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Merck Updates Prescribing Information for Rotateq, the Company's Vaccine to Help Prevent Rotavirus Gastroenteritis in Infants and Children

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Feb 13, 2007 - Merck & Co., Inc. today updated the prescribing information for ROTATEQ(R) (rotavirus vaccine, live, oral pentavalent), the Company's vaccine to help prevent rotavirus gastroenteritis in infants and children.

The labeling update includes post-marketing reports of intussusception and hematochezia to the Vaccine Adverse Events Reporting System (VAERS), a national vaccine safety surveillance program. A naturally occurring event in infants, intussusception is estimated to occur in the U.S. in approximately 1 in 2,000 infants during the first year of life.

Cases of intussusception can occur when no vaccine has been given and the cause is usually unknown. Today, the U.S. Food and Drug Administration (FDA) reported that since the licensure of ROTATEQ on Feb. 3, 2006 until Jan. 31, 2007, 28 cases of intussusception in infants who received ROTATEQ have been reported in the U.S. to VAERS and that this number does not exceed the number of cases expected based on the background rate. The FDA Public Health Notification on this label change is available at http://www.fda.gov/cber/safety/phnrota021307.htm.

ROTATEQ is approved for the prevention of rotavirus gastroenteritis in infants and children caused by serotypes G1, G2, G3 and G4, and is administered as a three-dose series to infants between the ages of 6 to 32 weeks. Since approval, more than 3.5 million doses of ROTATEQ have been sold.

ROTATEQ was approved based on the results of the landmark Rotavirus Efficacy and Safety Trial (REST), which involved nearly 70,000 infants, about half receiving ROTATEQ and half receiving placebo. REST was specifically designed to evaluate vaccine safety with respect to intussusception. Intussusception occurs when the bowel folds in on itself causing an intestinal blockage. In REST, there was no increased risk of intussuception with ROTATEQ, compared to placebo.

"It is common for post-marketing experience information with a vaccine to be reported to VAERS and for the prescribing information to be updated accordingly," said Mark Feinberg, M.D., Ph.D, vice president of policy, public health and medical affairs, Merck Vaccines. "Merck places public health and patient safety as our highest priorities, and we are very confident in the data supporting the safety profile of ROTATEQ from the placebo-controlled Rotavirus Efficacy and Safety Trial. Merck will continue to work with the FDA and the Centers for Disease Control and Prevention (CDC) to monitor post-marketing experience with ROTATEQ by collecting data from additional systems including active, controlled surveillance studies in addition to passive reporting systems such as VAERS."

The "Adverse Reactions" section of the label for ROTATEQ has also been updated to include information on hematochezia (bloody stools) from the pre-licensure clinical trials. In REST, the rate of hematochezia was comparable between the vaccine and placebo recipients within six weeks following any dose.

VAERS is a national vaccine safety surveillance program cosponsored by the FDA and the CDC. VAERS collects and analyzes information from voluntary reports of adverse events that occur after the administration of licensed vaccines. A report to VAERS does not mean that a causal relationship between an event and vaccination has been established - just that the event occurred after vaccination. Merck encourages healthcare providers and consumers to report any adverse experience associated with ROTATEQ to the Company and to VAERS.

ROTATEQ is recommended by the CDC's Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP). Among children under five in the United States, it is estimated that 2.7 million episodes of rotavirus gastroenteritis occur each year, with an estimated 250,000 emergency room visits and up to 70,000 hospitalizations.

Selected Safety Information about ROTATEQ

ROTATEQ should not be administered to infants with a demonstrated history of hypersensitivity to any component of the vaccine. No safety or efficacy data are available for the administration of ROTATEQ to infants who are potentially immunocompromised, including those who have received blood products within 42 days of vaccination. Over 71,000 infants were evaluated in three placebo-controlled clinical trials. Serious adverse events occurred in 2.4% of recipients of ROTATEQ when compared to 2.6% of placebo recipients within the 42-day period of a dose of ROTATEQ. Hematochezia reported as a serious adverse event for ROTATEQ compared to placebo was less than 0.1% vs less than 0.1%. The most frequently reported serious adverse events for ROTATEQ compared to placebo were bronchiolitis (0.6% vs 0.7%), gastroenteritis (0.2% vs 0.3%), pneumonia (0.2% vs 0.2%), fever (0.1% vs 0.1%), and urinary tract infection (0.1% vs 0.1%).

In a subset of more than 11,000 infants in these trials, the presence of adverse events was reported for 42 days after each dose. Fever was observed at similar rates in vaccine and placebo recipients (42.6% vs 42.8%). Adverse events that occurred at a statistically higher incidence within 42 days of any dose among recipients of ROTATEQ as compared with placebo recipients were diarrhea (24.1% vs 21.3%), vomiting (15.2% vs 13.6%), otitis media (14.5% vs 13.0%), nasopharyngitis (6.9% vs 5.8%), and bronchospasm (1.1% vs 0.7%). In post-marketing experience, cases of intussusception have been reported in temporal association with ROTATEQ.

As with any vaccine, vaccination with ROTATEQ may not result in complete protection in all recipients.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Full prescribing information for ROTATEQ is attached.

ROTATEQ(R)is a registered trademark of Merck & Co., Inc. -0-

                                                               9714301


                          Patient Information

                RotaTeq(R)** (pronounced "RO-tuh-tek")

              rotavirus vaccine, live, oral, pentavalent


    You should read this information before your child receives the

RotaTeq vaccine and ask your child's doctor any questions you may

have. Your child will need 3 doses of the vaccine over the course of a

few months. So read the leaflet before your child receives each dose

of the vaccine in case any of the information about the vaccine

changes. This leaflet is a summary of certain information about the

vaccine. If you would like additional information, your health care

provider can give you more complete information about this vaccine

that is written for health care professionals. This leaflet does not

take the place of talking with your child's doctor.


