Vaccine Information: VARIVAX (Page 2 of 5)

6.2 Post-Marketing Experience

The following adverse events have been identified during post approval use of VARIVAX. Because the events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

Body as a Whole

Anaphylaxis (including anaphylactic shock) and related phenomena such as angioneurotic edema, facial edema, and peripheral edema.

Eye Disorders

Necrotizing retinitis (in immunocompromised individuals).

Hemic and Lymphatic System

Aplastic anemia; thrombocytopenia (including idiopathic thrombocytopenic purpura (ITP)).

Infections and Infestations

Varicella (vaccine strain).

Nervous/Psychiatric

Encephalitis; cerebrovascular accident; transverse myelitis; Guillain-Barré syndrome; Bell’s palsy; ataxia; non-febrile seizures; aseptic meningitis; meningitis; dizziness; paresthesia.

Cases of encephalitis or meningitis caused by vaccine strain varicella virus have been reported in immunocompetent individuals previously vaccinated with VARIVAX months to years after vaccination. Reported cases were commonly associated with preceding or concurrent herpes zoster rash [see Clinical Pharmacology (12.2)].

Respiratory

Pharyngitis; pneumonia/pneumonitis.

Skin

Stevens-Johnson syndrome; erythema multiforme; Henoch-Schönlein purpura; secondary bacterial infections of skin and soft tissue, including impetigo and cellulitis; herpes zoster.

The vaccine virus (Oka/Merck strain) contained in VARIVAX may establish latency of varicella zoster virus in immunocompetent individuals, with the potential for later development of herpes zoster [see Clinical Pharmacology (12.2)].

7 DRUG INTERACTIONS

7.1 Salicylates

No cases of Reye syndrome have been observed following vaccination with VARIVAX. Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with VARIVAX, as Reye syndrome has been reported following the use of salicylates during wild-type varicella infection [see Warnings and Precautions (5.5)].

7.2 Immune Globulins and Transfusions

Administration of immune globulins and other blood products concurrently with VARIVAX may interfere with the expected immune response [see Warnings and Precautions (5.4)] {9}. The ACIP has specific recommendations for intervals between administration of antibody-containing products and live virus vaccines.

7.3 Tuberculin Skin Testing

Tuberculin skin testing, with tuberculin purified protein derivative (PPD), may be performed before VARIVAX is administered or on the same day, or at least 4 weeks following vaccination with VARIVAX, as other live virus vaccines may cause a temporary depression of tuberculin skin test sensitivity leading to false negative results.

7.4 Use with Other Vaccines

VARIVAX can be administered concurrently with other live viral vaccines. If not given concurrently, at least 1 month should elapse between a dose of a live attenuated measles virus-containing vaccine and a dose of VARIVAX. In children through the age of 12 years at least 3 months should elapse between administration of 2 doses of a live attenuated varicella virus-containing vaccine. For adolescents and adults, 2 doses of VARIVAX may be separated by 1 month [see Dosage and Administration (2.1)].

VARIVAX may be administered concomitantly with M-M-R II® (Measles, Mumps, and Rubella Virus Vaccine Live), Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant). Additionally, VARIVAX may be administered concomitantly with inactivated diphtheria-tetanus and acellular pertussis vaccines [see Clinical Studies (14.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

VARIVAX is contraindicated for use in pregnant women because the vaccine contains live, attenuated varicella virus, and it is known that wild-type varicella virus, if acquired during pregnancy, can cause congenital varicella syndrome [see Contraindications (4.5) and Patient Counseling Information (17)]. No increased risk for miscarriage, major birth defect or congenital varicella syndrome was observed in a pregnancy exposure registry that monitored outcomes after inadvertent use. There are no relevant animal data.

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.

Human Data

A pregnancy exposure registry was maintained from 1995 to 2013 to monitor pregnancy and fetal outcomes following inadvertent administration of VARIVAX. The registry prospectively enrolled 1522 women who received a dose of VARIVAX during pregnancy or within three months prior to conception. After excluding elective terminations (n=60), ectopic pregnancies (n=1) and those lost to follow-up (n=556), there were 905 pregnancies with known outcomes. Of these 905 pregnancies, 271 (30%) were in women who were vaccinated within the three months prior to conception. Miscarriage was reported for 10% of pregnancies (95/905), and major birth defects were reported for 2.6% of live born infants (21/819). These rates of assessed outcomes were consistent with estimated background rates. None of the women who received VARIVAX vaccine delivered infants with abnormalities consistent with congenital varicella syndrome.

