Pneumococcal Vaccine Polyvalent PNU-IMUNE® 23 is a sterile preparation intended for intramuscular or subcutaneous use. PNU-IMUNE 23 is indicated for immunization against infections caused by the 23 most prevalent types of Streptococcus pneumoniae (pneumococci) which are responsible for approximately 90% of serious pneumococcal disease in the United States and worldwide. ^{1 - 5} PNU-IMUNE 23 consists of a mixture of purified capsular polysaccharides from 23 types of S pneumoniae.

Each of the pneumococcal polysaccharide types is produced separately to assure a high degree of purity. After an individual pneumococcal type is grown, the polysaccharide is separated from the cell and purified by a series of steps including ethanol fractionation. The vaccine is formulated to contain 25 µg of each of the 23 purified polysaccharide types per 0.5 mL dose of vaccine. Thimerosal (a mercury derivative) at a final concentration of 0.01% is added as a preservative.

The vaccine is a clear, colorless liquid.

Disease caused by S pneumoniae remains an important cause of morbidity and mortality in the US, particularly in the very young, the elderly, and persons with certain high-risk conditions. Pneumococcal pneumonia accounts for 10% to 25% of all pneumonias and an estimated 40,000 deaths annually. ²

Studies suggest annual rates of bacteremia of 15-19/100,000 for the total population, and 50/100,000 for persons 65 and older. Certain population groups, eg, Native Americans may have considerably higher disease rates. ²

Mortality from pneumococcal disease is highest in patients with bacteremia or meningitis, patients with underlying medical conditions, and older persons. In some high-risk patients, mortality has been reported to be over 40% for bacteremic disease and 55% for meningitis, despite appropriate antimicrobial therapy. ²

In addition to the very young and persons 65 years of age or older, patients with certain chronic conditions are at increased risk of developing pneumococcal infection and severe pneumococcal illness. Patients with chronic cardiovascular or pulmonary disease, diabetes mellitus, alcoholism, and cirrhosis are generally immunocompetent but have increased risk. Other patients at greater risk because of decreased responsiveness to polysaccharide antigens or more rapid decline in serum antibody include those with functional or anatomic asplenia (eg, sickle cell disease or splenectomy), Hodgkin' disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, and organ transplantation. Studies indicate that patients with acquired immunodeficiency syndrome (AIDS) are also at increased risk of pneumococcal disease. ^6,7 Recurrent pneumococcal meningitis may occur in patients with cerebrospinal fluid leakage that complicates skull fractures or neurologic procedures.

The polysaccharide capsules of pneumococci give these organisms resistance to the phagocytic action of polymorphonuclear leukocytes and monocytes. However, type-specific antibody facilitates their destruction in the body by the mechanism of complement-mediated lysis.

Most healthy adults, including the elderly, demonstrate at least a two-fold rise in type-specific antibodies within two to three weeks of immunization. Similar antibody responses have been reported in patients with alcoholic cirrhosis and diabetes mellitus. In contrast, elderly individuals with chronic pulmonary disease failed to mount a comparable immune response. ⁸ In immunocompromised patients, the response to immunization may also be lower. Children under two years of age respond poorly to most capsular polysaccharide types. Further, response to some pneumococcal types (eg, 6A and 14) important in pediatric infection is decreased in children less than 5 years of age. ⁹

In clinical studies with PNU-IMUNE® 23, more than 90% of all adults showed two-fold or greater increase in geometric mean antibody titer for each capsular type contained in the vaccine. ¹⁰

Patients over the age of 2 years, with anatomical or functional asplenia and otherwise intact lymphoid function, generally respond to pneumococcal vaccines with a serological conversion comparable to that observed in healthy individuals of the same age. ¹¹

Patients with acquired immunodeficiency syndrome (AIDS) may have an impaired antibody response to pneumococcal vaccine. ^7,12 However, asymptomatic human immunodeficiency virus (HIV)-infected patients, or those with generalized lymphadenopathy, respond to the 23-valent pneumococcal vaccine. ¹³

Following immunization of healthy adults, antibody levels remain elevated for at least 5 years, but in some individuals these may fall to preimmunization levels within 10 years. ^14,15 A more rapid decline in antibodies may occur in children, particularly those who have undergone a splenectomy and those with sickle cell disease, in whom antibodies for some types can fall to preimmunization levels 3 to 5 years after immunization. ^16,17 Similar rates of decline can occur in children with nephrotic syndrome. ¹⁸