    What is RotaTeq and How Does it Work?


    RotaTeq is a vaccine that can help protect your child from getting

a virus infection that can cause fever, vomiting, and diarrhea. The

vaccine is given by mouth at 3 different times, each about one to two

months apart. Nearly all children become infected with the rotavirus

by the time they are 5 years old.


    RotaTeq helps protect against diarrhea and vomiting only if they

are caused by the rotavirus. It does not protect against diarrhea and

vomiting that are caused by anything else.


    RotaTeq may not fully protect all children that get the vaccine,

and if your child already has the virus it will not help them.


    What are the Symptoms of a Rotavirus Infection?


    Infection with the Rotavirus is the most common cause of severe

diarrhea in infants. Sometimes the diarrhea and vomiting can be severe

and lead to the loss of body fluids (dehydration) and even to death.


    Signs that your infant is dehydrated include:


    --  Sleepiness


    --  Dry mouth and tongue


    --  Fussiness


    --  Dry diaper for several hours


    If your infant shows signs that they are dehydrated, you should

call the doctor immediately.


    What should I tell the doctor before my child gets RotaTeq?


    There are some things your doctor should know before your child

gets the vaccine. You should tell your doctor if your child:


    --  Has any illness with fever. A mild fever or cold by itself is

        not a reason to delay taking the vaccination.


    --  Has diarrhea or has been vomiting.


    --  Has not been gaining weight.


    --  Is not growing as expected.


    --  Has a blood disorder.


    --  Has any type of cancer.


    --  Has a weak immune system because of a disease (this includes

        HIV/AIDS).


    --  Gets treatment or takes medicines that may weaken the immune

        system (such as high doses of steroids) or has received a

        blood transfusion or blood products within the past 42 days.


    --  Was born with gastrointestinal problems, or has had a blockage

        or abdominal surgery.


    --  Has regular close contact with a member of the family or

        household who has a weakened immune system. For example, a

        person in the house with cancer or one who is taking medicines

        that may weaken their immune system.


    Who should not receive RotaTeq?


    Your child should not get the vaccine if:


    --  He or she had an allergic reaction after getting a dose of

        this vaccine.


    --  He or she is allergic to any of the ingredients of the

        vaccine. A list of ingredients can be found at the end of this

        leaflet.


    What important information should I know about RotaTeq?


    Intussusception is a serious and life-threatening event that

occurs when a part of the intestine (the tube that goes from the

stomach to the anus) gets blocked or twisted. Cases of intussusception

can occur when no vaccine has been given and the cause is usually

unknown. However, a different rotavirus vaccine was associated with

intussusception and is no longer available.


    In clinical trials, RotaTeq was studied in 70,000 infants (35,000

infants received RotaTeq and 35,000 received placebo), and no

increased risk of intussusception was found. However, since RotaTeq

has been on the market, cases of intussusception in infants who

received RotaTeq have been reported to the Vaccine Adverse Event

Reporting System (VAERS). Intussusception occurred at various times

after vaccination with RotaTeq. Some of these infants required

hospitalization and surgery on their intestine or a special enema to

treat this problem.


    Call your child's doctor right away if your child has vomiting,

diarrhea, severe stomach pain, blood in their stool or change in their

bowel movements as these may be signs of intussusception. It is

important to contact your doctor if you have questions or if your

child has any of these symptoms, at any time after vaccination, even

if it has been several weeks since the last vaccine dose.


    What are the possible side effects of RotaTeq?


    The most common side effects reported after taking RotaTeq were

diarrhea, vomiting, fever, runny nose and sore throat, wheezing or

coughing, and ear infection.


    These are NOT all the possible side effects of RotaTeq. You can

ask your doctor or health care provider for a more complete list.


    If your child seems to be having any side effects that are not

mentioned in this leaflet, please call your doctor or other healthcare

provider. If the condition continues or worsens, you should seek

medical attention.


    You, as a parent or guardian may also report any adverse reactions

to your child's health care provider or directly to the Vaccine

Adverse Event Reporting System (VAERS). The VAERS toll-free number is

1-800-822-7967 or report on line to www.vaers.hhs.gov.


    Can RotaTeq be given with other vaccines?


    Your child may get RotaTeq at the same time as other childhood

vaccines.


    How is RotaTeq given?


    The vaccine is given by mouth. Your child will receive 3 doses of

the vaccine. The first dose is given when your child is 6 to 12 weeks

of age, the second dose is given 4 to 10 weeks later and the third

dose is given 4 to 10 weeks after the second dose. The last (third)

dose should be given to your child by 32 weeks of age.


    Your health care provider will gently squeeze the vaccine into

your child's mouth (see Figure 1). Your infant may spit out some or

all of it. If this happens, the dose does not need to be given again

during that visit.


    What do I do if my child misses a dose of RotaTeq?


    All 3 doses of the vaccine should be given to your child by 32

weeks of age. Your health care provider will tell you when your child

should come for the follow-up doses. It is important to keep those

appointments. If you forget or are not able to go back at the planned

time, ask your health care provider for advice.


    What else should I know about RotaTeq?


    This leaflet gives a summary of certain information about the

vaccine. If you have any questions or concerns about RotaTeq, talk to

your health care provider. You can also visit www.rotateq.com.


    What are the ingredients in RotaTeq?


    Active Ingredient: 5 live rotavirus strains (G1, G2, G3, G4, and

P1).


    Inactive Ingredients: sucrose, sodium citrate, sodium phosphate

monobasic monohydrate, sodium hydroxide, polysorbate 80 and also fetal

bovine serum.


