Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 43, Num. 3, 2011, pp. 258-261

Indian Journal of Pharmacology, Vol. 43, No. 3, May-June, 2011, pp. 258-261

Research Article

Adverse drug reaction profile of oseltamivir in Indian population: A prospective observational study

Ashish P Anovadiya¹, Manish J Barvaliya¹, Rajesh A Shah², Vishal M Ghori¹, Jayesh J Sanmukhani¹, Tejas K Patel¹, CB Tripathi¹

¹ Department of Pharmacology, Government Medical College, Bhavnagar, Gujarat, India
² Department of Pharmacology, Government Dental College and Hospital, Ahmedabad, Gujarat, India

Correspondence Address: C B Tripathi, Department of Pharmacology, Government Medical College, Bhavnagar, Gujarat, India, cbrtripathi@yahoo.co.in

Date of Submission: 30-Jun-2010
Date of Decision: 13-Feb-2011
Date of Acceptance: 23-Feb-2011

Code Number: ph11071

DOI: 10.4103/0253-7613.81509

Abstract

Keywords: Adverse drug reactions, H1N1 influenza A, oseltamivir

Introduction

H1N1 influenza A (Swine flu) has caused major pandemic alarm. On June 11, 2009, the World Health Organization raised its pandemic alert to the highest level, phase 6, indicating widespread community transmission on at least two continents. ^[1] The first case of H1N1 influenza A was reported in California, United States, followed by hundreds of cases in Mexico. ^[2] In India, first case of H1N1 influenza A was diagnosed in May 16, 2009 in New Delhi and within one year of its occurrence, total number of H1N1 influenza A positive cases reached to 31 826, causing 1 509 deaths. ^[3] Genetic sequencing of this new H1N1 influenza A virus showed segments from the following four influenza viruses: North American Swine, North American Avian, Human Influenza and Eurasian Swine. ^[4]

Spread of the virus among human population takes place commonly through sneezing and coughing via large-particle aerosols as well as by contact with surfaces that have been contaminated with respiratory droplets. The incubation period of H1N1 infection ranges from 1 to 4 days. In human, frequently observed symptoms include sudden onset of fever (94%), cough (92%), sore throat (66%), running nose, and body ache. A significant number have diarrhea (25%) and vomiting (25%). ^[5] Abortion and preterm birth have also been reported among pregnant women, especially who had pneumonia. ^[6]

Oseltamivir and zanamivir are the antiviral drugs available for prophylaxis and treatment of H1N1 influenza A. Among them, oseltamivir is currently seen as the most suitable drug that can be taken orally, as zanamivir has to be taken in inhalation form. ^[7],[8] Oseltamivir is a potent selective neuraminidase enzyme inhibitor, which is responsible for cleaving sialic acid residues on newly formed virions and is essential for the release of recently formed viral particles from the infected cells. Thus, blocking this enzyme oseltamivir inhibits the release of progeny virions from the infected cells, thereby preventing and treating infection. Recommended therapeutic regimen is 75 mg twice a day for 5 days and 75 mg once a day for at least one week for prophylaxis. ^[7],[9],[10] Common adverse drug reactions (ADRs) found in phase III trial of oseltamivir are nausea, vomiting, diarrhea, abdominal pain, bronchitis, dizziness, vertigo, fatigue, and headache. ^[10] Even after thorough search, we could not find any study on safety of oseltamivir phosphate in Indian population. As this is a new drug with limited exposure, we planned this study to analyze ADR profile of oseltamivir in Indian population and to compare frequency of ADRs with the data available from phase III trial.

Materials and Methods

This prospective study was conducted at Sir Takhtsinhji General Hospital attached to Government Medical College, Bhavnagar, Gujarat, India between October, 2009 and April, 2010 during epidemic of H1N1 influenza A. Approval was taken from Institutional Review Board (IRB) Government Medical College, Bhavnagar, before starting the study. It was an observational study; inclusion criteria were suspected or confirmed cases of H1N1 influenza A receiving therapeutic regimen of oseltamivir, close contacts of cases H1N1 influenza A receiving prophylactic regimen of oseltamivir, and those who had given written informed consent. Oseltamivir was administered 75 mg once a day for 10 days in prophylactic group and 75 mg twice a day for 5 days in therapeutic group. Data were collected by personal interview after obtaining written informed consent in case record form approved by IRB. Interview was conducted during the treatment and follow-up was done after 15 days. Case record form included patient information including date of admission, date of discharge, age, gender, weight, duration of hospital stay, therapeutic group or prophylactic group, and drug information including date of starting therapy, dose, frequency of administration, duration of therapy, concomitant medications, and compliance. ADR, if any, time of ADR occurrence after drug ingestion, and rescue treatment given for ADRs were also recorded.

Data were analyzed for causality assessment by Naranjo′s scale ^[11] and severity assessment by modified Hartwig and Siegel′s scale. ^[12] Assessment of preventability is done by modified Schumock and Thornton scale. ^[13] The Naranjo′s algorithm is a questionnaire-based scale consisting of 10 objective questions with three types of answers--yes, no, or do not know. Scores are given accordingly and the drug reaction can be classified as definite (total score >9), probable (total score 5-8), or possible (total score 1-4). The modified Schumock and Thornton scale classifies ADRs as definitely preventable, probably preventable, and not preventable based on questions for each level. The modified Hartwig and Siegel scale classifies severity of ADR as mild, moderate, or severe, depending on factors like requirement for change in treatment, duration of hospital stay, and disability produced by the ADR. Records of all the individuals were coded and kept confidential. Data were expressed in proportions. Proportions in various groups were compared with phase III trial ^[10] of oseltamivir by using Chi-square test by GraphPad InStat 3.06 (demo version).

