Prescription Drugs

CLINICAL PHARMACOLOGY Tetanus (tetanus toxoid) manifests systemic toxicity primarily by neuromuscular dysfunction caused by a potent exotoxin elaborated by Clostridium tetani. Following routine use of tetanus toxoid (tetanus (tetanus toxoid) toxoid) in the United States (US), the occurrence of tetanus (tetanus toxoid) decreased dramatically from 560 reported cases in 1974 to an average of 50-100 cases reported annually from the mid 1970s through the late 1990s. The case-fatality rate has been relatively constant at approximately 30%. During the years 1982-1998, 52% of reported cases were among persons 60 years of age or older. In the mid to late 1990s, the age distribution of reported cases shifted to a younger age group, in part due to an increased number of cases among injection drug users in California. From 1995-1997, persons 20 to 59 years of age accounted for 60% of all cases, with persons60 years of age or older accounting for only 35%. In the US, tetanus (tetanus toxoid) occurs almost exclusively among unvaccinated or inadequately vaccinated persons.1 In 4% of tetanus (tetanus toxoid) cases reported during 1987 and 1988, no wound or other condition was implicated. Non-acute skin lesions, such as ulcers, or medical conditions such as abscesses, were reported in association with 14% of cases.2 Neonatal tetanus (tetanus toxoid) occurs among infants born under unhygienic conditions to inadequately vaccinated mothers. Vaccinated mothers confer protection to their infants through transplacental transfer of maternal antibody. From 1972 through 1984, 29 cases of neonatal tetanus (tetanus toxoid) were reported in the US.2 Since 1984, only three cases of neonatal tetanus (tetanus toxoid) have been reported in all infants of unvaccinated or inadequately vaccinated mothers.3 Spores of C. tetani are ubiquitous. Serologic tests indicate that naturally acquired immunity to tetanus (tetanus toxoid) toxin does not occur in the US.2 Thus, universal primary vaccination, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age-groups. Tetanus toxoid (tetanus (tetanus toxoid) toxoid) is a highly effective antigen, and a completed primary series generally induces protective levels of serum antitoxin that persists for 10 or more years.2 In a trial of 26 adults given a booster dose of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) , 81% of the subjects demonstrated a 2-fold or greater rise in serum antitoxin antibody levels.4 There are no studies of this product used as a primary series. REFERENCES 1. CDC. Training and Education Branch, National Immunization Program. Epidemiology and Prevention of Vaccine-Preventable Diseases, W. Atkins, et al, 6th Edition:61, 2000 2. Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus (tetanus toxoid) , and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40:No. RR-10, 1991 3. CDC. Neonatal Tetanus (tetanus toxoid) Montana, 1998. MMWR 47 (43):928-930, 1998 4. Aventis Pasteur Inc., Data on File 073001

Tetanus Toxoid For Booster Use Only (Not recommended for primary immunization) Caution: Federal (USA) law prohibits dispensing without prescription. DESCRIPTION Tetanus Toxoid, for intramuscular or subcutaneous use, is a sterile solution of toxoid in isotonic sodium chloride solution. The vaccine is clear or slightly turbid in appearance. Clostridium tetani culture is grown in a peptone-based medium and detoxified with formaldehyde. The detoxified material is then purified by serial ammonium sulfate fractionation, followed by sterile filtration. The toxoid is then diluted with physiological saline solution (0.85%). Each dose contains the preservative thimerosal [(mercury derivative), 25 mg mercury/dose]. This product does not contain an aluminum-containing adjuvant. Each 0.5 mL dose is formulated to contain 4 Lf (flocculation units) of tetanus toxoid (tetanus (tetanus toxoid) toxoid) and passes the guinea pig potency test. The residual formaldehyde content, by assay, is less than 0.02%.

