There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving oseltamivir phosphate [see Adverse Reactions (6.2) ]. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir phosphate usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, 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. Closely monitor oseltamivir phosphate capsules-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing oseltamivir phosphate capsules for each patient.
There is no evidence for efficacy of oseltamivir phosphate capsules in any illness caused by pathogens other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Oseltamivir phosphate capsules has not been shown to prevent such complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.
The following serious adverse reactions are discussed below and elsewhere in the labeling:
• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1) ]
• Neuropsychiatric events [see Warnings and Precautions (5.2) ]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions from Treatment and Prophylaxis Trials in Adult and Adolescent Subjects (13 years of age and older)
The overall safety profile of oseltamivir phosphate is based on data from 2,646 adult and adolescent subjects that received the recommended dosage of 75 mg orally twice daily for 5 days for treatment of influenza and 1,943 adult and adolescent subjects that received the recommended dosage of 75 mg orally once daily for up to 6 weeks for prophylaxis of influenza in clinical trials.
The most common adverse reactions in the pooled treatment and pooled prophylaxis trials in adults and adolescents are displayed in Table 5. The majority of these adverse reactions were reported on a single occasion, occurred on either the first or second treatment day and resolved spontaneously within 1-2 days. This summary includes otherwise healthy adults/adolescents and subjects “at risk” (subjects at higher risk of developing complications associated with influenza, e.g., elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the subjects “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents.Table 5 Adverse Reactions Occurring in ≥1% of Adults and Adolescents (13 years of age and older) in Treatment and Prophylaxis Trials*
|System Organ Class Adverse Reaction||Treatment Trials||Prophylaxis Trials|
|Oseltamivir phosphate 75 mg twice daily (n = 2646)||Placebo (n = 1977)||Oseltamivir phosphate 75 mg once daily (n = 1943)||Placebo (n = 1586)|
|Nervous System Disorders Headache General Disorders Pain||2%<1%||1%<1%||17%4%||16%3%|
* Adverse reactions that occurred in ≥1% of oseltamivir phosphate-treated adults and adolescents and ≥1% greater in oseltamivir phosphate-treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials.
Adverse Reactions from Treatment and Prophylaxis Trials in Pediatric Subjects (1 year to 12 years of age)
A total of 1,481 pediatric subjects (including otherwise healthy pediatric subjects aged 1 year to 12 years and asthmatic pediatric subjects aged 6 to 12 years) participated in clinical trials of oseltamivir phosphate for the treatment of influenza. A total of 859 pediatric subjects received treatment with oseltamivir phosphate for oral suspension either at a 2 mg per kg twice daily for 5 days or weight-band dosing. Vomiting was the only adverse reaction reported at a frequency of >1% in subjects receiving oseltamivir phosphate (16%) compared to placebo (8%).
Amongst the 148 pediatric subjects aged 1 year to 12 years who received oseltamivir phosphate at doses of 30 to 60 mg once daily for 10 days in a post-exposure prophylaxis study in household contacts (n = 99), and in a separate 6– week seasonal influenza prophylaxis safety study (n = 49), vomiting was the most frequent adverse reaction (8% on oseltamivir phosphate versus 2% in the no prophylaxis group).
Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age)
Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open-label studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age) exposed to oseltamivir phosphate at doses ranging from 2 to 3.5 mg per kg of the formulation for oral suspension twice daily orally for 5 days. The safety profile of oseltamivir phosphate was similar across the age range studied, with vomiting (9%), diarrhea (7%) and diaper rash (7%) being the most frequently reported adverse reactions, and was generally comparable to that observed in older pediatric and adult subjects.
Adverse Reactions from the Prophylaxis Trial in Immunocompromised Subjects
In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 year to 12 years of age, the safety profile in the 238 subjects receiving oseltamivir phosphate 75 mg once daily was consistent with that previously observed in other oseltamivir phosphate prophylaxis clinical trials [see Clinical Studies (14.2) ].
The following adverse reactions have been identified during post-approval use of oseltamivir phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to oseltamivir phosphate exposure.
General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia
Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)]
Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis
Cardiac Disorders: Arrhythmia
Hepatobiliary Disorders: Hepatitis, abnormal liver function tests
Nervous System Disorders: Seizure
Metabolism and Nutrition Disorders: Aggravation of diabetes
Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]
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