Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,687 adults including 371 healthy subjects and 2,084 patients with chemotherapy induced nausea and vomiting (CINV). Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. The safety profile of aprepitant was evaluated in approximately 6,500 individuals.

Oral aprepitant
The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %).

Tabulated list of adverse reactions - aprepitant
The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies in adults at a greater incidence with oral aprepitant than with standard therapy or in post marketing use:

Frequencies are defined as: 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) and very rare (<1/10,000), not known (cannot be estimated from the available data).
System organ class                        Adverse reaction                Frequency Infection and infestations       candidiasis, staphylococcal infection             rare Blood and lymphatic system       febrile neutropenia, anaemia                   uncommon disorders
Immune system disorders          hypersensitivity reactions including           not known anaphylactic reactions
Metabolism and nutrition         decreased appetite                              common disorders                        polydipsia                                        rare Psychiatric disorders            anxiety                                        uncommon disorientation, euphoric mood                     rare
Nervous system disorders         headache                                        common dizziness, somnolence                          uncommon cognitive disorder, lethargy, dysgeusia           rare
Eye disorders                    conjunctivitis                                    rare Ear and labyrinth disorders      tinnitus                                          rare Cardiac disorders                palpitations                                   uncommon bradycardia, cardiovascular disorder              rare
Vascular disorders               hot flush                                      uncommon Respiratory, thoracic and        hiccups                                         common mediastinal disorders            oropharyngeal pain, sneezing, cough,              rare postnasal drip, throat irritation
Gastrointestinal disorders       constipation, dyspepsia                         common eructation, nausea*, vomiting*,                uncommon gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence duodenal ulcer perforation, stomatitis,          rare abdominal distension, faeces hard,
neutropenic colitis
Skin and subcutaneous tissue     rash, acne                                     uncommon disorders                        photosensitivity reaction, hyperhidrosis,         rare seborrhoea, skin lesion, rash pruritic,
Stevens-Johnson syndrome/toxic epidermal necrolysis pruritus, urticaria                            not known
Musculoskeletal and              muscular weakness, muscle spasms                  rare connective tissue disorders
Renal and urinary disorders      dysuria                                        uncommon pollakiuria                                       rare
General disorders and            fatigue                                         common administration site conditions   asthaenia, malaise                             uncommon oedema, chest discomfort, gait disturbance        rare
Investigations                   ALT increased                                   common AST increased, blood alkaline phosphatase      uncommon increased red blood cells urine positive, blood sodium     rare decreased, weight decreased, neutrophil count decreased, glucose urine present,
urine output increased
*Nausea and vomiting were efficacy parameters in the first 5-days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.

Description of selected adverse reactions
The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies in adults for up to 6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.

In an additional active-controlled clinical study in 1,169 adult patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.

Additional adverse reactions were observed in adult patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.
*Reported in patients taking a higher dose of aprepitant

Fosaprepitant
In an active-controlled clinical study in adult patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND IV 150 mg compared to 1,169 patients receiving the 3-day regimen of aprepitant. Additionally, in a placebo-controlled clinical trial in adult patients receiving MEC, safety was evaluated for 504 patients receiving a single dose of EMEND IV 150 mg compared to 497 patients receiving the control regimen.

The safety profile was generally similar to that seen in the aprepitant table above.

Tabulated list of adverse reactions - fosaprepitant
The following are adverse reactions reported in adult patients receiving fosaprepitant in clinical studies or post marketing that have not been reported with aprepitant as described above: Frequencies are defined as: 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) and very rare (<1/10,000), not known (cannot be estimated from the available data).
System organ class                       Adverse reaction                     Frequency Vascular disorders              flushing, thrombophlebitis                         uncommon (predominantly, infusion-site thrombophlebitis)
Skin and subcutaneous           erythema                                           uncommon tissue disorders
General disorders and           infusion site erythema, infusion site pain,        uncommon administration site             infusion site pruritus conditions                      infusion site induration                               rare immediate hypersensitivity reactions               not known including flushing, erythema, dyspnoea,
anaphylactic reactions/anaphylactic shock
Investigations                  blood pressure increased                           uncommon 
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 events should be reported to the Ministry of Health according to the National Regulation by using an online form http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@mo h.gov.il