    Rx only


    Issued January 2007


    Registered trademark of MERCK & Co., Inc., Whitehouse Station, NJ,

08889 USA COPYRIGHT (C) 2006 MERCK & Co., Inc. All rights reserved

-0-
RotaTeq(R)                                                     9714301

Rotavirus Vaccine, Live, Oral, Pentavalent)


     DESCRIPTION


    RotaTeq* is a live, oral pentavalent vaccine that contains 5 live

reassortant rotaviruses. The rotavirus parent strains of the

reassortants were isolated from human and bovine hosts. Four

reassortant rotaviruses express one of the outer capsid proteins (G1,

G2, G3, or G4) from the human rotavirus parent strain and the

attachment protein (P7) from the bovine rotavirus parent strain. The

fifth reassortant virus expresses the attachment protein, P1A

(genotype P(8)), hereafter referred to as P1(8), from the human

rotavirus parent strain and the outer capsid protein G6 from the

bovine rotavirus parent strain (see Table 1).


                                Table 1

                                             Reassortant

                                  Bovine        Outer

                                 Rotavirus      Surface

             Human Rotavirus       Parent      Protein

                  Parent        Strain and    Composition Minimum Dose

                 Strains           Outer       (Human        Levels

            and Outer Surface     Surface     Rotavirus     (10(6)

  Name of         Protein        Protein       Component   infectious

Reassortant    Compositions     Composition    in Bold)      units)

----------------------------------------------------------------------

    G1       WI79 - G1, P1(8)                 G1, P7(5)           2.2

-------------------------------             --------------------------

    G2       SC2 - G2, P2(6)    WC3 - G6,     G2, P7(5)           2.8

-------------------------------    P7(5)    --------------------------

    G3       WI78 - G3, P1(8)                 G3, P7(5)           2.2

-------------------------------             --------------------------

    G4       BrB - G4, P2(6)                  G4, P7(5)           2.0

-------------------------------             --------------------------

   P1(8)     WI79 - G1, P1(8)                 G6, P1(8)           2.3

----------------------------------------------------------------------


    The reassortants are propagated in Vero cells using standard cell

culture techniques in the absence of antifungal agents.


    The reassortants are suspended in a buffered stabilizer solution.

Each vaccine dose contains sucrose, sodium citrate, sodium phosphate

monobasic monohydrate, sodium hydroxide, polysorbate 80, cell culture

media, and trace amounts of fetal bovine serum. RotaTeq contains no

preservatives.


    RotaTeq is a pale yellow clear liquid that may have a pink tint.


    CLINICAL PHARMACOLOGY


    Rotavirus is a leading cause of severe acute gastroenteritis in

infants and young children, with over 95% of these children infected

by the time they are 5 years old.(1) The most severe cases occur among

infants and young children between 6 months and 24 months of age.(2)


    Mechanism of Action


    The exact immunologic mechanism by which RotaTeq protects against

rotavirus gastroenteritis is unknown (see CLINICAL STUDIES,

Immunogenicity). RotaTeq is a live viral vaccine that replicates in

the small intestine and induces immunity.


    CLINICAL STUDIES


    Overall, 72,324 infants were randomized in 3 placebo-controlled,

phase 3 studies conducted in 11 countries on 3 continents. The data

demonstrating the efficacy of RotaTeq in preventing rotavirus

gastroenteritis come from 6,983 of these infants from the US

(including Navajo and White Mountain Apache Nations) and Finland who

were enrolled in 2 of these studies: the Rotavirus Efficacy and Safety

Trial (REST) and Study 007. The third trial, Study 009, provided

clinical evidence supporting the consistency of manufacture and

contributed data to the overall safety evaluation.


    The racial distribution of the efficacy subset was as follows:

White (RotaTeq 68%, placebo 69%); Hispanic-American (RotaTeq 10%,

placebo 9%); Black (2% in both groups); Multiracial (RotaTeq 4%,

placebo 5%); Asian (less than 1% in both groups); Native American 

(RotaTeq 15%, placebo 14%), and Other (less than 1% in both groups).

The gender distribution was 52% male and 48% female in both

vaccination groups.


    The efficacy evaluations in these studies included: 1) Prevention

of any grade of severity of rotavirus gastroenteritis; 2) Prevention

of severe rotavirus gastroenteritis, as defined by a clinical scoring

system; and 3) Reduction in hospitalizations due to rotavirus

gastroenteritis.


    The vaccine was given as a three-dose series to healthy infants

with the first dose administered between 6 and 12 weeks of age and

followed by two additional doses administered at 4- to 10-week

intervals. The age of infants receiving the third dose was 32 weeks of

age or less. Oral polio vaccine administration was not permitted;

however, other childhood vaccines could be concomitantly administered.

Breast-feeding was permitted in all studies.


    The case definition for rotavirus gastroenteritis used to

determine vaccine efficacy required that a subject meet both of the

following clinical and laboratory criteria: (1) greater than or equal

to 3 watery or looser-than-normal stools within a 24-hour period

and/or forceful vomiting; and (2) rotavirus antigen detection by

enzyme immunoassay (EIA) in a stool specimen taken within 14 days of

onset of symptoms. The severity of rotavirus acute gastroenteritis was

determined by a clinical scoring system that took into account the

intensity and duration of symptoms of fever, vomiting, diarrhea, and

behavioral changes.


    The primary efficacy analyses included cases of rotavirus

gastroenteritis caused by serotypes G1, G2, G3, and G4 that occurred

at least 14 days after the third dose through the first rotavirus

season post vaccination.


    Analyses were also done to evaluate the efficacy of RotaTeq

against rotavirus gastroenteritis caused by serotypes G1, G2, G3, and

G4 at any time following the first dose through the first rotavirus

season postvaccination among infants who received at least one

vaccination (Intent-to-treat, ITT).


    Rotavirus Efficacy and Safety Trial


    Primary efficacy against any grade of severity of rotavirus

gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or

G4 through the first rotavirus season after vaccination was 74.0%

(95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5,

67.1). Primary efficacy against severe rotavirus gastroenteritis

caused by naturally occurring serotypes G1, G2, G3, or G4 through the

first rotavirus season after vaccination was 98.0% (95% CI: 88.3,

100.0), and ITT efficacy was 96.4%, (95% CI: 86.4, 99.6). See Table 2.


