September 7, 2012
This information supersedes the FDA communication issued on September 22, 2010
On September 22, 2010, FDA informed healthcare providers and the public that it had approved revised Prescribing Information and patient labeling for Rotarix, a vaccine manufactured by GlaxoSmithKline Biologicals (GSK) for the prevention of gastroenteritis caused by rotavirus infection in infants 6 weeks to 24 weeks of age. After FDA completed an evaluation of preliminary results from a postmarketing study conducted in Mexico, information was added to the existing intussusception (a form of blockage of the intestines) subsection of the Warnings and Precautions section. The interim analysis of this study suggested an increased risk of intussusception in the 31 day time period after the first dose of Rotarix (relative risk of 1.8 with a 99% confidence interval of 1.0 to 3.1).
These findings translated to potentially 0-4 additional cases of intussusception hospitalizations per 100,000 vaccinated infants within 31 days after the first dose of Rotarix in the United States. This took into consideration the rate of the natural occurrence (without vaccination) of intussusception hospitalizations in the United States, which is approximately 34 in 100,000 infants in the first year of life.
Further analysis showed that the increased number of intussusception cases occurred primarily within seven days after the first dose.
This information was also included in the Postmarketing Experience subsection of the Adverse Reactions section of the prescribing information and in the information for the patient.
The study in Mexico has been completed and FDA has evaluated the final results. The results show that Mexican infants diagnosed with intussusception were more likely to have developed this condition within the first month following the first dose of Rotarix, but particularly in the first week (7 days) following vaccination, compared to other points of time in the first year of life. FDA has approved revised Prescribing Information and patient labeling to reflect this information.
Summary information on the study conducted in Mexico
As a postmarketing commitment for the European Medicines Agency (EMA), GSK conducted a study in Mexico, where infants routinely receive Rotarix. The study was conducted at participating hospitals in Mexico that provided health services to approximately 1 million infants less than 1-year of age, over a two-year period. At these hospitals, 750 infants were diagnosed with intussusception during the study time period and therefore were included in the study. The goal of the study was to evaluate the association between Rotarix and intussusception following vaccination. As expected, because of the routine use of Rotarix in Mexico, most (698) of the 750 infants had been vaccinated with 1 dose or 2 doses of Rotarix.
What changes have been made to the Prescribing Information and patient labeling for Rotarix?
Revised information has been added to the existing intussusception subsection of the Warnings and Precautions section to inform healthcare providers that the final results from the postmarketing study conducted in Mexico showed an association between the first dose of Rotarix and intussusception; the highest risk period was within 7 days after vaccination. This information is now included in the Warnings and Precautions subsection of the Highlights section.
The Postmarketing Experience subsection of the Adverse Reactions section explains that among those infants identified with intussusception, the incidence of intussusception during the first 7 days after vaccination with Rotarix and during the 31-day period after vaccination with Rotarix was compared to a control period. The control period was from birth to one year, excluding the pre-defined risk period (first 7 days or first 31 days postvaccination, respectively).
Among 750 infants with intussusception, the relative incidence of intussusception in the 31‑day period after the first dose of Rotarix compared to the control period was 1.96 (95.5% CI: 1.46, 2.63)]; the relative incidence of intussusception in the first 7 days after the first dose of Rotarix compared to the control period was 6.07(95.5% CI: 4.20, 8.63). The analyses did not take into account all medical conditions that may have predisposed these infants to intussusception.
This signifies that Mexican infants diagnosed with intussusception were approximately 2 times more likely to have developed intussusception within 31 days following the first dose of Rotarix and were approximately 6 times more likely to have developed it in the first 7 days after the first dose of Rotarix, compared to other points of time in the first year of life.
The patient labeling conveys that a study in Mexico shows an increased risk of intussusception in the first month, but especially in the first 7 days, after the first dose of Rotarix.
What do these findings mean for the infant population in the United States who may receive Rotarix?
It may not be possible to generalize the findings to infants in the United States who have a lower yearly rate of naturally occurring (without vaccination) intussusception hospitalizations than Mexican infants. The Mexico study did not take into account all medical conditions that may have predisposed infants to intussusception. However, if an increased risk for intussusception following administration of Rotarix similar to that observed in Mexico does exist in the United States, it is estimated that approximately 1 to 3 additional cases of intussusception hospitalizations per 100,000 infants in the United States might occur within 7 days after receiving the first dose of Rotarix. This takes into consideration the yearly rate of the natural occurrence (without vaccination) of intussusception hospitalizations in the United States of approximately 34 in 100,000 infants less than 1-year of age. Studies to assess the risk of intussusception following administration of Rotarix in infants in the United States are currently underway.