Controlled clinical trials in South Africa involving 12,000 gold miners have shown a 6-valent and a 13-valent pneumococcal vaccine to be 78.5% effective in preventing type- specific pneumococcal pneumonia and 82.3% effective in preventing pneumococcal bacteremia with the types contained in the vaccine. ¹⁹ In a preliminary study of an 8-valent polysaccharide vaccine in a group consisting of 77 patients with sickle cell disease and 19 asplenic persons, there were no pneumococcal infections in the immunized patients within two years of immunization. There were eight cases of pneumococcal infection in 106 unimmunized, age-matched patients with sickle cell disease. Antibody response of the asplenic patients was comparable to that of normal controls. ²⁰

In a study carried out by Austrian and colleagues with 13-valent pneumococcal vaccines prepared for the National Institute of Allergy and Infectious Disease, the reduction in pneumonias caused by the capsular types present in the vaccines was 79%. Reduction in type-specific pneumococcal bacteremia was 82%. ¹⁹

In a double-blind study of a 14-valent pneumococcal vaccine carried out in Papua, New Guinea, pneumococcal infection was 84% lower in the immunized group and mortality from pneumonia 44% lower. ²¹

Five case-control studies in the US have evaluated the efficacy of pneumococcal vaccine in the prevention of serious pneumococcal disease. Four of these studies showed the vaccine to be efficacious, with point estimates of efficacy ranging from 61% to 70%. ^{22 - 25} One study failed to show efficacy in preventing pneumococcal bacteremia. ²⁶ This study was judged inadequate in determination of vaccination status, and the selection of controls was considered potentially biased. ²

A prospective study failed to demonstrate efficacy against pneumococcal pneumonia and bronchitis; ⁸ this study has been criticized for methodological flaws. ² In contrast, a prospective French study found pneumococcal vaccine to be 77% effective in reducing the incidence of pneumonia among nursing home residents. ²⁷

Despite conflicting findings, the data continue to support the use of pneumococcal vaccine for certain well-defined groups at risk. ²

PNU-IMUNE® 23 is indicated for immunization against pneumococcal disease caused by those pneumococcal types included in the vaccine.

Adults

1. All adults 65 or older, ² with emphasis on immunization of the older adult while in good health.
2. Immunocompetent adults who are at increased risk of pneumococcal disease or its complications because of chronic illnesses (eg, cardiovascular or pulmonary disease, diabetes mellitus, alcoholism, cirrhosis, or cerebrospinal fluid leaks). ²
3. Immunocompromised adults at increased risk of pneumococcal disease or its complications (eg, splenic dysfunction or anatomic asplenia, Hodgkin' disease, lymphoma, multiple myeloma, chronic renal failure, nephrotic syndrome, or conditions such as organ transplantation associated with immunosuppression). ²

Children

1. Children 2 years of age or older with chronic illnesses specifically associated with increased risk of pneumococcal disease or its complications (eg, anatomic or functional asplenia [including sickle-cell disease], nephrotic syndrome, cerebrospinal fluid leaks, and conditions associated with immunosuppression). ²

Special Groups

1. Persons living in special environments or social settings with an identified increased risk of pneumococcal disease or its complications. ²
2. Patients with acquired immunodeficiency syndrome (AIDS) have been shown to have an impaired antibody response to pneumococcal vaccine. However, asymptomatic or symptomatic human immunodeficiency virus (HIV)-infected patients or those with persistent generalized lymphadenopathy respond to the 23-valent vaccine. ²

Timing of Immunization

When elective splenectomy is being considered, pneumococcal vaccine should be given at least two weeks before surgery, if possible. ²

For planning cancer chemotherapy or other immunosuppressive therapy, the interval between immunization and initiation of chemotherapy or immunosuppression should be at least two weeks. ²

CONTRAINDICATIONS

HYPERSENSITIVITY TO ANY COMPONENT OF THE VACCINE, INCLUDING THIMEROSAL, A MERCURY DERIVATIVE, IS A CONTRAINDICATION TO THE USE OF THE PRODUCT.

THE OCCURRENCE OF ANY TYPE OF NEUROLOGICAL SYMPTOMS OR SIGNS FOLLOWING ADMINISTRATION OF THIS PRODUCT IS A CONTRAINDICATION TO FURTHER USE.

THE VACCINE SHOULD NOT BE ADMINISTERED TO PERSONS WITH ACUTE FEBRILE ILLNESSES UNTIL THEIR TEMPORARY SYMPTOMS AND/OR SIGNS HAVE ABATED.

