tion with chemotherapeutic agents. In a randomised controlled trial, the incidence of myeloid malignancy (acute myeloid leukaemia/myelodysplastic syndrome) was the same in patients receiving MEPACT plus chemotherapy as in patients receiving only chemotherapy (approximately 2.5%).
Metabolism and nutritional disorders
Anorexia (21%) was very commonly reported in trials of MEPACT in late stage cancer patients.
Nervous system disorders
Consistent with other generalised symptoms, the most common nervous system disorders were headache (50%) and dizziness (17%).
Ear and labyrinth disorders
Although hearing loss may be attributable to ototoxic chemotherapy, like cisplatin, it is unclear whether MEPACT in conjunction with multi-agent chemotherapy may increase hearing loss.
A higher percentage of objective and subjective hearing loss was observed overall in patients who received MEPACT and chemotherapy (12 % and 7%, respectively) in the phase III study (see Section 5.1 for a description of the trial) compared to those patients that received only chemotherapy (7% and 1%). All patients received a total dose of cisplatin of 480 mg/m2 as part of their induction (neoadjuvant) and/or maintenance (adjuvant) chemotherapy regimen.
Cardiac and vascular disorders
Mild-moderate tachycardia (50%), hypertension (26%) and hypotension (29%) were commonly reported in uncontrolled trials of MEPACT. One serious incident of subacute thrombosis was reported in early studies, but no serious cardiac events were associated with MEPACT in a large randomised controlled trial.
Respiratory disorders
Respiratory disorders, including dyspnoea (21%), cough (18%) and tachypnoea (13%) were very commonly reported, and two patients with pre-existing asthma developed mild to moderate respiratory distress associated with MEPACT treatment in a phase II study.
Gastrointestinal disorders
Gastrointestinal disorders were frequently associated with MEPACT administration, including nausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%) and abdominal pain.
Skin and subcutaneous disorders
Hyperhidrosis (11%) was very common in patients receiving MEPACT in uncontrolled studies.
Musculoskeletal and connective tissue disorders
Low grade pain was common in patients receiving MEPACT, including myalgia (31%), back pain (15%), extremity pain (12%) and arthralgia (10%).
General disorders and administration site conditions
The majority of patients experience chills (89%), fever (85%) and fatigue (53%). These are typically mild to moderate, transient in nature and generally respond to palliative treatment (e.g., paracetamol for fever). Other generalised symptoms that were typically mild to moderate and very common included hypothermia (23%), malaise (13%), pain (15%), asthenia (13%) and chest pain (11%). Oedema, chest discomfort, local infusion or catheter site reactions and 'feeling cold' were less frequently reported in these patients, mostly with late stage malignant disease.
Investigations
Increase in blood urea and blood creatinine was associated with MEPACT use in one patient with osteosarcoma.
4.9 Overdose
No case of overdose has been reported. The maximum tolerated dose in phase I studies was 4-6 mg/m2 with a high variability of adverse reactions. Signs and symptoms that were associated with higher doses and/or were dose limiting were not life-threatening, and included fev |