PATIENT INFORMATION As part of the child's or adult's immunization record, the date, lot number and manufacturer of the vaccine administered MUST be recorded.11-13 Patients should be fully informed of the benefits and risks of immunization with Tetanus (tetanus toxoid) Toxoid vaccine. The physician should inform the patients about the potential for adverse reactions that have been temporally associated with Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) administration. The health-care provider should provide the Vaccine Information Statements (VISs) which are required by the National Childhood Vaccine Injury Act of 1986 to be given with each immunization. Parents or guardians should be instructed to report any adverse reactions to their health-care provider. IT IS EXTREMELY IMPORTANT WHEN THE CHILD OR ADULT PATIENT RETURNS FOR THE NEXT DOSE IN THE SERIES, THE PARENT, GUARDIAN, OR ADULT PATIENT SHOULD BE QUESTIONED CONCERNING OCCURRENCE OF ANY SYMPTOMS AND/OR SIGNS OF AN ADVERSE REACTION AFTER THE PREVIOUS DOSE (SEE CONTRAINDICATIONS; ADVERSE REACTIONS SECTIONS). The health-care provider should inform the parent, guardian, or adult patient of the importance of completing the immunization series, unless a contraindication to further immunization exists. The US 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 1986.5 The toll-free number for VAERS forms and information is 1-800-822-7967. REFERENCES 11. CDC. Vaccine Adverse Event Reporting System United States. MMWR 39:730-733, 1990 12. CDC. National Childhood Vaccine Injury Act: requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200, 1988 13. Food and Drug Administration. New reporting requirements for vaccine adverse events. FDA Drug Bull 18 (2), 16-18, 1988

OVERDOSENo information provided. CONTRAINDICATIONS HYPERSENSITIVITY TO ANY COMPONENT OF THE VACCINE, INCLUDING THIMEROSAL, A MERCURY DERIVATIVE, IS A CONTRAINDICATION FOR FURTHER USE OF THIS VACCINE. It is a contraindication to use this or any other related vaccine after a serious adverse event temporally associated with a previous dose including an anaphylactic reaction. A history of systemic allergic or neurologic reactions following a previous dose of Tetanus (tetanus toxoid) Toxoid is an absolute contraindication for further use.2,5 If a contraindication to using tetanus toxoid (tetanus (tetanus toxoid) toxoid) -containing preparations exists in a person who has not completed a primary immunizing course of tetanus toxoid (tetanus (tetanus toxoid) toxoid) and other than a clean, minor wound is sustained, only passive immunization should be given using TIG (Human).2 Elective immunization should be deferred during the course of any febrile illness or acute infection. A minor afebrile illness such as a mild upper respiratory infection should not preclude immunization.2 Elective immunization procedures should be deferred during an outbreak of poliomyelitis.8 It is a contraindication to use this or any other related vaccine after a serious adverse reaction temporally associated with a previous dose, including an anaphylactic reaction. REFERENCES 2. Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus (tetanus toxoid) , and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40:No. RR-10, 1991 5. Report on the Committee of Infectious Diseases, ed 25. Elk Grove Village, IL. American Academy of Pediatrics, 2000 8. Wilson GS. The Hazards of Immunization. Provocation poliomyelitis:270-274, 1967

SIDE EFFECTS BODY SYSTEM AS A WHOLE Adverse reactions may be local and include redness, warmth, edema, induration with or without tenderness as well as urticaria, and rash. Malaise, transient fever, pain, hypotension, nausea and arthralgia may develop in some patients after the injection. Arthus-type hypersensitivity reactions, characterized by severe local reactions (generally starting 2 to 8 hours after an injection) may occur, particularly in persons who have received multiple prior boosters.2 On rare occasions, anaphylaxis has been reported following administration of products containing tetanus (tetanus toxoid) toxoid. Upon review, a report by the Institute of Medicine (IOM) concluded the evidence established a causal relationship between tetanus toxoid (tetanus (tetanus toxoid) toxoid) and anaphylaxis.17 Deaths have been reported in temporal association with the administration of tetanus toxoid (tetanus (tetanus toxoid) toxoid) -containing vaccines. NERVOUS SYSTEM The following neurologic illnesses have been reported as temporally associated with vaccines containing tetanus toxoid (tetanus (tetanus toxoid) toxoid) : neurological complications 18,19 including cochlear lesion, 20 brachial plexus neuropathies, 20,21 paralysis of the radial nerve, 22 paralysis of the recurrent nerve, 20 accommodation paresis, Guillain-Barré syndrome, and EEG disturbances with encephalopathy. The IOM, following review of the reports of neurologic events following vaccination with tetanus toxoid (tetanus (tetanus toxoid) toxoid) , DT or Td, concluded the evidence favored acceptance of a causal relationship between tetanus toxoid (tetanus (tetanus toxoid) toxoid) and brachial neuritis and GBS.17,23 Reporting of Adverse Events The National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act of 1986, requires physicians and other health-care providers who administer vaccines to maintain permanent vaccination records and to report occurrences of certain adverse events to the US Department of Health and Human