The clinical judgment of the attending physician should prevail at all times.

PNU-IMUNE® 23 is not an effective agent for prophylaxis against pneumococcal disease caused by types not present in the vaccine.

PNU-IMUNE 23 is not indicated for children under two years of age, since antibody response to most capsular polysaccharide types is poor in this age group. ²

Patients with impaired immune responsiveness whether due to the use of immunosuppressive therapy, a genetic defect, human immunodeficiency virus (HIV) infection, or other causes may have a reduced antibody response to active immunization procedures. ²

Patients who have received extensive chemotherapy and/or splenectomy for the treatment of Hodgkin' disease have been shown to have an impaired serum antibody response to pneumococcal vaccine. ^28,29

In one study, administration of the vaccine to patients on immunosuppressive drugs and/or irradiation for Hodgkin' disease resulted in reduction of preexisting antibody levels in several patients. ²⁸ It is unclear whether this effect was due to the vaccine or to the effects of irradiation and/or chemotherapy.

At least two weeks should elapse between immunization and the initiation of chemotherapy or immunosuppressive therapy. ²

Routine reimmunization with this vaccine is not recommended. For reimmunization recommendations (including recommendations regarding reimmunization of individuals at highest risk of fatal pneumococcal infection) see DOSAGE AND ADMINISTRATION .

In one study, local reactions after reimmunization were more severe than after initial immunization when the interval between immunizations was 13 months. ³⁰

Patients who have had episodes of pneumococcal pneumonia or other pneumococcal infection may have high levels of preexisting pneumococcal antibodies that may result in increased reactions to PNU-IMUNE® 23, mostly local, but occasionally systemic. ³¹ Caution should be exercised if such patients are considered for immunization withPNU-IMUNE 23.

Do not administer the vaccine intradermally since severe reactions may occur.

PRECAUTIONS

General

1. This product should not be used in children under 2 years of age.
2. PRIOR TO ADMINISTRATION OF ANY DOSE OF PNU-IMUNE® 23, THE PARENT, GUARDIAN, OR ADULT PATIENT SHOULD BE ASKED ABOUT THE RECENT HEALTH STATUS, MEDICAL AND IMMUNIZATION HISTORY OF THE PATIENT TO BE IMMUNIZED TO DETERMINE THE EXISTENCE OF ANY CONTRAINDICATION TO IMMUNIZATION WITH PNEUMOCOCCAL VACCINE (SEE CONTRAINDICATIONS , ).
3. BEFORE ADMINISTRATION OF ANY BIOLOGICAL, THE PHYSICIAN SHOULD TAKE ALL KNOWN PRECAUTIONS FOR PREVENTION OF ALLERGIC OR ANY OTHER REACTIONS. This includes: a review of the patient' history regarding possible sensitivity, the ready availability of epinephrine 1:1,000 and other appropriate agents used for control of immediate allergic reactions, and a knowledge of the recent literature pertaining to use of the biological concerned, including the nature of side effects and adverse reactions that may follow its use.
4. A separate sterile syringe and needle or a sterile disposable unit should be used for each individual patient to prevent transmission of infectious agents from one person to another.

PRIOR TO ADMINISTRATION OF THIS VACCINE, HEALTH CARE PERSONNEL SHOULD INFORM THE PARENT, GUARDIAN, OR ADULT PATIENT OF THE BENEFITS AND RISKS OF IMMUNIZATION WITH PNEUMOCOCCAL VACCINE.

Pregnancy Category C:   Animal reproduction studies have not been conducted with PNU-IMUNE® 23. It is also not known whether PNU-IMUNE 23 can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. PNU-IMUNE 23 is not recommended for use in pregnant women.

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PNU-IMUNE 23 is administered to a nursing woman.

ADVERSE REACTIONS

Pneumococcal Vaccine Polyvalent PNU-IMUNE® 23 is associated with a relatively low incidence of adverse reactions. The adverse reactivity observed in clinical studies was of short duration and not serious.

In a study of 32 individuals who received PNU-IMUNE 23, 23 (72%) experienced local reaction characterized by soreness at the injection site within 3 days after immunization. ¹⁰

Low grade fever (less than 37.8°C [100°F]) and mild myalgia occur occasionally and are usually confined to the 24-hour period following immunization. Rash and arthralgia have been reported infrequently.

Although rare, fever over 38.9°C (102°F) and marked local swelling have been reported with pneumococcal polysaccharide vaccine. Rash, urticaria, arthritis, arthralgia, and adenitis have been reported rarely.