Results

Among the 294 patients interviewed, 107 (41.63%) in prophylactic group (n = 257, 132 male) and 23 (62.16%) in therapeutic group (n = 37, 19 male) reported ADRs. Total number of ADRs was significantly (P = 0.029) higher in therapeutic group. Predominant system involved was gastrointestinal system [Table - 1]; frequently observed ADRs in both groups were gastritis, nausea, vomiting, diarrhea weakness, sedation, sadness, loneliness, headache, and abdominal pain [Figure - 1]. In both groups, gastritis was the most common ADR. Some rare ADRs reported in both groups were vertigo, hair loss, and urgency of micturition. Compared with phase III trial of oseltamivir, frequency of most of ADRs were same except weakness which was significantly (P<0.001) higher in therapeutic group of Indian population, whereas headache was significantly (P<0.0001) higher in prophylactic group of phase III trial [Table - 2]. Assessment of causality by Naranjo′s scale has shown all ADRs in probable category in prophylactic group, whereas in therapeutic group, 27.78% in probable category and 72.22% in possible category [Table - 3]. On severity assessment by modified Hartwig and Siegel scale, 76% were mild and 24% were moderate ADRs in therapeutic group, whereas in prophylactic group, 89% were mild and 11% were moderate ADRs. There were no ADRs in severe category. Moderately severe ADRs were significantly (P = 0.0416) higher in therapeutic group. Preventability assessment by modified Schumock and Thornton Scale has shown gastritis, nausea, and vomiting in definitely preventable category, while diarrhea in probably preventable and others in not preventable category [Table - 4].

Discussion

Oseltamivir was approved for marketing in India on October 25, 2005, ^[14] but widespread use started after H1N1 influenza A pandemic, before that it was not used in India in such large mass, so there are no data available about its tolerability in Indian population. Some of well-documented ADRs in phase III clinical trial of oseltamivir are nausea, vomiting, diarrhea, bronchitis, abdominal pain, dizziness, headache, cough, insomnia, vertigo, and fatigue. ^[10] Our study also showed that gastrointestinal ADRs were most common, most of them were reported within two days of start of therapy. Gastritis was the most common ADR reported in both groups in our study, it was not documented in the phase III clinical trial. Gastritis can be prevented by taking the drug after meal or by co administration of H ₂ receptor antagonists and antacids, as oseltamivir has good absorption in the presence of food and no pharmacokinetic interaction with antacids. ^[7],[11] Frequency of ADRs reported in our study were similar to data of phase III trial, except weakness which was found to be significantly (P<0.001) higher in therapeutic group and headache was significantly (P<0.0001) less in prophylactic group in Indian population as compared with phase III trial.

Severity of ADRs was assessed by modified Hartwig and Siegel′s scale. Though most of ADRs in both the groups were mild and did not lead to discontinuation or withholding of drug, moderately severe ADRs were significantly higher in therapeutic group. This could be due to higher dose of drug used in this group. Most common moderately severe ADR was gastritis. No severe ADRs were found in our study. Naranjo′s causality score in therapeutic group remained low due to co administered drugs; there were no ADRs in definite category because rechallenge was not performed in our study. Preventability assessment showed most of ADRs in nonpreventable category, while gastritis, nausea, vomiting were in definitely preventable [Table - 4]. Limited data are available on safety of oseltamivir during pregnancy; two confirmed cases of H1N1 influenza A in third trimester of pregnancy were given therapeutic regimen of oseltamivir and followed for 2 months. Both of them had normal delivery and healthy newborn.

This drug was also linked with neuropsychiatric ADRs and suicide, especially in Japan, where hallucination, confusion, suicidal tendency, depression, and convulsion ^[15] were reported. In our study, except sedation, sadness, and loneliness, no other neuropsychiatric ADRs were found. Additional ADRs reported in phase III clinical trial like unstable angina, pseudomembranous colitis, anemia, peritonsillar abscess, and humerus fracture were not reported in our study. ^[10] Frequency of these ADRs in phase III trial were <1%; in our study, sample size was small that might be the reason why such ADRs were not reported. In our study, four female patients (three in prophylactic group and one in therapeutic group) of 20 to 24 years of age reported increased hair loss and two male patients (one in each group) aged 20 to 30 years reported urgency of micturition. Both the ADRs showed temporal association with oseltamivir. These ADRs have not been reported in phase III trial or any case report with oseltamivir before. Though there was no objective evidence as study was based on history and interviewing, we cannot ignore reporting these rare but unusual ADRs.

In conclusion, oseltamivir is well tolerated in Indian population, with gastrointestinal ADRs being most common, which can be easily prevented by taking the drug after meal or with H ₂ receptor antagonists and antacids. Similar studies can be used to assess prevention of expected ADRs.

References

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