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VII. PREGNANCY
Animal studies do not indicate direct or
indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.
GARDASIL induced a specific antibody response against HPV Types 6, 11, 16, and 18 in pregnant rats
following one or multiple intramuscular injections. Antibodies against all 4 HPV types were transferred
to the offspring during gestation and possibly during lactation.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, pregnancy
should be avoided during the vaccination regimen for GARDASIL.
In clinical studies, women underwent urine pregnancy testing prior to administration of
each dose of GARDASIL. Women who were found to be pregnant before completion of a 3-dose regimen
of GARDASIL were instructed to defer completion of their vaccination regimen until resolution of the pregnancy.
Such non-standard regimens resulted in Postdose 3 anti- HPV 6, anti-HPV 11, antiHPV 16, and anti-HPV
18 responses that were comparable to those observed in women who received a standard 0, 2, and 6 month
vaccination regimen (see DOSAGE AND ADMINISTRATION).
During clinical trials, 3,620 women (vaccine = 1,796 vs placebo = 1,824) reported at least one pregnancy.
The overall proportions of pregnancies that resulted in an adverse outcome defined as the combined
numbers of spontaneous abortion, late fetal death and congenital anomaly cases out of the total number
of pregnancy outcomes for which an outcome was known (and excluding elective terminations),
were 23.3% (423/1,812) in subjects who received GARDASIL and 24.1% (438/1,820) in subjects who received placebo.
Further sub-analyses were done to evaluate pregnancies with estimated onset within 30 days
or more than 30 days from administration of a dose of GARDASIL or placebo. For pregnancies with
estimated onset within 30 days of vaccination, 5 cases of congenital anomaly were observed in the
group that received GARDASIL compared to 1 case of congenital anomaly in the group that received placebo.
Conversely, in pregnancies with onset more than 30 days following vaccination, 35 cases of congenital
anomaly were observed in the group that received GARDASIL compared with 29 cases of congenital anomaly
in the group that received placebo. The types of anomalies observed were consistent (regardless of when
pregnancy occurred in relation to vaccination) with those generally observed in pregnancies in women aged 16 through 45 years.
Thus, there is no evidence to suggest that administration of GARDASIL adversely affects fertility, pregnancy, or infant outcomes.
VIII. NURSING MOTHERS
It is not known whether vaccine antigens or antibodies
induced by the vaccine are excreted in human milk. GARDASIL may be administered to lactating women.
GARDASIL or placebo were given to a total of 1,132 women who were breastfeeding at any time
during the relevant Phase III clinical studies._ In these studies, the rates of adverse experiences
in the mother and the nursing infant were comparable between vaccination groups. In addition, vaccine
immunogenicity was comparable among nursing mothers and women who did not nurse during the vaccine administration.
IX. PEDIATRIC USE
The safety and efficacy of GARDASIL have not been evaluated in children younger than 9 years.
X. USE IN ELDERLY
The safety and efficacy of GARDASIL have not been evaluated in adults above the age of 26 years.
XI. USE IN OTHER SPECIAL POPULATIONS
The safety, immunogenicity, and efficacy of GARDASIL have not been fully evaluated in HIV infected individuals.
XII. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
There are no data to suggest that GARDASIL affects the ability to drive or operate machinery.
XIII. DRUG INTERACTIONS
Use with Other Vaccines: Results from clinical
studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant).
Use with Common Medications: In clinical studies, 11.9%, 9.5%, 6.9%, and 4.3% of
individuals used analgesics, anti-inflammatory drugs, antibiotics, and vitamin preparations, respectively.
The efficacy, immunogenicity, and safety of the vaccine were not impacted by the use of these medications.
Use with Hormonal Contraceptives: In clinical studies, 57.5% of women (aged 16 to 26 years)
who received GARDASIL used hormonal contraceptives. Use of hormonal contraceptives did not appear to affect the immune responses to GARDASIL.
