Chickenpox Complications May Be Serious Scientists Report At CDC Immunization Conference

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INDICATIONS AND USAGE

VARIVAX is indicated for vaccination against varicella in individuals 12 months of age and older.

Revaccination

The duration of protection of VARIVAX is unknown at present and the need for booster doses is not defined. However, a boost in antibody levels has been observed in vaccinees following exposure to natural varicella as well as following a booster dose of VARIVAX administered four to six years postvaccination.(5)

In a highly vaccinated population, immunity for some individuals may wane due to lack of exposure to natural varicella as a result of shifting epidemiology. Post-marketing surveillance studies are ongoing to evaluate the need and timing for booster vaccination.

Vaccination with VARIVAX may not result in protection of all healthy, susceptible children, adolescents, and adults (see CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

A history of hypersensitivity to any component of the vaccine, including gelatin.

A history of anaphylactoid reaction to neomycin (each dose of reconstituted vaccine contains trace quantities of neomycin).

Individuals with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems.

Individuals receiving immunosuppressive therapy. Individuals who are on immunosuppressant drugs are more susceptible to infections than healthy individuals. Vaccination with live attenuated varicella vaccine can result in a more extensive vaccine-associated rash or disseminated disease in individuals on immunosuppressant doses of corticosteroids.

Individuals with primary and acquired immunodeficiency states, including those who are immunosuppressed in association with AIDS or other clinical manifestations of infection with human immunodeficiency virus;(23) cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states.

A family history of congenital or hereditary immunodeficiency, unless the immune competence of the potential vaccine recipient is demonstrated.

Active untreated tuberculosis.

Any febrile respiratory illness or other active febrile infection.

Pregnancy; the possible effects of the vaccine on fetal development are unknown at this time.

However, natural varicella is known to sometimes cause fetal harm. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for three months following vaccination. (See PRECAUTIONS, Pregnancy).

WARNINGS

Children and adolescents with acute lymphoblastic leukemia (ALL) in remission can receive the vaccine under an investigational protocol. More information is available by contacting the VARIVAX coordinating center, Bio- Pharm Clinical Services, Inc., 4 Valley Square, Blue Bell, PA 19422 215-283-0897.

PRECAUTIONS

General

Adequate treatment provisions, including epinephrine injection (1:1000), should be available for immediate use should an anaphylactoid reaction occur.

The duration of protection from varicella infection after vaccination with VARIVAX is unknown.

It is not known whether VARIVAX given immediately after exposure to natural varicella virus will prevent illness.

Vaccination should be deferred for at least 5 months following blood or plasma transfusions, or administration of immune globulin or varicella zoster immune globulin (VZIG).(24)

Following administration of VARIVAX, any immune globulin including VZIG should not be given for 2 months thereafter unless its use outweighs the benefits of vaccination.(24)

Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with VARIVAX as Reye's Syndrome has been reported following the use of salicylates during natural varicella infection (see CLINICAL PHARMACOLOGY, Reye's Syndrome).

The safety and efficacy of VARIVAX have not been established in children and young adults who are known to be infected with human immunodeficiency viruses with and without evidence of immunosuppression (see also CONTRAINDICATIONS).

Care is to be taken by the health care provider for safe and effective use of VARIVAX.

The health care provider should question the patient, parent, or guardian about reactions to a previous dose of VARIVAX or a similar product.

The health care provider should obtain the previous immunization history of the vaccinee.

VARIVAX should not be injected into a blood vessel.

Vaccination should be deferred in patients with a family history of congenital or hereditary immunodeficiency until the patient's own immune system has been evaluated.

A separate sterile needle and syringe should be used for administration of each dose of VARIVAX to prevent transfer of infectious diseases.

Needles should be disposed of properly and should not be recapped.

Transmission

Post-marketing experience suggests that transmission of vaccine virus may occur rarely between healthy vaccinees who develop a varicella-like rash and healthy susceptible contacts. Transmission of vaccine virus from vaccinees without a varicella-like rash has been reported but has not been confirmed.

Therefore, vaccine recipients should attempt to avoid, whenever possible, close association with susceptible high risk individuals for up to six weeks. In circumstances where contact with high-risk individuals is unavoidable, the potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting natural varicella virus. Susceptible high risk individuals include:

• immunocompromised individuals
• pregnant women without documented history of chickenpox or laboratory evidence of prior infection
• newborn infants of mothers without documented history of chickenpox or laboratory evidence of prior infection

Information for Patients

The health care provider should inform the patient, parent or guardian of the benefits and risks of VARIVAX.

