Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00053
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Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: June 2007
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Bibliographic ID: UF00087345
Volume ID: VID00053
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Jennifer Gailey, Pharm.D. Candidate

Rotavirus infection is the primary cause of
acute, dehydrating gastroenteritis worldwide, result-
ing in 500,000 deaths annually.1 Nearly 100% of
children are exposed by the fifth year of life. While
rotaviruses are proven to be the cause of only 5% -
10% of gastroenteritis episodes in children less than
5 years of age, they are responsible for 20% 60% of
hospital admissions secondary to gastroenteritis.2
The most severe of infections usually occur between
6 and 24 months of age. Infection rates are inde-
pendent of socioeconomic status, sanitation, and ge-
ography. The majority of cases in the United States
occur during late fall to early spring The peak sea-
son begins in the Southwest during November and
December, then travels sequentially towards the
Northeast, ending in April and May. Treatment is
limited to general supportive measures such as oral
rehydration; therefore, developing a vaccine against
rotavirus has been identified as high priority by the
World Heath Organization (WHO) and the Global
Alliance for Vaccines and Immunizations (GAVI).
Based on economic models on disease burden devel-
oped by the Centers for Disease Control (CDC), the
total cost of rotavirus gastroenteritis disease is esti-
mated to be between $1 and $1.3 billion annually in
the United States1 3

RotaShield (a tetravalent rhesus-human re-
assortant vaccine) was the first rotavirus vaccine ap-
proved in the United States to prevent rotavirus gas-
troenteritis. Created by Wyeth-Ayerst Pharmaceuti-
cals, it was licensed in 1998 but voluntarily with-
drawn from the market by Wyeth in 1999 due to an
association with intussusception.4 The CDC con-
ducted 2 large multi-state investigations to evaluate
the connection between patients who received the
vaccine and reported cases of intussusception. The
CDC estimated RotaShield increased the risk for
intussusception by 1 or 2 cases among each 10,000
infants vaccinated.5 Risk of developing intussuscep-
tion was greatest during days 3-14 after the first dose
and 3-7 days after the second dose.6 Research into
developing a human-bovine rotavirus vaccine contin-
ued due to the importance to public health.5'7
In February of 2006, RotaTeq (ro' to tEk),
manufactured by Merck & Co., was licensed in the
United States as the only FDA approved rotavirus
vaccine. RotaTeq is a live, oral, pentavalent, hu-
man-bovine vaccine (R-HBV) that contains 5 live
reassortant rotaviruses. R-HBV is indicated for the
prophylaxis of gastroenteritis caused by rotavirus
infection of the 4 serotypes (G1-4) in infants 6 to 32

riL. .,rl





Volume 22, Issue 9 June 2007


weeks of age.8 This article will review the pharma-
cology, efficacy, safety profile, dosing, and clinical
trials of this R-HBV.

R-HBV contains 5 live reassortant rotaviruses
(serotypes G1, G2, G3, G4, and P[8]) isolated from
human and bovine hosts. The backbone of the 5 vi-
ruses within the vaccine is the bovine strain WC3.
Each of the 5 strains incorporate either the VP4 gene
from a P[8] human rotavirus or the VP7 gene from a
Gl, G2, G3, or G4 human rotavirus. The most com-
mon G and P serotypes of known human rotavirus
are represented by the VP4 and VP7 genes.8'9
The exact mechanism by which R-HBV im-
munologically protects against rotavirus gastroenteri-
tis is unknown.10 This live viral vaccine replicates in
the small intestine in villous epithelial cells. After
1-4 weeks, antibody stimulation occurs and immu-
nity is induced.10' 11 Vaccinated infants are resistant
to developing a severe case of rotavirus caused by
applicable serotypes during the next season after vac-
cination. Some protection exists for up to 2 seasons,
but the true duration of immunity is unknown.12 Viral
shedding was observed 1-15 days after a dose; trans-
mission was not evaluated.