                               Table 2

Efficacy of RotaTeq against any grade of severity of and severe* G1-4

     rotavirus gastroenteritis through the first rotavirus season

                        postvaccination in REST

----------------------------------------------------------------------


                                 Per Protocol       Intent-to-Treat+

                               RotaTeq  Placebo   RotaTeq    Placebo

----------------------------------------------------------------------

Subjects vaccinated              2,834    2,839      2,834      2,839

Gastroenteritis cases

 Any grade of severity              82      315        150        371

 Severe*                             1       51          2         55

----------------------------------------------------------------------

Efficacy estimate % and (95%

 confidence interval)

----------------------------------------------------------------------

  Any grade of severity                    74.0                  60.0

                                    (66.8, 79.9)          (51.5, 67.1)

 Severe*                                   98.0                  96.4

                                   (88.3, 100.0)          (86.4, 99.6)

----------------------------------------------------------------------

*Severe gastroenteritis defined by a clinical scoring system based

on the intensity and duration of symptoms of fever, vomiting,

diarrhea, and behavioral changes

+ITT analysis includes all subjects in the efficacy cohort who

received at least one dose of vaccine.


    The efficacy of RotaTeq against severe disease was also

demonstrated by a reduction in hospitalizations for rotavirus

gastroenteritis among all subjects enrolled in REST. RotaTeq reduced

hospitalizations for rotavirus gastroenteritis caused by serotypes G1,

G2, G3, and G4 through the first two years after the third dose by

95.8% (95% CI: 90.5, 98.2). The ITT efficacy in reducing

hospitalizations was 94.7% (95% CI: 89.3, 97.3) as shown in Table 3.



                               Table 3

       Efficacy of RotaTeq in reducing G1-4 rotavirus-related

                       hospitalizations in REST


                                        Per Protocol     Intent-to-

                                                            Treat*

                                       RotaTeq Placebo RotaTeq Placebo

----------------------------------------------------------------------

Subjects vaccinated                    34,035  34,003  34,035  34,003

Number of hospitalizations                  6     144      10     187

----------------------------------------------------------------------

Efficacy estimate % and                          95.8            94.7

(95% confidence interval)                 (90.5, 98.2)    (89.3, 97.3)

----------------------------------------------------------------------

*ITT analysis includes all subjects who received at least one dose

of vaccine.


    Study 007


    Primary efficacy against any grade of severity of rotavirus

gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or

G4 through the first rotavirus season after vaccination was 72.5%

(95% CI: 50.6, 85.6) and the ITT efficacy was 58.4% (95% CI: 33.8,

74.5). Primary efficacy against severe rotavirus gastroenteritis

caused by naturally occurring serotypes G1, G2, G3, or G4 through the

first rotavirus season after vaccination was 100% (95% CI: 13.0,

100.0) and ITT efficacy against severe rotavirus disease was 100%,

(95% CI: 30.9, 100.0) as shown in Table 4.


                               Table 4

Efficacy of RotaTeq against any grade of severity of and severe* G1-4

     rotavirus gastroenteritis through the first rotavirus season

                     postvaccination in Study 007


                                     Per Protocol    Intent-to-Treat+

                                   RotaTeq  Placebo  RotaTeq  Placebo

----------------------------------------------------------------------

Subjects vaccinated                    650      660      650      660

Gastroenteritis cases

Any grade of severity                   15       54       27       64

Severe*                                  0        6        0        7

----------------------------------------------------------------------

Efficacy estimate % and (95% confidence interval)

----------------------------------------------------------------------

Any grade of severity                          72.5              58.4

                                        (50.6, 85.6)      (33.8, 74.5)

Severe*                                       100.0             100.0

                                       (13.0, 100.0)     (30.9, 100.0)

----------------------------------------------------------------------

*Severe gastroenteritis defined by a clinical scoring system ba sed on

 the intensity and duration of symptoms of fever, vomiting, diarrhea,

 and behavioral change

+ITT analysis includes all subjects in the efficacy cohort who

 received at least one dose of vaccine.



    Multiple Rotavirus Seasons


    The efficacy of RotaTeq through a second rotavirus season was

evaluated in a single study (REST). Efficacy against any grade of

severity of rotavirus gastroenteritis caused by rotavirus serotypes

G1, G2, G3, and G4 through the two rotavirus seasons after vaccination

was 71.3% (95% CI: 64.7, 76.9). The efficacy of RotaTeq in preventing

cases occurring only during the second rotavirus season

postvaccination was 62.6% (95% CI: 44.3, 75.4). The efficacy of

RotaTeq beyond the second season postvaccination was not evaluated.


    Rotavirus Gastroenteritis Regardless of Serotype


    The rotavirus serotypes identified in the efficacy subset of REST

and Study 007 were G1, P1(8); G2, P1(4); G3, P1(8); G4, P1(8); and G9,

P1(8).


    In REST, the efficacy of RotaTeq against any grade of severity of

naturally occurring rotavirus gastroenteritis regardless of serotype

was 71.8% (95% CI: 64.5, 77.8) and efficacy against severe rotavirus

disease was 98.0% (95% CI: 88.3, 99.9). The ITT efficacy starting at

dose 1 was 51.0% (95% CI: 41.7, 58.9) for any grade of severity of

rotavirus disease and was 96.4% (95% CI: 86.4, 99.6) for severe

rotavirus disease.