Patients with otherwise stabilized idiopathic thrombocytopenic purpura have, on rare occasions, experienced a relapse in their thrombocytopenia, occurring 2 to 14 days after immunization, and lasting up to 2 weeks. ³²

Reactions of greater severity, or extent are unusual. Rarely, anaphylactoid reactions have been reported.

Temporal association of neurological disorders such as paresthesias and acute radiculoneuropathy, including Guillain-Barré syndrome, have been reported following parenteral injections of biological products including pneumococcal vaccine.

DOSAGE AND ADMINISTRATION

The immunization schedule consists of a single 0.5 mL dose given intramuscularly or subcutaneously. Intradermal administration should be avoided. Do not inject intravenously.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration (see ).

Before injection, the skin at the injection site should be cleansed with a suitable germicide. After insertion of the needle, aspirate to help avoid inadvertent injection into a blood vessel.

Simultaneous Administration with Other Vaccines

Many patients who receive pneumococcal vaccine should also be immunized with influenza vaccine which may be given simultaneously at a different site. In contrast to pneumococcal vaccine, influenza vaccine is recommended annually. ²

Reimmunization

The incidence of local reactions after reimmunization were found to be more severe than after initial immunization when the interval between immunizations was 13 months. ²⁹ Reports of reimmunization after longer intervals in children and adults, including a large group of elderly persons reimmunized at least 4 years after primary immunization, suggest a similar incidence of such reactions. ² The Immunization Practices Advisory Committee (ACIP) recommendations regarding reimmunization are as follows: Persons who receive the 14-valent vaccine should not routinely be reimmunized with the 23-valent vaccine. However, reimmunization with 23-valent vaccine should be strongly considered for persons who received the 14-valent vaccine if they are at highest risk of fatal pneumococcal infection (eg, asplenic patients). Reimmunization should also be carefully considered for adults at highest risk who received the 23-valent vaccine more than 6 years before and for those shown to have a rapid decline in antibody levels (eg, patients with nephrotic syndrome, renal failure, or transplant patients). Reimmunization should be carefully considered after 3 to 5 years for children with nephrotic syndrome, asplenia, or sickle cell anemia who would be 10 years old or younger at the time of reimmunization. ²

HOW SUPPLIED

PNU-IMUNE® 23 is supplied as follows:

NDC 0005-2309-31 2.5 mL Vial, for use with syringe only.

NDC 0005-2309-33 5 × One Dose (0.5 mL) LEDERJECT® Disposable Syringes.

STORAGE

DO NOT FREEZE. STORE REFRIGERATED, AWAY FROM FREEZER COMPARTMENT AT 2°C TO 8°C (36°F TO 46°F).

Directions for Use of the LEDERJECT Disposable Syringe:

1. Twist the plunger rod clockwise to be sure the rod is secure to rubber plunger base.
   
2. Hold needle shield in place with index finger and thumb of one hand while, with the other thumb, exert light pressure on plunger rod until the plunger base has been freed and demonstrates slight movement when pressure is applied.
   