Clinical Trials
During the 1993-1994 rotavirus season, an
efficacy trial was carried out with a quadrivalent pre-
cursor to R-HBV that contained the G1, G2, G3, and
P[8] elements. This study was a randomized 3-dose
trial including 439 infants at 10 sites in the United
States. During this study, infants 8 weeks of age re-
ceived the first dose, and the following 2 doses were
separated by 6 to 8 week intervals. ELISA technol-

ogy was used to measure serum IgA levels, the most
sensitive indicator of vaccine efficacy. Seroconver-
sion was defined as a >3 fold increase in serum rota-
virus IgA levels between the time of the first vaccine
dose and 2 to 4 weeks after the last dose, and was
found to have occurred in 87.6% of vaccine recipi-
ents and 1.6% of placebo recipients. ELISA also
measured stool rotavirus IgA levels, where 74.2% of
vaccine recipients and 3.8% of placebo recipients
were found to have >3 fold increases between the
time of their first dose and 2 to 4 weeks after the fi-
nal dose. One of the 10 study sites determined im-
munogenicity separately after each vaccine dose in
37 vaccine and 37 placebo recipients. In this
substudy, stool samples were obtained before and 2
to 4 weeks after each dose and quantified by ELISA
to determine how many vaccine recipients had a >3
fold increase in rotavirus IgA. In total, 16, 19, and
15 recipients had increases in IgA after 1, 2, and 3
doses, respectively. This indicates a 3-dose regimen
to illicit an increased immune response by this vac-

The RotaTeq Efficacy and Safety Trial
(REST) was randomized, placebo-controlled, and
double-blinded (including sponsor), included 11
countries, and took place from 2001 to 2004. In to-
tal, it contained 69,274 infant subjects and measured
efficacy by preventing rotavirus gastroenteritis
(RGE) >14 days after completing the R-HBV series
through the first rotavirus season. The vaccine was
given as a 3-dose series to healthy infants with the
first dose given between ages 6 and 12 weeks and the
2 additional doses given 4 to 10 weeks apart. All
infants receiving the third dose were less than 32
weeks of age. Analyses were also conducted to

Table 1. Efficacy* of pentavalent rotavirus vaccine against G1-4 RGE in REST13

Efficacy %
Vaccine Placebo Efficacy %
Disease severityPlacebo (95% Confidence
Disease s(N=2207) (N=2305) n n(95% Confidence

Any 82 315 74.0 (66.8-79.9) 60.0 (51.5 -67.1)

Severe 1 51 98.0 (88.8-100.0) 96.4 (86.2 99.6)

Includes only cases that occurred at least 2 weeks after dose 3 in the clinical-efficacy substudy group
**Severity determined by scoring system of Clark HF, et al.16

PharmaNote 10 Volume 22, Issue 9 June 2007

Table 2. Efficacy of rotavirus vaccine in reducing G1-4 rotavirus-associated hospitalizations in REST13

Vaccine Placebo ITT* vaccine ITT* placebo
(N=28,646) (N=28,488) (N=34,035) (N=34,003)

Number of Hospitalizations 6 144 10 187

Percent reduction in
hospitalizations 95.8 (90.5 98.2) 94.7 (89.3 97.3)
(95% CI)
ITT analysis includes all subjects who received at least one vaccine dose.

evaluate efficacy among infants who received at least
one vaccination (Intent-to-Treat; ITT). Efficacy
against any severity of RGE caused by serotypes Gl-
4 through the first rotavirus season was 74.0% and
the ITT efficacy was 60.0%. Efficacy against severe
RGE was 98.0% and ITT efficacy was 96.4% (Table
1). Efficacy of the vaccine against serious disease
was also confirmed by a decrease in hospitalizations
for RGE among all subjects enrolled in this trial.
Hospitalizations in vaccinated infants were reduced
during the first 2 years after the third dose by 95.8%.
The efficacy of the ITT group reduced hospitaliza-
tions was 94.7% (Table 2).13
The efficacy of the R-HBV through a second
rotavirus season was evaluated in REST. Efficacy
against any grade severity RGE caused by serotypes
G1-4 occurring through the two seasons after vacci-
nation was 71.3% (95% CI = 64.7 76.9). The effi-
cacy in preventing RGE only in the second season
after vaccination was 62.6% (95% CI = 44.3 75.4).
The efficacy of the vaccine beyond this time frame
was not evaluated.13

Dosing and Administration
The oral R-HBV should be given at least 1
month apart from any other live vaccine if possible.
Efficacy is not proven if the patient does not receive
all 3 doses, nor if administered with a pertussis vac-
cine. Data and efficacy are not established in im-
munocompromised infants or those with blood

dyscrasias. The R-HBV is indicated for infants 6 to
32 weeks of age and all three oral doses should be
given in that time frame. The first dose of 2 ml
should be given between 6 and 12 weeks of age. The
next two doses of 2 ml each will be administered at
intervals of 4 to 10 weeks, and the final dose should
be given before infant is 32 weeks old. Repeat dos-
ing is not necessary if an infant regurgitates the dose
and any remaining doses in the series should be
given. 12,13