Services.11-13 Reportable events include those listed in the Act for each vaccine and events such as anaphylaxis or anaphylactic shock within 7 days, brachial neuritis within 28 days; any acute complication or sequela (including death) of an illness, 5 disability, injury, or condition referred to above, or any events that would contraindicate further doses of vaccine, according to this Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) for Booster Use Only package insert. Adverse events following immunization with vaccine should be reported by health-care providers to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Reporting forms and information about reporting requirements or completion of the form can be obtained from VAERS through a toll-free number 1-800-822-7967.11-13 Health-care providers also should report these events to the Pharmacovigilance Department, Aventis Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 or call 1-800-822-2463. DRUG INTERACTIONS If passive immunization for tetanus (tetanus toxoid) is needed, TIG (Human) is the product of choice. It provides longer protection than antitoxin of animal origin and causes few adverse reactions. The currently recommended prophylactic dose of TIG (Human) for wounds of average severity is 250 units intramuscularly. When a vaccine containing tetanus toxoid (tetanus (tetanus toxoid) toxoid) is given at the same time as TIG (Human), separate syringes and separate sites should be used. The ACIP recommends the use of only adsorbed toxoid in this situation.2 The vaccine should be administered subcutaneously in patients on anticoagulant therapy. Immunosuppressive therapies may reduce the response to vaccines (see PRECAUTIONS section). REFERENCES 2. Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus (tetanus toxoid) , and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40:No. RR-10, 1991 5. Report on the Committee of Infectious Diseases, ed 25. Elk Grove Village, IL. American Academy of Pediatrics, 2000 11. CDC. Vaccine Adverse Event Reporting System United States. MMWR 39:730-733, 1990 12. CDC. National Childhood Vaccine Injury Act: requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 37:197-200, 1988 13. Food and Drug Administration. New reporting requirements for vaccine adverse events. FDA Drug Bull 18 (2), 16-18, 1988 17. Institute of Medicine. Adverse events associated with childhood vaccines. Evidence Bearing on Causality. National Academy Press, Washington, DC, 1994 18. Rutledge SL, et al. Neurologic complications of immunizations. J Pediatr 109:917-924, 1986 19. Schlenska GK. Unusual neurological complications following tetanus toxoid (tetanus (tetanus toxoid) toxoid) administration. J Neurol 215:299-302, 1977 20. Wilson GS. The Hazards of Immunization. Allergic manifestations:post-vaccinal neuritis. pp 153-156, 1967 21. Tsairis P, et al. Natural history of brachial plexus neuropathy. Arch Neurol 27:109-117, 1972 22. Blumstein GI, et al. Peripheral neuropathy following tetanus toxoid (tetanus (tetanus toxoid) toxoid) administration. JAMA 198:1030-1031, 1966 23. Pollard JD, et al. Relapsing neuropathy due to tetanus toxoid (tetanus (tetanus toxoid) toxoid) :report of a case. J Neurol Sci 37:113-125, 1978

WARNINGS Intramuscular injections should be given with great care in patients suffering from thrombocytopenia or other coagulation disorders. In this situation, subcutaneous administration of Tetanus (tetanus toxoid) Toxoid may be advisable. A routine booster should not be given more frequently than every ten years. (This guideline should not preclude wound management considerations.) Persons who experienced Arthus-type hypersensitivity reactions or temperature greater than 39.4°C (103°F) after a previous dose of a tetanus toxoid (tetanus (tetanus toxoid) toxoid) -containing preparation usually have very high serum tetanus (tetanus toxoid) antibody levels and should not be given even emergency doses of tetanus toxoid (tetanus (tetanus toxoid) toxoid) -containing preparation more frequently than every 10 years, even if they have a wound that is neither clean nor minor.9 Deaths have been reported in temporal association with the administration of Tetanus Toxoid (see ADVERSE REACTIONS section). PRECAUTIONS GENERAL Care is to be taken by the health-care provider for the safe and effective use of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) . EPINEPHRINE INJECTION (1:1, 000) MUST BE IMMEDIATELY AVAILABLE SHOULD AN ACUTE ANAPHYLACTIC REACTION OCCUR DUE TO ANY COMPONENT OF THE VACCINE. There is an increased incidence of local and systemic reactions to booster doses of tetanus toxoid (tetanus (tetanus toxoid) toxoid) when given to previously immunized persons. (Refer to DOSAGE AND ADMINISTRATION section for timing of booster injections.) Prior to an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. The physician should have a current knowledge of the literature concerning the use of the vaccine under consideration, including the nature of the adverse reactions that may follow its use. The patients medical history should be reviewed with respect to possible sensitivity and any previous adverse reactions to the vaccine or similar vaccines, possible sensitivity to dry natural latex rubber, previous immunization history, and current health status (see CONTRAINDICATIONS section). Persons who have a history of Guillain-Barré syndrome (GBS) may be at increased risk of recurrent GBS after subsequent doses