Patients, parents, or guardians should be instructed to report any adverse reactions to their health care provider.

The U.S. Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept 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.(25) The VAERS toll-free number for VAERS forms and information is 1-800-822-7967.

Pregnancy should be avoided for three months following vaccination.

Drug Interactions

See PRECAUTIONS, General, regarding the administration of immune globulins, salicylates, and transfusions.

Drug Interactions, Use with Other Vaccines

Results from clinical studies indicate that VARIVAX can be administered concomitantly with M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live).

Limited data from an experimental product containing varicella vaccine suggest that VARIVAX can be administered concomitantly with DTaP (diphtheria, tetanus, acellular pertussis) and PedvaxHIB using separate sites and syringes (see CLINICAL PHARMACOLOGY, Studies with Other Vaccines).(5) However, there are no data relating to simultaneous administration of VARIVAX with DTP or OPV.

Carcinogenesis, Mutagenesis, Impairment of Fertility

VARIVAX has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.

Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with VARIVAX. It is also not known whether VARIVAX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, VARIVAX should not be administered to pregnant females; furthermore, pregnancy should be avoided for three months following vaccination (see CONTRAINDICATIONS).

Nursing Mothers

It is not known whether varicella vaccine virus is secreted in human milk. Therefore, because some viruses are secreted in human milk, caution should be exercised if VARIVAX is administered to a nursing woman.

Pediatric Use

No clinical data are available on safety or efficacy of VARIVAX in children less than one year of age and administration to infants under twelve months of age is not recommended.

ADVERSE REACTIONS

In clinical trials,(4,5,9-15) VARIVAX was administered to 11,102 healthy children, adolescents, and adults.

VARIVAX was generally well tolerated.

In a double-blind placebo controlled study among 914 healthy children and adolescents who were serologically confirmed to be susceptible to varicella, the only adverse reactions that occurred at a significantly (p less than 0.05) greater rate in vaccine recipients than in placebo recipients were pain and redness at the injection site.(4)

Children 1 to 12 Years of Age

In clinical trials involving healthy children monitored for up to 42 days after a single dose of VARIVAX, the frequency of fever, injection-site complaints, or rashes were reported as follows:

In addition, the most frequently (greater than or equal to 1%) reported adverse experiences, without regard to causality, are listed in decreasing order of frequency: upper respiratory illness, cough, irritability/nervousness, fatigue, disturbed sleep, diarrhea, loss of appetite, vomiting, otitis, diaper rash/contact rash, headache, teething, malaise, abdominal pain, other rash, nausea, eye complaints, chills, lymphadenopathy, myalgia, lower respiratory illness, allergic reactions

(including allergic rash, hives), stiff neck, heat rash/prickly heat, arthralgia, eczema/dry skin/dermatitis, constipation, itching.

Pneumonitis has been reported rarely (less than1%) in children vaccinated with VARIVAX; a causal relationship has not been established.

Febrile seizures have occurred rarely (less than 0.1%) in children vaccinated with VARIVAX; a causal relationship has not been established.

Adolescents and Adults 13 Years of Age and Older

In clinical trials involving healthy adolescents and adults, the majority of whom received two doses of VARIVAX and were monitored for up to 42 days after any dose, the frequency of fever, injection-site complaints, or rashes were reported as follows:

In addition, the most frequently (greater than or equal to 1%) reported adverse experiences, without regard to causality, are listed in decreasing order of frequency: upper respiratory illness, headache, fatigue, cough, myalgia, disturbed sleep, nausea, malaise, diarrhea, stiff neck, irritability/nervousness, lymphadenopathy, chills, eye complaints, abdominal pain, loss of appetite, arthralgia, otitis, itching, vomiting, other rashes, constipation, lower respiratory illness, allergic reactions (including allergic rash, hives), contact rash, cold/canker sore.

As with any vaccine, there is the possibility that broad use of the vaccine could reveal adverse reactions not observed in clinical trials.

The following additional adverse reactions have been reported since the vaccine has been marketed:

Body As A Whole: Anaphylaxis.

Hemic and Lymphatic System: Thrombocytopenia.

Nervous/Psychiatric: Encephalitis; Guillain-Barr syndrome; transverse myelitis; Bell's palsy; ataxia; paresthesia.

Respiratory: Pharyngitis.