Toxicity and Safety
Due to the withdrawal of RotaShield, it was
pertinent to conduct proper safety investigations re-
garding intussusception during the develop of new
rotavirus vaccines. Of the 68,038 subjects who re-
ceived at least one dose of vaccine or placebo,
67,756 (99.6%) were followed for 42 days after re-
ceiving their last dose, and 56,310 (81.3%) were fol-
lowed for at least 1 year after their first dose. Within
the 42-day period after any dose of the vaccine, 6
vaccine recipients and 5 placebo recipients had con-
firmed cases of intussusception. Within the first year
after any dose, there were 12 reported cases of intus-
susception in the vaccine group and 15 confirmed
cases in the placebo group. Neither of these figures
are statistically significant (Table 3). Serious ad-
verse events (SAE) occurred in 2.4% of vaccine re-
cipients and 2.6% of placebo recipients within the
42-day period of any dose in phase III studies. The

Table 3. Intussusception cases in rotavirus vaccine recipients vs. placebo during REST13
Vaccine Placebo
(n=34,035) (n=34,003)
Confirmed cases within 42 days of any 6
vaccine dose

Confirmed cases within 365 days of first 1
12 15
vaccine dose

PharmaNote Volume 22, Issue 9 June 2007

Table 4. Adverse events occurring within 42 dayss
Vaccine (N=6,138) Placebo (N=5,573)
Adverse event (n%)
(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%)

only SAE that occurred more commonly in the vac-
cine group is bronchiolitis. Rates of pneumonia, fe-
ver, and urinary tract infections were similar or
higher with placebo. Overall, 44 deaths in 68,038
subjects occurred in the study; 24 in the vaccine
group and 20 in the placebo group. The most com-
mon cause of death in both groups was sudden infant
death syndrome. A substudy of 11,711 participants
of REST were asked to record any adverse events
occurring 42 days after each dose.12 13 Non-serious
adverse events in both groups include irritability, fe-
ver, vomiting, diarrhea, otitis media, nasopharyngi-
tis, and bronchospasm. The adverse events associ-
ated with the use of R-HBV more frequently than
placebo are detailed in Table 4.

The catalog price for RotaTeq is $62.50 per
dose when purchased as a pack of 10 single-dose
tubes, making a complete series of doses $187.50.15

Rotavirus infections are the leading cause of
severe gastroenteritis in young children. R-HBV
vaccine, when administered during the first few
months of life, can greatly reduce the morbidity and
mortality associated with RGE caused by serotypes
G1-4 during the first rotavirus season after vaccina-
tion. The 3-dose series can be easily incorporated
into already-existing vaccination regimens. Serious
adverse events occurred less frequently in the vac-
cine group than in the placebo group, including in-
tussusception, which caused RotaShield to be with-
drawn from the market. Additional studies would be
beneficial to further evaluate the safety and efficacy
of R-HBV.

1. Parashar UD, Hummelman EG, et al. Global
illness and deaths caused by rotavirus disease in

children. Emerg Infect Dis 2003; 9: 565-72.
2. Wilhelmi I, Roman E, Sanchez-Fauquier A. Vi-
ruses causing gastroenteritis. Clin Microbiol In-
fect 2003; 9: 247 -62.
3. Jin S, Kilgore PE, Holman RC, Clarke MJ.
Trends in hospitalizations for diarrhea in United
States children from 1979 through 1992: esti-
mates of the morbidity associated with rotavirus.
Pediatr Infect Dis J 1996; 15: 397-404.
4. Intussusception among recipients of rotavirus
vaccine United States, MMWR Morb Mortal
Wkly Rep 1999; 48: 577-81.
5. Simonsen L, Viboud C. More on RotaShield and
intussusception: the role of age at the time of
vaccination. J of Infec Dis 2005; 192: 36-43.
6. Murphy TV, Gargiullo PM, Massoudi MS, et al.
Intussusception among infants given an oral
rotavirus vaccine. N Engl J Med 2001; 344:64-
7. Lynch M, Bresee J, Tatti K, et al. Intussusception
After Administration of the Rhesus Tetravalent
Rotavirus Vaccine (Rotashield): The Search for a
Pathogenic Mechanism Pediatrics 2006; 117:
8. RotaTeq [package insert]. Whitehouse Station,
NJ. Merck & Co Inc; 2006.
9. Kapikian A, Hoshino Y, Knipe D, et al. Rotavi-
rus. Field's Virology 2001; 4: 1787-1833.
10. Ward R, Berstein D, Smith V. Rotavirus
Immunoglobulin A responses stimulated by each
of 3 doses of a quadrivalent human-bovine
reassortant rotavirus vaccine. J Infec Dis 2004;
189: 2290-3.
11. Reents S, Seymour J. Clinical Pharmacology
(2.21), [RotaTeq]. Gold Standard Multimedia
Inc., producers, Tampa, FL; 2006.
12. Clark H, Offit P. The new pentavalent rotavirus
vaccine composed of bovine (Strain WC3) -
human rotavirus reassortants. Pediatr Infect Dis J
2006: 25: 577-83.

