Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Infusion-related reactions (IRRs), including anaphylactic reactions, were reported in clinical trials with olaratumab. The majority of these reactions occurred during or following the first olaratumab infusion. Symptoms of IRRs included flushing, shortness of breath, bronchospasm, or fever/chills, and in some cases manifested as severe hypotension, anaphylactic shock, or fatal cardiac arrest. Severe IRRs such as anaphylactic reactions can occur despite the use of premedication. Patients should be monitored during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. For management and dose adjustments in patients who experience Grade 1 or 2 IRR during the infusion, see section 4.2. In patients who have experienced a previous Grade 1 or 2 IRR, premedication with diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone is recommended. Olaratumab should be immediately and permanently discontinued in patients who experience Grade 3 or 4 IRR (see sections 4.2 and 4.8).
Patients receiving olaratumab and doxorubicin are at risk of neutropenia (see section 4.8). Neutrophil count should be checked prior to Olaratumab dosing on Day 1 and Day 8 of each cycle. Neutrophil count should be monitored during the treatment with olaratumab and doxorubicin and supportive care should be administered such as antibiotics or G-CSF as per local guidelines. For dosage adjustments related to neutropenia, refer to section 4.2.
Patients receiving olaratumab and doxorubicin are at risk of haemorrhagic events (see section 4.8). Platelet counts should be checked prior to olaratumab dosing on Day 1 and Day 8 of each cycle. Coagulation parameters should be monitored in patients with conditions predisposing to bleeding, such as anticoagulant use. In a study of olaratumab in combination with liposomal doxorubicin, there was one case of fatal intracranial haemorrhage in a patient who had experienced a fall while on treatment.
The risk of cardiac toxicity rises with increasing cumulative doses of anthracyclines, including doxorubicin. There are no data for the combination of olaratumab and doxorubicin in anthracycline pre-treated patients, including pre-treatment with doxorubicin (see section 4.1).
This medicinal product contains 22 mg sodium per each 19 mL vial and 57 mg sodium per each 50 mL vial. To be taken into consideration by patients on a controlled sodium diet.
Doxorubicin can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses and is higher in individuals with a history of cardiomyopathy, mediastinal irradiation or pre-existing cardiac disease. To minimise doxorubicin-related cardiotoxicity, the use of appropriate cardioprotective measures (LVEF measurement, such as ECHO or MUGA scan, ECG monitoring, and/or use of cardioprotective agents) should be considered and planned in all patients before the start and throughout the treatment.
In the phase 2 trial, patients in both treatment groups that received 5 or more cycles of doxorubicin received dexrazoxane prior to each dose of doxorubicin from cycle 5 onwards to minimize the risk of doxorubicin-related cardiotoxicity (see sections 4.8 and 5.1).
As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the toxicity of doxorubicin is enhanced in patients with hepatic impairment. Refer to doxorubicin SmPC for appropriate monitoring of hepatic function and doxorubicin dose adjustments in patients with impaired liver function.
Olaratumab is a human monoclonal antibody. In a dedicated DDI study, no pharmacokinetic interactions were observed in patients between olaratumab and doxorubicin.
No other formal DDI studies with olaratumab and medicinal products commonly used in cancer patients, including those with STS (e.g. antiemetics, analgesics, anti-diarrheal drugs, oral contraceptives, etc.), have been performed.
As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of olaratumab. Conversely, olaratumab is not anticipated to affect the pharmacokinetics of co-administered medicinal products.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving olaratumab in combination with doxorubicin.
Women of childbearing potential should be advised to avoid becoming pregnant while on olaratumab and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 3 months following the last dose of olaratumab.
There are no or limited amount of data from the use of olaratumab in pregnant women. Reproductive and development toxicity study conducted with an anti-murine PDGFRα antibody in mice showed foetal malformations and skeletal alterations (see section 5.3). Based on its mechanism of action (see section 5.1), olaratumab has the potential to cause foetal harm. Olaratumab is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefit justifies the potential risk to the foetus.
It is not known whether olaratumab is excreted in human milk. Human IgG is excreted in human milk, therefore breast-feeding is not recommended during treatment with olaratumab and for at least 3 months following the last dose.
There are no data on the effect of olaratumab on human fertility.
Olaratumab may have minor influence on the ability to drive and use machines. Due to frequent occurrence of fatigue, patients should be advised to use caution when driving or operating machinery.
