of transmural infarction on ECG
• 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.

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 OGIVRIu2019s 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
Infections and infestations Infection Frequent
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 Frequent
Bronchitis 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
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
Ataxia frequent
Lethargy 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 frequent
Deafness 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 frequent
Chest discomfort frequent
Pericardial effusion less frequent
Cardiogenic shock frequency unknown
Pericarditis frequency unknown
Bradycardia frequency unknown
Gallop rhythm present frequency unknown
Vascular disorders Hot flush frequent
Lymphoedema frequent
+1 Hypotension frequent
Vasodilatation frequent
Hypertension frequent
Respiratory, thoracic and mediastinal disorders +1 Wheezing frequent
+ Dyspnoea frequent
Oropharyngeal pain frequent
Cough frequent
Epistaxis frequent
Rhinorrhoea frequent
+ Pneumonia frequent
Asthma frequent
Lung disorder frequent
Pharyngitis frequent
Hiccups frequent
Exertional dyspnoea frequent
+ Pleural effusion frequent
Pneumonitis less frequent
+ Pulmonary fibrosis frequency unknown
+ 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
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
Dry mouth frequent
Gastritis frequent
Hepatobiliary disorders Hepatocellular injury frequent
Hepatitis frequent
Liver tenderness frequent
Abnormal liver function 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 frequent
Onychorrhexis frequent
Onychoclasis frequent
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 frequent
Musculoskeletal pain frequent
Renal and urinary disorders Renal disorder frequent
Dysuria 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 frequent
Mucosal inflammation 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.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions & Quality Problem Reporting Formu201d, found online under SAHPRAu2019s publications: https://sahpra.org.za/wp-ontent/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf or to Imperial Market Access Healthcare South Africa (Pty) Ltd. via email: [email protected].

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