    In Study 007, the primary efficacy of RotaTeq against any grade of

severity of rotavirus gastroenteritis regardless of serotype was 72.7%

(95% CI: 51.9, 85.4) and efficacy against severe rotavirus disease was

100% (95% CI: 12.7, 100). The ITT efficacy starting at dose 1 was

48.0% (95% CI: 21.6, 66.1) for any grade of severity of rotavirus

disease and was 100% (95% CI: 31.0, 100.0) for severe rotavirus

disease.


    Rotavirus Gastroenteritis By Serotype


    The efficacy against any grade of severity of rotavirus

gastroenteritis by serotype in REST is shown in Table 5.


                               Table 5

Serotype-specific efficacy of RotaTeq against any grade of severity of

            rotavirus gastroenteritis among infants in REST

  through the first rotavirus season postvaccination (Per Protocol)


                                    Number of cases

                                                        % Efficacy

                                  RotaTeq   Placebo  (95% Confidence

Serotype identified by PCR       (N=2,834) (N=2,839)     Interval)

----------------------------------------------------------------------

Serotypes present in RotaTeq

----------------------------------------------------------------------

           G1, P1(8)                   72       286  74.9 (67.3, 80.9)

----------------------------------------------------------------------

           G2, P1(4)                    6        17   63.4 (2.6, 88.2)

----------------------------------------------------------------------

           G3, P1(8)                    1         6         NS

----------------------------------------------------------------------

           G4, P1(8)                    3         6         NS

----------------------------------------------------------------------

Serotypes not present in RotaTeq

----------------------------------------------------------------------

           G9, P1(8)                    1         3         NS

----------------------------------------------------------------------

Unidentified*                          11        15         NS

----------------------------------------------------------------------

N=number vaccinated

NS=not significant

----------------------------------------------------------------------

*Includes rotavirus antigen-positive samples in which the specific

serotype could not be identified by PCR


    Immunogenicity


    A relationship between antibody responses to RotaTeq and

protection against rotavirus gastroenteritis has not been established.

In phase 3 studies, 92.9% to 100% of 439 recipients of RotaTeq

achieved a 3-fold or more rise in serum anti-rotavirus IgA after a

three-dose regimen when compared to 12.3%-20.0% of 397 placebo

recipients.


    INDICATIONS AND USAGE


    RotaTeq is indicated for the prevention of rotavirus

gastroenteritis in infants and children caused by the serotypes G1,

G2, G3, and G4 when administered as a 3-dose series to infants between

the ages of 6 to 32 weeks. The first dose of RotaTeq should be

administered between 6 and 12 weeks of age (see DOSAGE AND

ADMINISTRATION).


    CONTRAINDICATIONS


    A demonstrated history of hypersensitivity to any component of the

vaccine.


    Infants who develop symptoms suggestive of hypersensitivity after

receiving a dose of RotaTeq should not receive further doses of

RotaTeq.


    PRECAUTIONS


    General


    Prior to administration of RotaTeq, the health care provider

should determine the current health status and previous vaccination

history of the infant, including whether there has been a reaction to

a previous dose of RotaTeq or other rotavirus vaccine.


    Febrile illness may be reason for delaying use of RotaTeq except

when, in the opinion of the physician, withholding the vaccine entails

a greater risk. Low-grade fever (less than 100.5(degree)F 

(38.1(degree)C)) itself and mild upper respiratory infection do

not preclude vaccination with RotaTeq.


    The level of protection provided by only one or two doses of

RotaTeq was not studied in clinical trials.


    As with any vaccine, vaccination with RotaTeq may not result in

complete protection in all recipients.


    Regarding post-exposure prophylaxis, no clinical data are

available for RotaTeq when administered after exposure to rotavirus.


    Intussusception


    Following administration of a previously licensed live rhesus

rotavirus-based vaccine, an increased risk of intussusception was

observed.(3) In REST (n=69,625), the data did not show an increased

risk of intussusception for RotaTeq when compared to placebo.


    In post-marketing experience, cases of intussusception have been

reported in temporal association with RotaTeq. See ADVERSE REACTIONS,

Intussusception and Post-marketing Reports.


    Immunocompromised Populations


    No safety or efficacy data are available for the administration of

RotaTeq to infants who are potentially immunocompromised including:


    --  Infants with blood dyscrasias, leukemia, lymphomas of any

        type, or other malignant neoplasms affecting the bone marrow

        or lymphatic system.


    --  Infants on immunosuppressive therapy (including high-dose

        systemic corticosteroids). RotaTeq may be administered to

        infants who are being treated with topical corticosteroids or

        inhaled steroids.


    --  Infants with primary and acquired immunodeficiency states,

        including HIV/AIDS or other clinical manifestations of

        infection with human immunodeficiency viruses; cellular immune

        deficiencies; and hypogammaglobulinemic and

        dysgammaglobulinemic states. There are insufficient data from

        the clinical trials to support administration of RotaTeq to

        infants with indeterminate HIV status who are born to mothers

        with HIV/AIDS.


    --  Infants who have received a blood transfusion or blood

        products, including immunoglobulins within 42 days.


    No safety or efficacy data are available for administration of

RotaTeq to infants with a history of gastrointestinal disorders

including infants with active acute gastrointestinal illness, infants

with chronic diarrhea and failure to thrive, and infants with a

history of congenital abdominal disorders, abdominal surgery, and

intussusception. Therefore, caution is advised when considering

administration of RotaTeq to these infants.


    Shedding and Transmission


    Shedding was evaluated among a subset of subjects in REST 4 to 6

days after each dose and among all subjects who submitted a stool

antigen rotavirus positive sample at any time. RotaTeq was shed in the

stools of 32 of 360 (8.9%, 95% CI (6.2%, 12.3%)) vaccine recipients

tested after dose 1; 0 of 249 (0.0%, 95% CI (0.0%, 1.5%)) vaccine

recipients tested after dose 2; and in 1 of 385 (0.3%, 95% CI 

(less than 0.1%, 1.4%)) vaccine recipients after dose 3. In phase 3

studies, shedding was observed as early as 1 day and as late as 15 

days after a dose. Transmission was not evaluated.