In the olaratumab plus doxorubicin arm, the most serious (Grade ≥3) adverse drug reactions (ADRs) observed were neutropenia (54.7%) and musculoskeletal pain (7.8%). The most frequently occurring ADRs were nausea, musculoskeletal pain, neutropenia and mucositis.
The most frequent ADRs associated with permanent treatment discontinuation occurred in 3 (4.7%) patients of which the most frequent were infusion-related reactions (3.1%) and mucositis (1.6%).
Known toxicities reported for doxorubicin, observed in the combination of olaratumab and doxorubicin include fatigue, anaemia, thrombocytopenia and alopecia. Please refer to the doxorubicin SmPC for complete descriptions of all adverse events associated with doxorubicin treatment
ADRs which were reported in patients with soft tissue sarcoma treated with olaratumab in combination with doxorubicin in the Phase 2 study are listed below in Table 2 in MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: 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).
Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Table 2. Adverse reactions in patients receiving olaratumab plus doxorubicin for soft tissue sarcoma during the Phase 2 portion of a Phase 1b/2 study:
| System organ class | Adverse Reactiona | Frequency overall | Grade 3/4 frequency |
|---|---|---|---|
| Blood and lymphatic system disorders | Neutropenia | Very Common | Very Common |
| Lymphopenia | Very Common | Common | |
| Nervous system disorders | Headache | Very Common | None reported |
| Gastrointestinal disorders | Diarrhoea | Very Common | Common |
| Mucositis | Very Common | Common | |
| Nausea | Very Common | Common | |
| Vomiting | Very Common | None reported | |
| Musculoskeletal and connective tissue disorders | Musculoskeletal Painb | Very Common | Common |
| General disorders and administrative site conditions | Infusion-related Reactionsc | Very Common | Common |
a Refer to NCI CTCAE Criteria (Version 4.03) for each Grade of toxicity
b Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, groin pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in extremity.
c Infusion-related reactions includes anaphylactic reactions/anaphylactic shock.
IRRs were reported in 12.5% of patients and mainly present as chills, fever or dyspnoea. Severe IRRs, also including a fatal case (see section 4.4) were reported in 3.1% of patients and mainly presented with shortness of breath, loss of consciousness and hypotension. All severe IRRs occurred during or immediately after the first administration of olaratumab.
In the phase 2 trial, the incidence of neutropenia was 59.4% (all Grades) and 54.7% (Grade 3) in the olaratumab plus doxorubicin arm and 38.5% (all Grades) and 33.8% (Grade 3) in the doxorubicin alone arm. The rate of febrile neutropenia was 12.5% in the olaratumab plus doxorubicin arm and 13.8% in the doxorubicin alone arm. For dose adjustments, refer to section 4.2
In the phase 2 trial the incidence of Musculoskeletal pain was 64.1% (all Grades) and 7.8% (Grade 3) in the olaratumab plus doxorubicin arm and 24.6% (all Grades) and 1.5% (Grade 3) in the doxorubicin alone arm. In the majority of patients the pain was related to the patients' underlying cancer or metastases or pre-existing or concomitant conditions. The majority of these events occurred in the first 4 cycles. The pain can last from few days to up to 200 days. In some patients there was a recurrence of pain .The pain did not worsen with time or during recurrence.
No clinically meaningful difference in doxorubicin-related cardiotoxicity was observed between the two treatment arms of the study. The rate of cardiac arrhythmias was similar in both arms (15.6% in the Investigational Arm and 15.4% in the Control Arm). The rate of treatment-emergent cardiac dysfunction was comparable between the two treatment arms (7.8% in the Investigational Arm and 6.2% in the Control Arm).
In the phase 2 trial, the frequency of haemorrhagic events considered related to any study drug was 3.1% in either treatment arm. All of these events were Grade ½ and were confounded by multiple factors. Three Grade ≥3 events, including one fatal, have been reported across the clinical development programme of olaratumab (see section 4.4).
There was a higher incidence of Grade ≥3 adverse reactions, adverse reactions leading to discontinuation and a higher rate of haematological toxicity in the elderly population compared to the overall study population (see section 4.2). The rates of discontinuation were comparable between treatment arms across all age groups.
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 national reporting system listed in Appendix V.
The medicinal product should not be administered or mixed with dextrose containing solutions.
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