PharmaNote Volume 22, Issue 9 June 2007

Volume 22, Issue 9 June 2007


13. Vesikari T, Matson DO, Dennehy P. Safety and k
efficacy of a pentavalent human-bovine reassor- Rotigotine (Neupro) Schwarz Pharma Inc.
tant rotavirus vaccine. N Eng J Med 2006; 354: Rotigotine is a lipid-soluble, selective dopa-
23-33. mine (D2) receptor agonist approved on May 9,
14. Lanata C, Black R, Butron B. Safety, immuno- 2007 for the symptomatic treatment (hypokinesia,
genicity, and protective efficacy of one and three k rigidity) of Parkinson's disease. Rotigotine is a
doses of the tetravalent rhesus rotavirus vaccine non-ergot derivative available as a transdermal
in infants in Lima, Peru. J Infect Dis 1996; 164: | patch that delivers continuous dopaminergic stimu-
268-75. nation over 24 hours. This delivery system may
15. CDC Vaccine Price List. Last updated 03/01/07. reduce motor complications associated with ad-
Available at: http://www.cdc.gov/nip/vfc/ vancing Parkinson's disease. 2, 4 and 6 mg/24
cdc vac price list.htm Accessed 20 March hour patches are expected to be available in June
2007. The starting dose is 2 mg/24 hours and may
Sbe increased as tolerated.
16. Clark H, Berstein D, Dennehy P, et al. Safety,
efficacy, and immunogenicity of a live, quadriva- ,.................................
lent human-bovine reassortant rotavirus vaccine ,
in healthy infants. J Pediatrics 2004; 144: 184-
90. Retapamulin (AltabaxR) GlaxoSmithKline

R D. Retapamulin is a semisynthetic antibiotic
S RECENT DRUG APPROALS similar to pleuromutilin that binds to the 50S ribo-
,............................ I somal subunit thereby preventing protein synthesis.
S................. ........................... Retapamulin is available as a 1% topical ointment
for the treatment of impetigo due to methicillin-
Levocetirizine (Xyzal*) UCB Inc.
susceptible Staphylococcus aureus and Streptococ-
$ cus pyogenes in patients greater than 9 months oft
Levocetirizine is the levo isomer of cetiriz- age. Treatment consists of application of a thin
ine that has twice the affinity for H1 receptors than laver to affected area twice a dav for 5 davs
Scetirizine. Levocetirizine received FDA approval
on M ay 29, 2007 for the treatment of seasonal and ; "....... .........................
perennial allergic rhinitis and chronic idiopathic | -"' '
| urticaria in adults and children 6 years of age and The PharmaNote is Published by:
Solder. The most common adverse reactions during The Department of Pharmacy
Sthe clinical trials were somnolence, nasopharyngi-
tis, pharyngitis, fatigue, and dry mouth. The rec- services, UF Family Practice Medical
ommended dose for children ages 6-11 years is 2.5 Group, Departments of Community
mg daily and 5 mg daily for patients 12 years or Health and Family Medicine and
Pharmacy Practice
^^^^^^^^^,^^^^^^^ i University of Florida
' L3brelM (90 img leoiiorgesirel and 20 incg '
Sethinyl estradiol) Wyeth Pharmaceuticals Inc. $

Lybrel is low-dose combination oral con- John G. Gums Editor
traceptive regimen that suppresses the hypotha- Pharm.D.
Slamic-pituitary system ultimately suppressing ovu-
lation and menstration. This combination is de- R. Whit Curry, M.D. Associate Editor
signed to be taken daily without interruption for as
k long as the woman wishes to suppress her periods. Shawn Anderson Assistant Editor
The long-term safety of continuous oral contracep- Pharm.D.
tion is unknown beyond three years and many
women still experience breakthrough bleeding and
Spotting. 28 day packs are expected to be available
IIn JLII\ 2(0'

Volume 22, Issue 9 June 2007


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