    Caution is advised when considering whether to administer RotaTeq

to individuals with immunodeficient close contacts such as:


    --  Individuals with malignancies or who are otherwise

        immunocompromised; or


    --  Individuals receiving immunosuppressive therapy.


    There is a theoretical risk that the live virus vaccine can be

transmitted to non-vaccinated contacts. The potential risk of

transmission of vaccine virus should be weighed against the risk of

acquiring and transmitting natural rotavirus.


    Information for Parents/Guardians


    Parents or guardians should be given a copy of the required

vaccine information and be given the "Patient Information" appended to

this insert. Parents and/or guardians should be encouraged to read the

patient information that describes the benefits and risks associated

with the vaccine and ask any questions they may have during the visit.

See PRECAUTIONS and Patient Information.


    Drug Interactions


    Immunosuppressive therapies including irradiation,

antimetabolites, alkylating agents, cytotoxic drugs and

corticosteroids (used in greater than physiologic doses), may reduce

the immune response to vaccines.


    For administration of RotaTeq with other vaccines, see DOSAGE AND

ADMINISTRATION, Use with Other Vaccines.


    Carcinogenesis, Mutagenesis, Impairment of Fertility


    RotaTeq has not been evaluated for its carcinogenic or mutagenic

potential or its potential to impair fertility.


    Pediatric Use


    Safety and efficacy have not been established in infants less than

6 weeks of age or greater than 32 weeks of age.


    Data are available from clinical studies to support the use of

RotaTeq in pre-term infants according to their age in weeks since

birth (see ADVERSE REACTIONS, Safety in Pre-Term Infants).


    Data are available from clinical studies to support the use of

RotaTeq in infants with controlled gastroesophageal reflux disease.


    ADVERSE REACTIONS


    71,725 infants were evaluated in 3 placebo-controlled clinical

trials including 36,165 infants in the group that received RotaTeq and

35,560 infants in the group that received placebo. Parents/guardians

were contacted on days 7, 14, and 42 after each dose regarding

intussusception and any other serious adverse events. The racial

distribution was as follows: White (69% in both groups);

Hispanic-American (14% in both groups); Black (8% in both groups);

Multiracial (5% in both groups); Asian (2% in both groups); Native

American (RotaTeq 2%, placebo 1%), and Other (less than 1% in both 

groups). The gender distribution was 51% male and 49% female in both

vaccination groups.


    Because clinical trials are conducted under conditions that may

not be typical of those observed in clinical practice, the adverse

reaction rates presented below may not be reflective of those observed

in clinical practice.


    Serious Adverse Events


    Serious adverse events occurred in 2.4% of recipients of RotaTeq

when compared to 2.6% of placebo recipients within the 42-day period

of a dose in the phase 3 clinical studies of RotaTeq. The most

frequently reported serious adverse events for RotaTeq compared to

placebo were:


    bronchiolitis           (0.6% RotaTeq vs. 0.7% Placebo),

    gastroenteritis         (0.2% RotaTeq vs. 0.3% Placebo),

    pneumonia               (0.2% RotaTeq vs. 0.2% Placebo),

    fever                   (0.1% RotaTeq vs. 0.1% Placebo), and

    urinary tract infection (0.1% RotaTeq vs. 0.1% Placebo).


    Deaths


    Across the clinical studies, 52 deaths were reported. There were

25 deaths in the RotaTeq recipients compared to 27 deaths in the

placebo recipients. The most commonly reported cause of death was

sudden infant death syndrome, which was observed in 8 recipients of

RotaTeq and 9 placebo recipients.


    Intussusception


    In REST, 34,837 vaccine recipients and 34,788 placebo recipients

were monitored by active surveillance to identify potential cases of

intussusception at 7, 14, and 42 days after each dose, and every

6 weeks thereafter for 1 year after the first dose.


    For the primary safety outcome, cases of intussuception occurring

within 42 days of any dose, there were 6 cases among RotaTeq

recipients and 5 cases among placebo recipients (see Table 6). The

data did not suggest an increased risk of intussusception relative to

placebo.



                               Table 6

   Confirmed cases of intussusception in recipients of RotaTeq as

             compared with placebo recipients during REST


                                                RotaTeq     Placebo

                                                (n=34,837)  (n=34,788)

----------------------------------------------------------------------

Confirmed intussusception cases within 42 days

 of any dose                                       6           5

Relative risk (95% CI)+                            1.6 (0.4, 6.4)

----------------------------------------------------------------------

Confirmed intussusception cases within 365

 days of dose 1                                    13          15

Relative risk (95% CI)                             0.9 (0.4, 1.9)

----------------------------------------------------------------------

+ Relative risk and 95% confidence interval based upon group

sequential design stopping criteria employed in REST.


    Among vaccine recipients, there were no confirmed cases of

intussusception within the 42-day period after the first dose, which

was the period of highest risk for the rhesus rotavirus-based product

(see Table 7).


                               Table 7

    Intussusception cases by day range in relation to dose in REST


           Dose 1          Dose 2          Dose 3         Any Dose

----------------------------------------------------------------------

 Day

 Range RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo

----------------------------------------------------------------------

  1-7       0       0       1       0       0       0       1       0

----------------------------------------------------------------------

 1-14       0       0       1       0       0       1       1       1

----------------------------------------------------------------------

 1-21       0       0       3       0       0       1       3       1

----------------------------------------------------------------------

 1-42       0       1       4       1       2       3       6       5

----------------------------------------------------------------------


    All of the children who developed intussusception recovered

without sequelae with the exception of a 9-month-old male who

developed intussusception 98 days after dose 3 and died of

post-operative sepsis. There was a single case of intussusception

among 2,470 recipients of RotaTeq in a 7-month-old male in the phase 1

and 2 studies (716 placebo recipients).


