"The U.S. Food and Drug Administration today approved the first adjuvanted vaccine for the prevention of H5N1 influenza, commonly known as avian or bird flu. The vaccine, Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, is for use in peopl"...
The following serious adverse reactions are discussed below and elsewhere in the labeling:
- Serious skin and hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
- Neuropsychiatric events [see WARNINGS AND PRECAUTIONS]
The most common adverse reactions are nausea and vomiting.
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment Studies in Adult and Adolescent Subjects (13 years of age and older)
A total of 1171 subjects who participated in adult controlled clinical trials for the treatment of influenza were treated with TAMIFLU. The most frequently reported adverse events in these studies were nausea and vomiting. These events were generally of mild to moderate severity and usually occurred on the first 2 days of administration. Less than 1% of subjects discontinued prematurely from clinical trials due to nausea and vomiting.
Adverse events that occurred with an incidence of 1% or greater in 1440 subjects taking placebo or TAMIFLU 75 mg twice daily in adult treatment studies are shown in Table 6. This summary includes 945 healthy young adults and 495 “at risk” subjects (elderly patients and patients with chronic cardiac or respiratory disease). Those events reported numerically more frequently in subjects taking TAMIFLU compared with placebo were nausea, vomiting, bronchitis, insomnia, and vertigo.
Prophylaxis Studies in Adult and Adolescent Subjects (13 years of age and older)
A total of 4187 subjects (adolescents, healthy adults, and elderly) participated in prophylaxis studies, of whom 1790 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing (see Table 6). Events reported more frequently in subjects receiving TAMIFLU compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhea, dyspepsia and upper respiratory tract infections. However, the difference in incidence between TAMIFLU and placebo for these events was less than 1%. There were no clinically relevant differences in the safety profile of the 942 elderly subjects who received TAMIFLU or placebo, compared with the younger population.
Table 6 : Most Frequent Adverse Events in Studies in
Naturally Acquired Influenza in Subjects 13 Years of Age and Older
|TAMIFLU 75 mg twice daily
|Placebo/ No Prophylaxis†
|TAMIFLU 75 mg once daily
|Nausea (without vomiting)||40(6%)||72(10%)||56(3%)||129 (7%)|
|Abdominal pain||16(2%)||16(2%)||25(1%)||37 (2%)|
|Vertigo||4(1%)||7(1%)||4( < 1%)||4 ( < 1%)|
|* Adverse events included are all events reported in the
treatment studies with frequency ≥ 1% in the TAMIFLU 75 mg twice daily
† The majority of subjects received placebo; 254 subjects from a randomized, open-label postexposure prophylaxis study in households did not receive placebo or prophylaxis therapy.
Additional adverse events occurring in less than 1% of patients receiving TAMIFLU for treatment included unstable angina, anemia, pseudomembranous colitis, humerus fracture, pneumonia, pyrexia, and peritonsillar abscess.
Treatment Studies in Pediatric Subjects (1 to 12 years of age)
A total of 1032 pediatric subjects aged 1 to 12 years (including 698 otherwise healthy pediatric subjects aged 1 to 12 years and 334 asthmatic pediatric subjects aged 6 to 12 years) participated in controlled clinical trials of TAMIFLU given for the treatment of influenza. A total of 515 pediatric subjects received treatment with TAMIFLU for oral suspension.
Adverse events occurring in 1% or greater of pediatric subjects receiving TAMIFLU treatment are listed in Table 7. The most frequently reported adverse event was vomiting. Other events reported more frequently by pediatric subjects treated with TAMIFLU included abdominal pain, epistaxis, ear disorder, and conjunctivitis. These events generally occurred once and resolved despite continued dosing resulting in discontinuation of drug in 8 out of 515 (2%) cases.
The adverse event profile in adolescents is similar to that described for adult subjects and pediatric subjects aged 1 to 12 years.
Prophylaxis Studies in Pediatric Subjects (1 to 12 years of age)
Pediatric subjects aged 1 to 12 years participated in a postexposure prophylaxis study in households, both as index cases (n=134) and as contacts (n=222). Gastrointestinal events were the most frequent, particularly vomiting. In a separate 6-week, uncontrolled, pediatric seasonal prophylaxis study (n=49), the adverse events noted were consistent with those previously observed (see Table 7).
Table 7 : Most Frequent Adverse Events Occurring in
Children Aged 1 to 12 Years in Studies in Naturally Acquired Influenza
|Adverse Event‡||Treatment Trials*||Household Prophylaxis Trial†|
|TAMIFLU 2 mg/kg twice daily
|Prophylaxis with TAMIFLU once daily§
|Asthma (including aggravated)||19(4%)||18(3%)||1(1%)||1(1%)|
|Conjunctivitis||2( < 1%)||5(1%)||-||-|
|Tympanic membrane disorder||6(1%)||5(1%)||-||-|
|* Pooled data from trials of
TAMIFLU treatment of naturally acquired influenza.
† A randomized, open-label study of household transmission in which household contacts received either prophylaxis or no prophylaxis but treatment if they became ill. Only contacts who received prophylaxis or who remained on no prophylaxis are included in this table.
‡ Adverse events included in Table 7are all events reported in the treatment studies with frequency ≥ 1% in the TAMIFLU 75 mg twice daily group.
§ Unit dose = age-based dosing of 30 mg, 45 mg, or 60 mg
Treatment Studies in Pediatric Subjects (2 weeks to less than 1 year of age)
Assessment of adverse reactions is 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 TAMIFLU at doses ranging from 2 to 3.5 mg/kg twice daily for 5 days. The safety profile was similar across the age range studied, with vomiting, diarrhea and diaper rash being the most frequently reported adverse reactions. The safety profile observed in subjects 2 weeks to less than 1 year of age was consistent with the established safety profile of adults and pediatric subjects older than 1 year of age.
Prophylaxis Study in Immunocompromised Subjects
In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 to 12 years of age, the safety profile in the 238 subjects receiving TAMIFLU was consistent with that previously observed in other TAMIFLU prophylaxis clinical trials.
The following adverse reactions have been identified during postapproval use of TAMIFLU. 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 TAMIFLU exposure.
Digestive: Hepatitis, liver function tests abnormal
Metabolic: Aggravation of diabetes
Psychiatric: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see WARNINGS AND PRECAUTIONS]
Read the Tamiflu (oseltamivir phosphate) Side Effects Center for a complete guide to possible side effects
The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.
Overall Drug Interaction Profile for Oseltamivir
Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low.
In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases.
Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Coadministration of probenecid results in an approximate two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid.
No pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), or warfarin.
Read the Tamiflu Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/24/2014
This monograph has been modified to include the generic and brand name in many instances.
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