Adverse reactions : תופעות לוואי

6       ADVERSE REACTIONS
See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm (5.1) and allergic-like reactions (5.2), and for safety information in patients with underlying airways disease (5.1).
6.1     Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The placebo used in clinical trials consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation.
Treatment of Influenza: Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence 1.5% in treatment trials are listed in Table 1. This table shows adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).


Table 1. Summary of Adverse Events 1.5% Incidence During Treatment in Adults and Adolescents
RELENZA
10 mg b.i.d.       All Dosing              Placebo
Inhaled         Regimens    a      (Lactose Vehicle)
Adverse Event                 (n = 1,132)       (n = 2,289)           (n = 1,520) Body as a whole
Headaches                                 2%                2%                     3% Digestive
Diarrhea                                  3%                3%                     4% Nausea                                    3%                3%                     3% Vomiting                                  1%                1%                     2% Respiratory
Nasal signs and symptoms                  2%                3%                     3% Bronchitis                                2%                2%                     3% Cough                                     2%                2%                     3% Sinusitis                                 3%                2%                     2% Ear, nose, and throat infections          2%                1%                     2% Nervous system
Dizziness                                 2%                1%                    <1% a
Includes trials where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently recommended dose.

Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.
The most frequent laboratory abnormalities in Phase III treatment trials included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness.
Clinical Trials in Pediatric Subjects: Adverse events that occurred with an incidence 1.5% in children receiving treatment doses of RELENZA in 2 Phase III trials are listed in Table 2. This table shows adverse events occurring in pediatric Subjects aged 5 to 12 years old receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA).


Table 2. Summary of Adverse Events 1.5% Incidence During Treatment in Pediatric Subjectsa
RELENZA                     Placebo
10 mg b.i.d. Inhaled       (Lactose Vehicle)
Adverse Event                       (n = 291)                 (n = 318) Respiratory
Ear, nose, and throat infections                5%                        5% Ear, nose, and throat hemorrhage               <1%                        2% Asthma                                         <1%                        2% Cough                                          <1%                        2% Digestive
Vomiting                                        2%                        3% Diarrhea                                        2%                        2% Nausea                                         <1%                        2% a
Includes a subset of subjects receiving RELENZA for treatment of influenza in a prophylaxis trial.

In 1 of the 2 trials described in Table 2, some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients.

6.2     Postmarketing Experience
In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of zanamivir (RELENZA). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (RELENZA).
Allergic Reactions: Allergic or allergic-like reaction, including oropharyngeal edema [see Warnings and Precautions (5.2)].
Psychiatric: Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares [see Warnings and Precautions (5.3)].
Cardiac: Arrhythmias, syncope.

Neurologic: Seizures. Vasovagal-like episodes have been reported shortly following inhalation of zanamivir.
Respiratory: Bronchospasm, dyspnea [see Warnings and Precautions (5.1)].
Skin: Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria [see Warnings and Precautions (5.2)].

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@m oh.gov.il