    Hematochezia


    Hematochezia reported as an adverse experience occurred in 0.6%

(39/6,130) of vaccine and 0.6% (34/5,560) of placebo recipients within

42 days of any dose. Hematochezia reported as a serious adverse

experience occurred in less than 0.1% (4/36,150) of vaccine and less 

than 0.1% (7/35,536) of placebo recipients within 42 days of any dose.


    Seizures


    All seizures reported in the phase 3 trials of RotaTeq (by

vaccination group and interval after dose) are shown in Table 8.


                               Table 8

Seizures reported by day range in relation to any dose in the phase 3

                           trials of RotaTeq


Day range                           1-7          1-14        1-42

----------------------------------------------------------------------

RotaTeq                             10            15          33

Placebo                              5            8           24

----------------------------------------------------------------------



    Seizures reported as serious adverse experiences occurred in less 

than 0.1% (27/36,150) of vaccine and less than 0.1% (18/35,536) of 

placebo recipients (not significant). Ten febrile seizures were 

reported as serious adverse experiences, 5 were observed in vaccine

recipients and 5 in placebo recipients.


    Most Common Adverse Events


    Solicited Adverse Events


    Detailed safety information was collected from 11,711 infants

(6,138 recipients of RotaTeq) which included a subset of subjects in

REST and all subjects from Studies 007 and 009 (Detailed Safety

Cohort). A Vaccination Report Card was used by parents/guardians to

record the child's temperature and any episodes of diarrhea and

vomiting on a daily basis during the first week following each

vaccination. Table 9 summarizes the frequencies of these adverse

events and irritability.


                               Table 9

Solicited adverse experiences within the first week after doses 1, 2,

                    and 3 (Detailed Safety Cohort)


  Adverse experience       Dose 1          Dose 2          Dose 3

                       RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo

----------------------------------------------------------------------

Elevated temperature*  n=5,616 n=5,077 n=5,215 n=4,725 n=4,865 n=4,382

                        17.1%   16.2%   20.0%   19.4%   18.2%   17.6%

----------------------------------------------------------------------

                       n=6,130 n=5,560 n=5,703 n=5,173 n=5,496 n=4,989

       Vomiting           6.7%    5.4%    5.0%    4.4%    3.6%    3.2%


       Diarrhea          10.4%    9.1%    8.6%    6.4%    6.1%    5.4%


     Irritability         7.1%    7.1%    6.0%    6.5%    4.3%    4.5%

----------------------------------------------------------------------

* Temperature (greater than=)100.5(degree)F (38.1(degree)C) rectal

equivalent  obtained by adding 1 degree F to otic and oral

temperatures and 2 degrees F to axillary temperatures



    Other Adverse Events


    Parents/guardians of the 11,711 infants were also asked to report

the presence of other events on the Vaccination Report Card for

42 days after each dose.


    Fever was observed at similar rates in vaccine (N=6,138) and

placebo (N=5,573) recipients (42.6% vs. 42.8%). Adverse events that

occurred at a statistically higher incidence (i.e., 2-sided p-value

less than 0.05) within the 42 days of any dose among recipients of

RotaTeq as compared with placebo recipients are shown in Table 10.


                               Table 10

  Adverse events that occurred at a statistically higher incidence

                      within 42 days of any dose

   among recipients of RotaTeq as compared with placebo recipients


                                   RotaTeq              Placebo

Adverse event                      N=6,138              N=5,573

----------------------------------------------------------------------

                                    n (%)                n (%)

----------------------------------------------------------------------

Diarrhea                        1,479 (24.1%)        1,186 (21.3%)

Vomiting                         929 (15.2%)          758 (13.6%)

Otitis media                     887 (14.5%)          724 (13.0%)

Nasopharyngitis                   422 (6.9%)          325 (5.8%)

Bronchospasm                      66 (1.1%)            40 (0.7%)

----------------------------------------------------------------------


    Safety in Pre-Term Infants


    RotaTeq or placebo was administered to 2,070 pre-term infants (25

to 36 weeks gestational age, median 34 weeks) according to their age

in weeks since birth in REST. All pre-term infants were followed for

serious adverse experiences; a subset of 308 infants was monitored for

all adverse experiences. There were 4 deaths throughout the study, 2

among vaccine recipients (1 SIDS and 1 motor vehicle accident) and 2

among placebo recipients (1 SIDS and 1 unknown cause). No cases of

intussusception were reported. Serious adverse experiences occurred in

5.5% of vaccine and 5.8% of placebo recipients. The most common

serious adverse experience was bronchiolitis, which occurred in 1.4%

of vaccine and 2.0% of placebo recipients. Parents/guardians were

asked to record the child's temperature and any episodes of vomiting

and diarrhea daily for the first week following vaccination. The

frequencies of these adverse experiences and irritability within the

week after dose 1 are summarized in Table 11.


                               Table 11

Solicited adverse experiences within the first week of doses 1, 2, and

                       3 among pre-term infants


                           Dose 1          Dose 2          Dose 3

Adverse event          RotaTeq Placebo RotaTeq Placebo RotaTeq Placebo

----------------------------------------------------------------------

                        N=127   N=133   N=124   N=121   N=115   N=108

Elevated temperature*   18.1%   17.3%   25.0%   28.1%   14.8%   20.4%

----------------------------------------------------------------------

                        N=154   N=154   N=137   N=137   N=135   N=129

Vomiting                5.8%    7.8%    2.9%    2.2%    4.4%    4.7%


Diarrhea                6.5%    5.8%    7.3%    7.3%    3.7%    3.9%


Irritability            3.9%    5.2%    2.9%    4.4%    8.1%    5.4%

----------------------------------------------------------------------

* Temperature = greater than 100.5(degree)F (38.1(degree)C) rectal

equivalent obtained by adding 1 degree F to otic and oral temperatures

and 2 degrees F to axillary temperatures



    Post-marketing Reports


    The following adverse events have been identified during

post-approval use of RotaTeq from reports to the Vaccine Adverse Event

Reporting System (VAERS).


