Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Mifamurtide was studied as a single agent in 248 patients with mostly advanced malignancies during the early, single arm phase I and II clinical studies. The most frequent adverse reactions are chills, pyrexia, fatigue, nausea, tachycardia and headache. Many of the very commonly reported adverse reactions as shown in the following summary table are thought to be related to the mechanism of action of mifamurtide (see table 1). The majority of these events were reported as either mild or moderate.

Tabulated list of adverse reactions

Adverse reactions are classified according to system organ class and frequency. Frequency groupings are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

System organ class                     Frequency category      Adverse reaction (preferred term) Infections and infestations            Common                  Sepsis, Cellulitis, Nasopharyngitis, Catheter site infection, Upper respiratory tract infection, Urinary tract infection, Pharyngitis, Herpes simplex infection
Neoplasms benign, malignant            Common                  Cancer pain and unspecified (incl. cysts and polyps)

System organ class               Frequency category   Adverse reaction (preferred term) Blood and lymphatic system       Very Common          Anaemia disorders
Common               Leukopenia, Thrombocytopenia,
Granulocytopenia, Febrile neutropenia
Metabolism and nutrition         Very common          Anorexia disorders
Common               Dehydration, Hypokalaemia, Decreased appetite
Psychiatric disorders            Common               Confusional state, Depression, Insomnia, Anxiety
Nervous system disorders         Very common          Headache, Dizziness Common               Paraesthesia, Hypoaesthesia, Tremor,
Somnolence, Lethargy
Eye disorders                    Common               Blurred vision
Ear and labyrinth disorders      Common               Vertigo, Tinnitus, Hearing loss Cardiac disorders                Very common          Tachycardia
Common               Cyanosis, Palpitations
Not known            Pericardial effusion
Vascular disorders               Very common          Hypertension, Hypotension Common               Phlebitis, Flushing, Pallor
Respiratory, thoracic and        Very common          Dyspnoea, Tachypnoea, Cough mediastinal disorders
Common               Pleural effusion, Exacerbated dyspnoea,
Productive cough, Haemoptysis,
Wheezing, Epistaxis, Exertional dyspnoea, Sinus congestion, Nasal congestion, Pharyngolaryngeal pain
Gastrointestinal disorders       Very common          Vomiting, Diarrhoea, Constipation, Abdominal pain, Nausea
Common               Upper abdominal pain, Dyspepsia,
Abdominal distension, Lower abdominal pain
Hepatobiliary disorders          Common               Hepatic pain
Skin and subcutaneous tissue     Very common          Hyperhidrosis disorders
Common               Rash, Pruritis, Erythema, Alopecia, Dry skin
Musculoskeletal and connective   Very common          Myalgia, Arthralgia, Back pain, Pain in tissue disorders                                      extremity
Common               Muscle spasms, Neck pain, Groin pain,
Bone pain, Shoulder pain, Chest wall pain, Musculoskeletal stiffness
Renal and urinary disorders      Common               Haematuria, Dysuria, Pollakiuria Reproductive system and breast   Common               Dysmenorrhoea disorders


System organ class                   Frequency category       Adverse reaction (preferred term) General disorders and                Very common              Fever, Chills, Fatigue, Hypothermia, administration site conditions                                Pain, Malaise, Asthenia, Chest pain Common                   Peripheral oedema, Oedema, Mucosal inflammation, Infusion site erythema,
Infusion site reaction, Catheter site pain,
Chest discomfort, Feeling cold
Investigations                       Common                   Weight decreased Surgical and medical                 Common                   Post-procedural pain procedures

Description of selected adverse reactions

Blood and lymphatic system disorders
Anaemia has very commonly been reported when mifamurtide is used in conjunction with chemotherapeutic agents. In a randomised controlled study, 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 (2.1%).

Metabolism and nutritional disorders
Anorexia (21%) was very commonly reported in phase I and II studies of mifamurtide 
Nervous system disorders
Consistent with other generalised symptoms, the very common nervous system disorders were headache (50%) and dizziness (17%). One patient in the phase III study experienced 2 episodes of grade 4 seizure while on study therapy with chemotherapy and mifamurtide. The second episode involved multiple grand mal seizures over the course of days. Mifamurtide treatment was continued for the remainder of the study without seizure recurrence.

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 4%, respectively) in the phase III study (see section 5.1 for a description of the study) 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 very commonly reported in uncontrolled studies of mifamurtide. One serious incident of subacute thrombosis was reported in early studies, but no serious cardiac events were associated with mifamurtide in a large randomised controlled study (see section 4.4).

Respiratory disorders
Respiratory disorders, including dyspnoea (21%), cough (18%) and tachypnoea (13%) were very commonly reported, and 2 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 mifamurtide administration, including nausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%) and abdominal pain (see section 4.4).


Skin and subcutaneous disorders
Hyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies.
Musculoskeletal and connective tissue disorders
Low grade pain was very common in patients receiving mifamurtide, 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
An osteosarcoma patient in a phase II study who had high creatinine level at enrolment showed an increase in blood urea and blood creatinine which was associated with mifamurtide use.

Immune system disorders
In a phase I study, there was one report of severe allergic reaction occurring after the first infusion of mifamurtide at 6 mg/m2 dose level. The patient experienced shaking, chills, fever, nausea, vomiting, uncontrollable coughing, shortness of breath, cyanotic lips, dizziness, weakness, hypotension, tachycardia, hypertension and hypothermia leading to study discontinuation. There was also one report of a grade 4 allergic reaction (hypertension) requiring hospitalization in the phase III study (see section 4.4).

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. Any suspected adverse reactions should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.