3. Grasp the rubber needle shield at its base; twist and pull to remove.
   
4. To prevent needle-stick injuries, needles should not be recapped, purposely bent, or broken by hand.

REFERENCES

1. Austrian R. Surveillance of pneumococcal infection for field trials of polyvalent vaccines. Annual Contract Prog Report to the Nat Inst of Allerg and Inf Dis 1975; Update to Dec. 1977, personal communication.
2. Immunization Practices Advisory Committee. Pneumococcal polysaccharide vaccine--recommendations of the ACIP. MMWR. 1989;38(5):64-76. Recommendations also published in: JAMA. 1989;261(9):1265-1267.
3. Lund E. Distribution of pneumococcal types at different times and different areas. In: Finland M, Marget W, Bartman K eds. Bayer-Symposium III Bacterial Infections. New York, NY:Springer-Verlag, 1971:49.
4. Mufson MA, Kruss DM, Wasil RE, et al. Capsular types and outcome of bacteremic pneumococcal disease in the antibiotic era. Arch Int Med. 1974;134:505-510.
5. Robbins JB, Austrian R, Lee CJ, et al. Consideration for formulating the second generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infec Dis. 1983; 148(6):1136-1159.
6. Lane CH, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309:453-458.
7. Ammann AJ, Schiffman G, Abrams D, et al. B-cell immunodeficiency in acquired immune deficiency syndrome. JAMA. 1984;251:1447-1449.
8. Simberkoff MS, Cross AP, Al-Ibrahim M, et al. Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans Administration cooperative study. N Eng J Med. 1986;315:1318-1327.
9. Douglas RM, Paton JC, Duncan SJ, et al. Antibody response to pneumococcal vaccination in children younger than five years of age. J Infect Dis. 1983;148:131-137.
10. Data on file, Lederle Laboratories.
11. Sullivan JL, Ochs HD, Schiffman G, et al. Immune response after splenectomy. Lancet. 1978;1:178-181.
12. Ballet J-J, Sulcebe G, Couderc L-J, et al. Impaired anti-pneumococcal antibody response in patients with AIDS-related persistent generalized lymphadenopathy. Clin Exp Immunol. 1987;68:479-487.
13. Huang K-L, Ruben FL, Rinaldo CR Jr, et al. Antibody responses after influenza and pneumococcal immunization in HIV-infected homosexual men. JAMA. 1987; 257:2047-2050.
14. Mufson MA, Krause HE, Schiffman G. Long term persistence of antibodies following immunization with pneumococcal polysaccharide vaccine. Proc Soc Exp Bio Med. 1983;173:270-275.
15. Mufson MA, Krause HE, Schiffman G, et al. Pneumococcal antibody levels one decade after immunization of healthy adults. Am J Med Sci. 1987;293:279-284.
16. Giebiuk GS, Le CT, Schiffman G. Decline of serum antibody in splenectomized children after vaccination with pneumococcal capsular polysaccharides. J Pediatr. 1984;105:576-582.
17. Weintrub PS, Schiffman G, Addiego JE Jr, et al. Long-term follow-up and booster immunization with polyvalent pneumococcal polysaccharide in patient with sickle cell anemia. J Pediatr. 1984;105:261-263.
18. Spika JS, Halsey NA, Le CT, et al. Decline of vaccine-induced antipneumococcal antibody in children with nephrotic syndrome. Am J Kidney Dis. 1986;7:466-470.
19. Austrian R, Douglas RM, Schiffman G, et al. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Phys. 1976;89:184-194.
20. Ammann AJ, Addiego K, Wara DW, et al. Polyvalent pneumococcal-polysaccharide immunization of patients with sickle-cell anemia and patients with splenectomy. N Engl J Med. 1977;297:897-900.
21. Riley ID, Tarr PI, Andrews M, et al. Immunisation with a polyvalent pneumococcal vaccine: reduction of adult respiratory mortality in a New Guinea Highlands community. Lancet. 1977;1:1338-1341.
22. Shapiro ED, Clemens JD. A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Ann Intern Med. 1984;101:325-330.
23. Shapiro ED, Austrian R, Adair RK, et al. The protective efficacy of pneumococcal vaccine (Abstract). Clin Res. 1988;36:470A.
24. Sims RV, Steinmann WC, McConville JH, et al. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med. 1988;108:653-657.
25. Bolan G, Broome CV, Facklam RR, et al. Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med. 1986;104:1-6.
26. Forrester HL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal vaccine in a high-risk population. Am J Med. 1987;83:425-430.
27. Gaillat J, Zmirou D, Mallaret MR, et al. Essai clinique du vaccin antipneumococcique chez des personnes agées vivant en institution. Rev Epid é miol Sant é Publique. 1985;33:437-444.
28. Siber GR, Weitzman SA, Aisenberg AC, et al. Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin' disease. N Eng J Med. 1978;299:442-448.
29. Siber GR, Gorham C, Martin P, et al. Antibody response to pretreatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin' disease. Ann Intern Med. 1986;104:467-475.
30. Borgono JM, McLean AA, Vella PP, et al. Vaccination and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc Soc Exper Biol Med. 1978;157:148-154.
31. Ponka A, Leinonen M: Adverse reactions to polyvalent pneumococcal vaccine. Scand J Infect Dis. 1982;14:67-71.
32. Kelton JG. Vaccination-associated relapse of immune thrombocytopenia. JAMA. 1981;245(4):369-371.

Manufactured by:

LEDERLE LABORATORIES

Division American Cyanamid Company

Pearl River, NY 10965

US Gov't. License No. 17

Marketed by:

WYETH-LEDERLE VACCINES AND PEDIATRICS

Wyeth-Ayerst Laboratories

Philadelphia, PA 19101

CI 4415-2 Revised October 5, 1998

PRODUCT PHOTO(S):