Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The overall safety profile of Tamiflu is based on data from 6049 adult/adolescent and 1473 paediatric patients treated with Tamiflu or placebo for influenza, and on data from 3990 adult/adolescent and 253 paediatric patients receiving Tamiflu or placebo/no treatment for the prophylaxis of influenza in clinical trials. In addition, 199 immunocompromised adult patients received Tamiflu for the treatment of influenza and 475 immunocompromised patients (including 18 children, of these 10 Tamiflu and 8 placebo) received Tamiflu or placebo for the prophylaxis of influenza.

In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea and vomiting in the treatment studies, and nausea in the prevention studies. The majority of these ARs were reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1-2 days. In children, the most commonly reported adverse reaction was vomiting. In the majority of patients, these ARs did not lead to discontinuation of Tamiflu.

The following serious adverse reactions have been rarely reported since oseltamivir has been marketed: Anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant hepatitis, hepatic function disorder and jaundice), angioneurotic oedema, Stevens-Johnson syndrome and toxic epidermal necrolysis, gastrointestinal bleeding and neuropsychiatric disorders.
(Regarding neuropsychiatric disorders, see section 4.4.)

Tabulated list of adverse reactions
The ARs listed in the tables below fall into the following categories: Very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1,000 to < 1/100), rare (³ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). ARs are added to the appropriate category in the tables according to the pooled analysis from clinical studies.

Treatment and prevention of influenza in adults and adolescents:
In adult/adolescent treatment and prevention studies, ARs that occurred the most frequently at the recommended dose (75 mg bid for 5 days for treatment and 75 mg od for up to 6 weeks for prophylaxis) are shown in Table 1.

The safety profile reported in subjects who received the recommended dose of Tamiflu for prophylaxis (75 mg once daily for up to 6 weeks) was qualitatively similar to that seen in the treatment studies, despite a longer duration of dosing in the prophylaxis studies.

Table 1     Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in adults and adolescents or through post-marketing surveillance
System Organ                          Adverse reactions according to frequency Class (SOC)         Very common       Common             Uncommon            Rare Infections and                        Bronchitis,
infestations                          Herpes simplex,
Nasopharyngitis,
Upper respiratory tract infections,
Sinusitis


System Organ                            Adverse reactions according to frequency Class (SOC)          Very common        Common             Uncommon           Rare Blood and                                                                     Thrombocytopenia lymphatic system disorders
Immune system                                                 Hypersensitivity     Anaphylactic disorders                                                     reaction             reactions, Anaphylactoid reactions
Psychiatric                                                                        Agitation, disorders                                                                          Abnormal behaviour, Anxiety,
Confusion,
Delusions, Delirium,
Hallucination,
Nightmares,
Self-injury
Nervous system       Headache            Insomnia             Altered level of disorders                                                     consciousness, Convulsion
Eye disorders                                                                      Visual disturbance Cardiac                                                       Cardiac disorders                                                     arrhythmia Respiratory,                             Cough,
thoracic and                             Sore throat,
mediastinal                              Rhinorrhea disorders
Gastrointestinal     Nausea              Vomiting                                  Gastrointestinal disorders                                Abdominal pain                            bleedings, (incl. upper                              Haemorrhagic abdominal pain),                          colitis
Dyspepsia
Hepatobiliary                                                 Elevated liver       Fulminant hepatitis, disorders                                                     enzymes              Hepatic failure, Hepatitis
Skin and                                                      Eczema,              Angioneurotic subcutaneous                                                  Dermatitis,          oedema, tissue disorders                                              Rash,                Erythema Urticaria            multiforme,
Stevens-Johnson syndrome,
Toxic epidermal necrolysis
General                                  Pain disorders and                            Dizziness (incl.
administration                           vertigo),
site conditions                          Fatigue,
Pyrexia,
Pain in limb

Treatment and prevention of influenza in children 1 year of age:

A total of 1473 children (including otherwise healthy children aged 1-12 years old and asthmatic children aged 6-12 years old) participated in clinical studies of oseltamivir given for the treatment of influenza. Of those, 851 children received treatment with oseltamivir suspension. A total of 158 children received the recommended dose of Tamiflu once daily in a post-exposure prophylaxis study in households (n = 99), a 6-week paediatric seasonal prophylaxis study (n = 49) and a 12-week paediatric seasonal prophylaxis study in immunocompromised subjects (n = 10).