Skin: Stevens-Johnson syndrome; erythema multiforme; herpes zoster.

DOSAGE AND ADMINISTRATION

FOR SUBCUTANEOUS ADMINISTRATION

Do not inject intravenously

Children 12 months to 12 years of age should receive a single 0.5 mL dose administered subcutaneously.

Adolescents and adults 13 years of age and older should receive a 0.5 mL dose administered subcutaneously at elected date and a second 0.5 mL dose 4 to 8 weeks later.

VARIVAX is for subcutaneous administration. The outer aspect of the upper arm (deltoid) is the preferred site of injection.

VARIVAX SHOULD BE STORED FROZEN at an average temperature of -15 degrees C (+5 degrees F) or colder until it is reconstituted for injection (see HOW SUPPLIED, Storage). Any freezer (e.g., chest, frost-free) that reliably maintains an average temperature of -15 degrees C and has a separate sealed freezer door is acceptable for storing VARIVAX. The diluent should be stored separately at room temperature or in the refrigerator. To reconstitute the vaccine, first withdraw 0.7 mL of diluent into the syringe to be used for reconstitution. Inject all the diluent in the syringe into the vial of lyophilized vaccine and gently agitate to mix thoroughly. Withdraw the entire contents into a syringe and inject the total volume (about 0.5 mL) of reconstituted vaccine subcutaneously, preferably into the outer aspect of the upper arm (deltoid) or the anterolateral thigh. IT IS RECOMMENDED THAT THE VACCINE BE ADMINISTERED IMMEDIATELY AFTER RECONSTITUTION, TO MINIMIZE LOSS OF POTENCY. DISCARD IF RECONSTITUTED VACCINE IS NOT USED WITHIN 30 MINUTES.

CAUTION: A sterile syringe free of preservatives, antiseptics, and detergents should be used for each injection and/or reconstitution of VARIVAX because these substances may inactivate the vaccine virus.

It is important to use a separate sterile syringe and needle for each patient to prevent transmission of infectious agents from one individual to another.

To reconstitute the vaccine, use only the Merck sterile diluent supplied with VARIVAX, M-M-R II, or the component vaccines of M-M-R II, since it is free of preservatives or other anti-viral substances which might inactivate the vaccine virus.

Do not freeze reconstituted vaccine.

Do not give immune globulin including Varicella Zoster Immune Globulin concurrently with VARIVAX (see also PRECAUTIONS).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VARIVAX when reconstituted is a clear, colorless to pale yellow liquid.

HOW SUPPLIED

No. 4826/4309 -- VARIVAX is supplied as follows: (1) a single-dose vial of lyophilized vaccine, NDC 0006-4826-00 (package A); and (2) a box of 10 vials of diluent (package B).

No. 4827/4309 -- VARIVAX is supplied as follows: (1) a box of 10 single- dose vials of lyophilized vaccine (package A), NDC 0006-4827-00; and (2) a box of 10 vials of diluent (package B) (6505-01-413-1331, Ten Pack).

Stability

VARIVAX retains a potency level of 1500 PFU or higher per dose for at least 18 months in a frost-free freezer with an average temperature of -15 degrees C (+5 degrees F) or colder.

VARIVAX has a minimum potency level of approximately 1350 PFU 30 minutes after reconstitution at room temperature (20-25 degrees C, 68-77 degrees F).

Prior to reconstitution, VARIVAX retains potency when stored for up to 72 continuous hours at refrigerator temperature (2-8 degrees C, 36-46 degrees F).

For information regarding stability under conditions other than those recommended call 1-800-9-VARIVAX.

Storage

During shipment, to ensure that there is no loss of potency, the vaccine must be maintained at a temperature of -20 degrees C (-4 degrees F) or colder.

Before reconstitution, store the lyophilized vaccine in a freezer at an average temperature of -15 degrees C (+5 degrees F) or colder. Any freezer (e.g., chest, frost-free) that reliably maintains an average temperature of -15 degrees C and has a separate sealed freezer door is acceptable for storing VARIVAX.

VARIVAX may be stored at refrigerator temperature (2-8 degrees C, 36-46 degrees F) for up to 72 continuous hours prior to reconstitution. Vaccine stored at 2-8 degrees C which is not used within 72 hours of removal from -15 degrees C storage should be discarded.

Before reconstitution, protect from light.

The diluent should be stored separately at room temperature (20-25 degrees C, 68-77 degrees F), or in the refrigerator.