    Reporting of adverse events following immunization to VAERS is

voluntary, and the number of doses of vaccine administered is not

known; therefore, it is not always possible to reliably estimate the

adverse event frequency or establish a causal relationship to vaccine

exposure using VAERS data.


    In post-marketing experience, the following adverse events have

been reported in infants who have received RotaTeq:


    Gastrointestinal:


    Intussusception


    Hematochezia


    Reporting Adverse Events


    Parents or guardians should be instructed to report any adverse

events to their health care provider.


    Health care providers should report all adverse events to the U.S.

Department of Health and Human Services' Vaccine Adverse Events

Reporting System (VAERS).


    VAERS accepts all reports of suspected adverse events after the

administration of any vaccine, including but not limited to the

reporting of events required by the National Childhood Vaccine Injury

Act of 1986. For information or a copy of the vaccine reporting form,

call the VAERS toll-free number at 1-800-822-7967 or report on line to

www.vaers.hhs.gov.(4)


    DOSAGE AND ADMINISTRATION


    FOR ORAL USE ONLY. NOT FOR INJECTION.


    The vaccination series consists of three ready-to-use liquid doses

of RotaTeq administered orally starting at 6 to 12 weeks of age, with

the subsequent doses administered at 4- to 10-week intervals. The

third dose should not be given after 32 weeks of age (see CLINICAL

STUDIES).


    There are no restrictions on the infant's consumption of food or

liquid, including breast milk, either before or after vaccination with

RotaTeq.


    Do not mix the RotaTeq vaccine with any other vaccines or

solutions. Do not reconstitute or dilute (see INSTRUCTIONS FOR USE).


    Each dose is supplied in a container consisting of a squeezable

plastic, latex-free dosing tube with a twist-off cap, allowing for

direct oral administration. The dosing tube is contained in a pouch

(see INSTRUCTIONS FOR USE).


    Use with Other Vaccines


    In clinical trials, RotaTeq was routinely administered

concomitantly with diphtheria and tetanus toxoids and acellular

pertussis (DTaP), inactivated poliovirus vaccine (IPV), H. influenzae

type b conjugate vaccine (Hib), hepatitis B vaccine, and pneumococcal

conjugate vaccine (see CLINICAL STUDIES). The safety data available

are in the ADVERSE REACTIONS section.


    There was no evidence for reduced antibody responses to the

diphtheria or tetanus toxoid components of DTaP or to the other

vaccines that were concomitantly administered with RotaTeq. However,

insufficient immunogenicity data are available to confirm lack of

interference of immune responses when RotaTeq is concomitantly

administered with childhood vaccines to prevent pertussis.


    INSTRUCTIONS FOR USE


To administer the vaccine:


Tear open the pouch and remove the dosing tube.


Clear the fluid from the dispensing tip by holding tube vertically and

 tapping cap.


Open the dosing tube in 2 easy motions:


1. Puncture the dispensing tip by screwing cap clockwise until it

 becomes tight.


2. Remove cap by turning it counterclockwise.


 Administer dose by gently squeezing liquid into infant's mouth toward

 the inner cheek until dosing tube is empty. (A residual drop may

 remain in the tip of the tube.)


 If for any reason an incomplete dose is administered (e.g., infant

 spits or regurgitates the vaccine), a replacement dose is not

 recommended, since such dosing was not studied in the clinical

 trials. The infant should continue to receive any remaining doses in

 the recommended series.


 Discard the empty tube and cap in approved biological waste

 containers according to local regulations.


    HOW SUPPLIED


    No. 4047 - RotaTeq, 2 mL, a suspension for oral use, is a pale

yellow clear liquid that may have a pink tint. It is supplied as

follows:


    NDC 0006-4047-31 package of 1 individually pouched single-dose

tube


    NDC 0006-4047-41 package of 10 individually pouched single-dose

tubes.


    Storage


    Store and transport refrigerated at 2-8(degree)C (36-46(degree)F).

RotaTeq should be administered as soon as possible after being removed

from refrigeration. For information regarding stability under

conditions other than those recommended, call 1-800-MERCK-90.


    Protect from light.


    RotaTeq should be discarded in approved biological waste

containers according to local regulations.


    The product must be used before the expiration date.


    REFERENCES


    1. Parashar UD et al. Global illness and deaths caused by

       rotavirus disease in children. Emerg Infect Dis

       2003;9(5):565-572.


    2. Parashar UD, Holman RC, Clarke MJ, Bresee JS, Glass RI.

       Hospitalizations associated with rotavirus diarrhea in the

       United States, 1993 through 1995: surveillance based on the new

       ICD-9-CM rotavirus-specific diagnostic code. J Infect Dis

       1998;177:13-7.


    3. Murphy TV, Gargiullo PM, Massoudi MS et al. Intussusception

       among infants given an oral rotavirus vaccine. N Engl J Med

       2001;344:564-572.


    4. Centers for Disease Control and Prevention. General

       recommendations on immunization: recommendations of the

       Advisory Committee on Immunization Practices (ACIP) and the

       American Academy of Family Physicians (AAFP). MMWR

       2002;51(RR-2):1-35.


    Issued January 2007


    Printed in USA


    * Registered trademark of MERCK & CO., Inc., Whitehouse Station,

NJ, 08889 USA COPYRIGHT (C) 2006 MERCK & CO., Inc. All rights reserved

Contact

Merck & Co., Inc.
Media:
Christine Fanelle, 215-652-3203
or
Christopher Loder, 908-423-3786
or
Investors:
Graeme Bell, 908-423-5185

Posted: February 2007


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