Use with Steroids: In clinical studies, 1.7% (n = 158), 0.6% (n = 56), and 1.0% (n = 89)
of individuals used inhaled, topical, and parenteral immunosuppressants, respectively, administered
dose to the time of administration of a dose of GARDASIL. These medicines did not appear to affect
the immune responses to GARDASIL. Very few subjects in the clinical studies were taking steroids,
and the amount of immunosuppression is presumed to have been low.
Use with Systemic Immunosuppressive Medications: There are no data on the concomitant
use of potent immunosuppressants with GARDASIL. Individuals receiving therapy with immunosuppressive agents
(systemic doses of corticosteroids, antimetabolites, alkylating agents, cytotoxic agents) may not
respond optimally to active immunization (see PRECAUTIONS, General).
XIV. SIDE EFFECTS
In 6 clinical trials (5 placebo-controlled),
subjects were administered GARDASIL or placebo on the day of enrollment and approximately 2 and 6 months thereafter.
GARDASIL demonstrated a favorable safety profile when compared with placebo (aluminum or non-aluminum containing).
Few subjects (≤0.3%) discontinued due to adverse experiences. In all except one of the clinical trials,
safety was evaluated using vaccination report card (VRC)-aided surveillance for 14 days after each
injection of GARDASIL or placebo. The subjects who were monitored using VRC-aided surveillance
included 8,068 subjects (6,996 females 9 through 45 years of age and 1,072 males 9 through 16 years
of age at enrollment) who received GARDASIL and 5,966 subjects who received placebo.
The following vaccine-related adverse experiences were observed among recipients of
GARDASIL at a frequency of at least 1.0% and also at a greater frequency than that observed
among placebo recipients. Very Common (≥1/10); Common (≥1/100, <1/10); Uncommon
(≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very Rare (<1/10,000)
General disorders and administration site conditions: Common: pyrexia, pain in extremity.
The following injection-site reactions occurred at a greater incidence in the group
that received GARDASIL compared with the saline placebo group: Very common: erythema, pain and swelling. Common: pruritus.
The following injection-site reactions were very common and occurred at a greater
incidence in the group that received GARDASIL compared with the group that received amorphous
aluminum hydroxyphosphate sulfate adjuvant-containing placebo: erythema, pain, and swelling.
Most injection-site reactions were mild to moderate.
In addition, bronchospasm was reported very rarely as a serious adverse experience.
The safety of GARDASIL when administered concomitantly with hepatitis B vaccine (recombinant)
was evaluated in a placebo-controlled study. The frequency of adverse experiences observed
with concomitant administration was similar to the frequency when GARDASIL was administered alone.
Post-Marketing Reports: The following adverse experiences have been spontaneously
reported during post-approval use of GARDASIL. Because these experiences were reported
voluntarily from a population of uncertain size, it is not possible to reliably estimate
their frequency or to establish a causal relationship to vaccine exposure.
Blood and lymphatic system disorders: lymphadenopathy.
Nervous system disorders: dizziness, Guillain-Barre syndrome, headache, syncope.
Gastrointestinal disorders: nausea, vomiting.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia.
General disorders and administration site conditions: asthenia, fatigue, malaise.
Immune system disorders: Hypersensitivity reactions including anaphylactic/anaphylactoid reactions,
bronchospasm and urticaria.
XV. OVERDOSAGE
There have been reports of administration of
higher than recommended doses of GARDASIL. In general, the adverse event profile reported
with overdose was comparable to recommended single doses of GARDASIL.
XVI. APPEARANCE AND AVAILABILITY
Sterile, white, cloudy, liquid suspension.
Packed in 0.5 mL single-dose vials (1s) and syringes (1s).
XVII. STORAGE
Store refrigerated at 2 to 8°C (36 to 46°F).
Do not freeze. Protect from light. GARDASIL should be administered as soon as possible
after being removed from refrigeration. GARDASIL can be out of refrigeration
(at temperatures at or below 25°C (77°F), for a total time of not more than 72 hrs.
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