Table 2 shows the most frequently reported ARs from paediatric clinical trials.

Table 2      Adverse reactions in studies investigating Tamiflu for treatment and prevention of influenza in children (age/weight-based dosing [30 mg to 75 mg o.d.])

System Organ                       Adverse reactions according to frequency Class (SOC)            Very common       Common             Uncommon                           Rare Infections and                      Otitis media infestations
Nervous system                             Headache disorders
Eye disorders:                             Conjunctivitis
(including red eyes, eye discharge and eye pain)
Ear and                                    Ear ache              Tympanic labyrinth                                                        membrane disorder disorders:
Respiratory,          Cough,               Rhinorrhoea thoracic and          Nasal congestion mediastinal disorders
Gastrointestinal      Vomiting             Abdominal pain disorders                                  (incl. upper abdominal pain),
Dyspepsia,
Nausea
Skin and                                                         Dermatitis subcutaneous                                                     (including allergic tissue disorders                                                 and atopic dermatitis)

Description of selected adverse reactions

Psychiatric disorders and nervous system disorders
Influenza can be associated with a variety of neurologic and behavioural symptoms which can include events such as hallucinations, delirium, and abnormal behaviour, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.

In patients with influenza who were receiving Tamiflu, there have been postmarketing reports of convulsions and delirium (including symptoms such as altered level of consciousness, confusion, abnormal behaviour, delusions, hallucinations, agitation, anxiety, nightmares), in a very few cases resulting in self-injury or fatal outcomes. These events were reported primarily among paediatric and adolescent patients and often had an abrupt onset and rapid resolution. The contribution of Tamiflu to those events is unknown. Such neuropsychiatric events have also been reported in patients with influenza who were not taking Tamiflu.

Hepato-biliary disorders
Hepato-biliary system disorders, including hepatitis and elevated liver enzymes in patients with influenza-like illness. These cases include fatal fulminant hepatitis/hepatic failure.

Other special populations

Older people and patients with chronic cardiac and/or respiratory disease The population included in the influenza treatment studies is comprised of otherwise healthy adults/adolescents and patients “at risk” (patients at higher risk of developing complications associated with influenza, e.g. older people and patients with chronic cardiac or respiratory disease). In general, the safety profile in the patients “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.

Immunocompromised patients
In a double blind study for the treatment of influenza, a total of 199 adult immunocompromised patients (evaluable for safety) were randomized to receive Tamiflu for 10 days: 98 patients received the standard dose (75 mg twice daily) and 101 patients received the double dose (150 mg twice daily). The safety profile of Tamiflu observed in this study was consistent with that observed in previous clinical trials where Tamiflu was administered for treatment of influenza in non-immunocompromised patients (otherwise healthy patients or “at risk” patients [i.e., those with respiratory and/or cardiac co-morbidities]). The percentage of patients reporting adverse events was lower in the standard dose group compared to the double dose group (49.0% vs 59.4 %, respectively) (See section 5.1).

In a 12-week prophylaxis study in 475 immunocompromised patients, including 18 children 1 to 12 years of age and older, the safety profile in the 238 patients who received oseltamivir was consistent with that previously observed in Tamiflu prophylaxis clinical studies.

Children with pre-existing bronchial asthma
In general, the adverse reaction profile in children with pre-existing bronchial asthma was qualitatively similar to that of otherwise healthy children.

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 /https://sideeffects.health.gov.il