8.2 Lactation

Risk Summary

It is not known whether varicella vaccine virus is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VARIVAX, and any potential adverse effects on the breastfed child from VARIVAX or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

8.4 Pediatric Use

No clinical data are available on safety or efficacy of VARIVAX in children less than 12 months of age.

8.5 Geriatric Use

Clinical studies of VARIVAX did not include sufficient numbers of seronegative subjects aged 65 and over to determine whether they respond differently from younger subjects.

11 DESCRIPTION

VARIVAX [Varicella Virus Vaccine Live] is a preparation of the Oka/Merck strain of live, attenuated varicella virus. The virus was initially obtained from a child with wild-type varicella, then introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures and finally propagated in human diploid cell cultures (WI-38). Further passage of the virus for varicella vaccine was performed at Merck Research Laboratories (MRL) in human diploid cell cultures (MRC-5) that were free of adventitious agents. This live, attenuated varicella vaccine is a lyophilized preparation containing sucrose, phosphate, glutamate, and processed gelatin as stabilizers.

VARIVAX, when reconstituted as directed, is a sterile preparation for subcutaneous injection. Each approximately 0.5-mL dose contains a minimum of 1350 plaque-forming units (PFU) of Oka/Merck varicella virus when reconstituted and stored at room temperature for a maximum of 30 minutes. Each 0.5-mL dose also contains approximately 25 mg of sucrose, 12.5 mg hydrolyzed gelatin, 3.2 mg of sodium chloride, 0.5 mg of monosodium L-glutamate, 0.45 mg of sodium phosphate dibasic, 0.08 mg of potassium phosphate monobasic, and 0.08 mg of potassium chloride. The product also contains residual components of MRC-5 cells including DNA and protein and trace quantities of sodium phosphate monobasic, EDTA, neomycin and fetal bovine serum. The product contains no preservative.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

VARIVAX induces both cell-mediated and humoral immune responses to varicella-zoster virus. The relative contributions of humoral immunity and cell-mediated immunity to protection from varicella are unknown.

12.2 Pharmacodynamics

Transmission

In the placebo-controlled efficacy trial, transmission of vaccine virus was assessed in household settings (during the 8-week postvaccination period) in 416 susceptible placebo recipients who were household contacts of 445 vaccine recipients. Of the 416 placebo recipients, three developed varicella and seroconverted, nine reported a varicella-like rash and did not seroconvert, and six had no rash but seroconverted. If vaccine virus transmission occurred, it did so at a very low rate and possibly without recognizable clinical disease in contacts. These cases may represent either wild-type varicella from community contacts or a low incidence of transmission of vaccine virus from vaccinated contacts. Post-marketing experience suggests that transmission of varicella vaccine virus (Oka/Merck) resulting in varicella infection including disseminated disease may occur rarely between vaccine recipients (who develop or do not develop a varicella-like rash) and contacts susceptible to varicella including healthy as well as high risk individuals [see Warnings and Precautions (5.3)] {1,10}.

Herpes Zoster

Overall, 9454 healthy children (12 months to 12 years of age) and 1648 adolescents and adults (13 years of age and older) have been vaccinated with VARIVAX in clinical trials. Eight cases of herpes zoster have been reported in children during 42,556 person-years of follow-up in clinical trials, resulting in a calculated incidence of at least 18.8 cases per 100,000 person-years. The completeness of this reporting has not been determined. One case of herpes zoster has been reported in the adolescent and adult age group during 5410 person-years of follow-up in clinical trials, resulting in a calculated incidence of 18.5 cases per 100,000 person-years. All 9 cases were mild and without sequelae. Two cultures (one child and one adult) obtained from vesicles were positive for wild-type VZV as confirmed by restriction endonuclease analysis {11}. The long-term effect of VARIVAX on the incidence of herpes zoster, particularly in those vaccinees exposed to wild-type varicella, is unknown at present.

In children, the reported rate of herpes zoster in vaccine recipients appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella {12}. The incidence of herpes zoster in adults who have had wild-type varicella infection is higher than that in children.

12.6 Duration of Protection

The duration of protection of VARIVAX is unknown; however, long-term efficacy studies have demonstrated continued protection up to 10 years after vaccination [see Clinical Studies (14.1)] {13}. A boost in antibody levels has been observed in vaccinees following exposure to wild-type varicella which could account for the apparent long-term protection after vaccination in these studies.

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