of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) vaccines. However, in a study in which an estimated 1.2 million doses of tetanus (tetanus toxoid) -containing toxoid were administered to persons >18 years of age, two cases of GBS were expected by chance alone during the 6 weeks after vaccination, and only one case was reported. This finding suggests that the risk of GBS after administration of tetanus toxoid (tetanus (tetanus toxoid) toxoid) is extremely low. The decision to administer tetanus (tetanus toxoid) -toxoid-containing vaccine to persons who have had GBS within 6 weeks after receiving tetanus toxoid (tetanus (tetanus toxoid) toxoid) should be based on the benefits of subsequent vaccination and the risk of the recurrence of GBS.9 The expected immune response to Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) may not be obtained in immunosuppressed patients. Administration of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) is not contraindicated in patients with HIV infection.10 Special care should be taken to ensure that the injection does not enter a blood vessel. Immunosuppressive therapies including radiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic drugs may reduce the immune response to vaccines. Therefore, routine vaccination should be deferred, if possible, while patients are receiving such therapy.2 If Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) has been administered to persons receiving immunosuppressive therapy, or having an immunodeficiency disorder, an adequate antibody response may not be obtained.5 When possible, immunosuppressive treatment should be interrupted when immunization is required due to a tetanus (tetanus toxoid) -prone wound. It is advisable to use DT (For Pediatric Use 6 years of age and younger) or Td (For Adult Use 7 years of age and older) in wound prophylaxis instead of tetanus toxoid (tetanus (tetanus toxoid) toxoid) alone in order to maintain adequate levels of diphtheria immunity.5 A separate, sterile syringe and needle or a sterile disposable unit must be used for each patient to prevent transmission of hepatitis or other infectious agents from person to person. Needles should not be recapped and should be properly disposed. Caution: The stopper of the vial contains dry natural latex rubber, that may cause allergic reactions. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY No studies have been performed to evaluate carcinogenicity, mutagenic potential, or impact on fertility. PREGNANCY REPRODUCTIVE STUDIES PREGNANCY CATEGORY C Adequate immunization by routine boosters in non-pregnant women of child-bearing age can obviate the need to vaccinate women during pregnancy (see DOSAGE AND ADMINISTRATION section). Animal reproduction studies have not been conducted with Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) . The risk to the fetus from tetanus toxoid (tetanus (tetanus toxoid) toxoid) is unknown. The ACIP recommends that an appropriate tetanus toxoid (tetanus (tetanus toxoid) toxoid) -containing preparation be given to inadequately immunized pregnant women because it affords protection against neonatal tetanus (tetanus toxoid) .10 Waiting until the second trimester is a reasonable precaution to minimize any theoretical teratogenic concern.5 It has been reported that Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) administered to pregnant women prevents neonatal tetanus (tetanus toxoid) in newborns.14,15 However, the data reported on the safety of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) when so used is inconclusive because the incidence of neonatal deaths in New Guinea was significantly higher than in the US.A prospective study in the US has not been done to confirm these reports.14 NURSING MOTHERS Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect immune response and is not a contraindication for vaccination.10 PEDIATRIC USE SAFETY AND EFFECTIVENESS OF TETANUS TOXOID (tetanus (tetanus toxoid) toxoid) IN INFANTS BELOW THE AGE OF SIX WEEKS HAS NOT BEEN ESTABLISHED. HOWEVER, THIS VACCINE IS NOT INDICATED FOR CHILDREN UNDER 7 YEARS OF AGE. GERIATRIC USE Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) should only be used in geriatric patients known to have received a primary series (at least 2 doses) of tetanus (tetanus toxoid) -containing vaccine, since many such persons have no prior immunity.16 Clinical studies of Tetanus Toxoid (tetanus (tetanus toxoid) toxoid) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. REFERENCES 2. Recommendations of the Immunization Practices Advisory Committee (ACIP). Diphtheria, Tetanus (tetanus toxoid) , and Pertussis: Recommendations for vaccine use and other preventive measures. MMWR 40:No. RR-10, 1991 5. Report on the Committee of Infectious Diseases, ed 25. Elk Grove Village, IL. American Academy of Pediatrics, 2000 9. CDC. Update:Vaccine Side Effects, Adverse Reactions, Contraindications, and Precautions (ACIP). MMWR 45:No. RR-12, 1996 10. ACIP. General recommendations on immunization. MMWR 43:No. RR-1, 1994 14. MacLennan R, et al. Immunization against neonatal tetanus (tetanus toxoid) in New Guinea. Antitoxin response of pregnant women to adjuvant and plain toxoids. Bull WHO 32:683-697, 1965 15. Newell KW, et al. The use of toxoid for the prevention of tetanus (tetanus toxoid) neonatorum. Bull WHO 35:863-871, 1966 16. Ruben FL, et al. Antitoxin responses in the elderly to tetanus (tetanus toxoid) -diphtheria (TD) immunization. Am J Epidemiol 108:145-149, 1978