REFERENCES

1. Balfour, H.H.; et al.: Acyclovir treatment of varicella in otherwise healthy children, Pediatr., 116: 633-639, 1990.
2. Ross, A.H.: Modification of chickenpox in family contacts by administration of gamma globulin, N. Engl. J. Med. 267: 369-376, 1962.
3. Preblud, S.R.: Varicella: Complications and Costs, Pediatrics, 78 (4 Pt 2): 728-735, 1986.
4. Weibel, R.E.; et al.: Live Attenuated Varicella Virus Vaccine, N. Engl. J. Med. 310(22): 1409-1415, 1984.
5. Unpublished data; files of Merck Research Laboratories.
6. Wharton, M.; et al.: Health Impact of Varicella in the 1980's. Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy, (Abstract #1138), 1990.
7. Bernstein, H.H.; et al.: Clinical Survey of Natural Varicella Compared with Breakthrough Varicella After Immunization with Live Attenuated Oka/Merck Varicella Vaccine. Pediatrics 92: 833-837, 1993.
8. Kuter, B.J.; et al.: Oka/Merck Varicella Vaccine in Healthy Children: Final Report of a 2-Year Efficacy Study and 7-Year Follow-up Studies, Vaccine, 9: 643-647, 1991.
9. Arbeter, A.M.; et al.: Varicella Vaccine Trials in Healthy Children, A Summary of Comparative and Follow-up Studies, AJDC 138: 434-438, 1984.
10. Weibel, R.E.; et al.: Live Oka/Merck Varicella Vaccine in Healthy Children, JAMA 254(17): 2435-2439, 1985.
11. Chartrand, D.M.; et al.: New Varicella Vaccine Production Lots in Healthy Children and Adolescents, Abstracts of the 1988 Inter-Science Conference Antimicrobial Agents and Chemotherapy: 237(Abstract #731).
12. Johnson, C.E.; et al.: Live Attenuated Vaccine in Healthy 12 to 24 month old Children, Pediatrics 81: 512-518, 1988.
13. Gershon, A.A.; et al.: Immunization of Healthy Adults with Live Attenuated Varicella Vaccine, Journal of Infectious Diseases, 158(1): 132-137, 1988.
14. Gershon, A.A.; et al.: Live Attenuated Varicella Vaccine: Protection in Healthy Adults Compared with Leukemic Children, Journal of Infectious Diseases, 161: 661-666, 1990.
15. White, C.J.; et al.: Varicella Vaccine (VARIVAX) in Healthy Children and Adolescents: Results From Clinical Trials, 1987 to 1989, Pediatrics, 87(5): 604-610, 1991.
16. Asano, Y.; et al.: Contact Infection from Live Varicella Vaccine Recipients, Lancet 1(7966): 965, 1976.
17. Hammerschlag, M.R.; et al.: Herpes Zoster in an Adult Recipient of Live Attenuated Varicella Vaccine, J Infect Dis 160(3); 535-537, 1989.
18. White, C.J.: Letters to the Editor, Pediatrics 318: 354, 1992.
19. Guess, H.A.; et al.: Epidemiology of Herpes Zoster in Children and Adolescents: A Population Based Study, Pediatrics 76(4): 512-517, 1985.
20. Ragozzino, M.; et al.: Population-Based Study of Herpes Zoster and Its Sequelae, Medicine 61(5): 310-316, 1982.
21. Morbidity and Mortality Weekly Report 34(1): 13-16, Jan. 11, 1985.
22. Dennehy, P.H.; et al.: Immunogenicity of Subcutaneous Versus Intramuscular Oka/Merck Varicella Vaccination in Healthy Children, Pediatrics 88(3): 604-607, 1991.
23. Center for Disease Control: Immunization of Children Infected with Human T-Lymphotropic Virus Type III/Lymphadenopathy -- Associated Virus, Annals of Internal Medicine, 106: 75-78, 1987.
24. Recommendations of the Advisory Committee on Immunization Practices (ACIP); General Recommendations on Immunization, MMWR 43(No. RR-1): 15-18, January 28, 1994.
25. Vaccine Adverse Event Reporting System _ United States, MMWR 39(41): 730-733, 1990.

(A) trademark of MERCK & CO., Inc. Varivax is the Merck registered trademark for Varicella Virus Vaccine Live (Oka/Merck)

CONTACT: Donna Cary of Merck & Co., 215-652-5558