Was the risk for intussusception evaluated before FDA approved Rotarix for infants in the United States?
Rotarix was determined to be effective in preventing both severe and mild cases of rotavirus-caused gastroenteritis during the first two years of life. The most common adverse reactions reported during clinical trials were fussiness, irritability, cough, runny nose, fever, loss of appetite and vomiting.
GSK conducted a study of more than 63,000 infants to assess whether there was an increased risk of intussusception. In that study, there was no increase in the risk of intussusception in those who received Rotarix (31,673 infants) compared to those who received placebo (31,552 infants). FDA approved Rotarix in April 2008 and required GSK to conduct a post-marketing safety study involving more than 40,000 infants to provide additional safety information. This study is ongoing and is currently enrolling study participants.
Are there any studies underway for Rotarix to assess the risk of intussusception in infants in the United States?
GSK is also conducting a postmarketing study in the United States to assess the potential risk of intussusception after vaccination and to identify unexpected serious risks that, based on available data, have the potential to occur with Rotarix. This study is ongoing and is currently enrolling study participants.
In addition, FDA is currently conducting a study in the Post Licensure Rapid Immunization Monitoring system (PRISM) to evaluate the risk of intussusception following administration of Rotarix. (http://mini-sentinel.org/work_products/PRISM/PRISM_Summary.pdf)
What does FDA want healthcare providers and parents and caregivers to keep in mind when Rotarix is administered?
Parents should closely watch their infants for signs of intussusception, especially within the first 7 days after vaccination with Rotarix. These include, stomach pain, vomiting, diarrhea, blood in the stool or change in bowel movements. It is important to contact the child's healthcare provider if the child has any of these signs at any time after vaccination, even if it has been several weeks since the last dose of vaccine.
The benefits of rotavirus vaccination are substantial, and include prevention of hospitalization for severe rotavirus disease and death in the U.S. and in other parts of the world. The benefits of rotavirus vaccination, which are known, outweigh any increased risk for intussusception.
Are there other vaccines licensed by FDA to protect infants from rotavirus disease?
Yes, FDA licensed RotaTeq, manufactured by Merck and Co., Inc., in February 2006. Like Rotarix, it is a live virus vaccine given to infants by mouth to prevent rotavirus disease.
Was the RotaTeq labeling changed with regard to intussusception?
No. The study conducted in Mexico did not evaluate RotaTeq. Information from studies that included fewer infants than the Mexico study has been evaluated by FDA does not indicate an increased risk of intussusception with RotaTeq. For example, a study conducted by the Vaccine Safety Datalink, a large database used by FDA and the CDC for vaccine safety monitoring, compared the rates of intussusception in infants who received RotaTeq with rates of intussusception in infants who did not receive RotaTeq in two analyses. No significant increased risk of intussusception was identified in either analysis. However, the number of infants evaluated is not large enough to rule out the level of risk observed in the postmarketing study of Rotarix in Mexico. FDA’s PRISM system is evaluating the risk of intussusception following RotaTeq which will provide more safety information and help to better understand if there is an increased risk of intussusception following vaccination with RotaTeq.
What is intussusception?
Intussusception is a serious and potentially life-threatening condition that occurs when the intestine gets blocked or twisted. One portion of the intestine telescopes into a nearby portion, causing the intestinal obstruction. The most common site is where the small intestine joins the large intestine. Because the two walls of the intestines press against each other, this causes inflammation, swelling, and eventually decreased blood flow. If it is not detected early, internal bleeding, a hole in the intestines and infection in the abdomen may occur because the intestinal tissue has died from the decreased blood flow. With prompt detection and treatment, almost all patients fully recover.
Intussusception can occur spontaneously in the absence of vaccination and people of any age can get intussusception, although it is most common among infants in the first year of life, generally between the ages of 5 and 9 months, and occurs in the United States in approximately 34 in 100,000 infants per year.
Are the vaccines that prevent rotavirus safe?
Although no medical products, such as vaccines or drugs, are 100 percent safe or effective, both Rotarix and RotaTeq have strong safety records, including clinical trials involving tens of thousands of infants as well as post-marketing experience with millions of recipients.
What is rotavirus disease and how commonly does it occur?
Rotavirus disease is the leading cause of severe diarrhea and dehydration in young infants worldwide. In the United States, the disease occurs more often during the winter, with most infections occurring from November to May. Most children, whether in the United States or elsewhere, are infected with rotavirus before they are two years old. Rotavirus disease is estimated to be responsible for the deaths of more than 500,000 infants around the world each year, primarily in poorer countries.
Before the introduction of a rotavirus vaccine in the United States, rotavirus resulted in an estimated 55,000-70,000 hospitalizations and 20-40 infant deaths in the United States each year.