Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is a live oral vaccine that replicates in the intestinal tract and induces immunity in persons with low or no pre-existing neutralizing antibodies. Pharmacodynamics Vaccine Virus Shedding Fecal shedding of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral strain viruses was evaluated in a safety and immunogenicity study of 58 subjects (30 vaccine recipients and 28 placebo recipients) [See Clinical Studies]. Stool or rectal swabs and throat swabs were collected on Day 0, 7, 14, 21, 28 and 56. Vaccine virus strains were shed in the stool as early as day 7 following vaccination. Eight of 30 vaccine recipients (27%) tested positive at least once for Adenovirus Type 4 fecal shedding; 18 of 30 vaccine recipients (60%) tested positive for Adenovirus Type 7 fecal shedding. No adenovirus shedding was detectable in any subject by 28 days following vaccination. Vaccine strain virus was not detected in the throat of any subject. Clinical Studies Multicenter Safety And Efficacy Trial A multicenter, double-blind, randomized, placebo-controlled study in US military recruits evaluated the safety and efficacy of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral to prevent wild Type 4 adenovirusassociated febrile acute respiratory disease (ARD) and to induce neutralizing antibody to Type 7 adenovirus. A seroconversion endpoint rather than prevention of clinical disease was used to assess efficacy of the Type 7 adenovirus vaccine component of this product as the incidence of febrile ARD due to Type 7 adenovirus was not anticipated to be high enough to permit a meaningful statistical assessment of the clinical effect of this vaccine component. Subjects were randomized to either the vaccine group or the placebo group in a 3:1 ratio. 4041 subjects were randomized, and 4040 subjects were analyzed. Females and males aged 17 or older and in good physical health were included in the study. No subjects were immunosuppressed or being treated with systemic immunosuppressive therapy. Baseline serology data is presented in Table 3. Table 3: Baseline Serology in Multicenter Safety and Efficacy Trial Vaccine N=3031 n (%) Placebo N=1009 n (%) Total N=4040 n (%) Type 4 Titer Negative* 1906 (63%) 678 (67%) 2584 (64%) Positive** 1123 (37%) 331 (33%) 1454 (36%) Type 7 Titer Negative* 1159 (38%) 377 (37%) 1536 (38%) Positive** 1870 (62%) 632 (63%) 2502 (62%) *Titer value was < 1:4 at visit 0. ** Titer value was ≥ 1:4 at visit 0. Adenovirus Type 4 Efficacy and Immunogenicity Febrile Acute Respiratory Disease (ARD): The results for the primary analysis of vaccine efficacy (VE) for adenovirus Type 4 and rate of wild Type 4 febrile ARD, are summarized in Table 4. Cases were defined as subjects with one or more clinical signs and symptoms of ARD (mild to severe: sore throat, cough, rhinorrhea, nasal congestion, rales or rhonchi), an oral temperature > 100.5°F, and throat culture positive for wild Type 4 adenovirus infection. Vaccine type Adenovirus was distinguished from wild type by a Polymerase Chain Reaction (PCR) assay. Table 4: Wild Adenovirus Type 4 Febrile ARD Cases (Day 0-56) In the Multicenter Safety and Efficacy Trial Adeno Type 4 ARD case Statistic Vaccine N=3031 Placebo N=1009 Yes n 1* 48 VE (95% CI)§ 99.3% (96.0%, 99.9%) *one additional subject met the case definition but had non-vaccine serotype (B3) adenovirus §Vaccine efficacy (VE) defined as: VE = 1 - RR, where RR = P(vaccine)/P(placebo) was the relative risk of ARD attack in subjects who received vaccine compared to placebo; 2-sided confidence interval, by using exact statistical methods. Seroconversion Rate: Adenovirus Type 4 seroconversion rate is presented in Table 5. Seroconversion is defined as the development of a Type 4 neutralizing antibody titer of greater or equal to 1:8 at Day 26 after vaccination in subjects whose baseline titer was less than 1:4. Table 5: Adenovirus Type 4 Seroconversion Rate (Day 26) in the Multicenter Safety and Efficacy Study Adenovirus Type 4 and Type 7 Vaccine, Live Oral Placebo N Seroconversion N Seroconversion n % (95% CI) n % (95% CI) 1841 1739 94.5% ( 93.4%, 95.5% ) 653 69 10.6 % ( 8.2%, 12.9% ) Adenovirus Type 7 Immunogenicity Febrile Acute Respiratory Disease: No Type 7 adenovirus-associated febrile or afebrile ARD cases were reported for either placebo or vaccine groups. This was expected given the estimated attack rate of adenovirus Type 7 in the military base training setting at the time of the study. Seroconversion was the primary evaluation of Type 7 effectiveness. Seroconversion Rate: Results for the primary analysis of adenovirus Type 7 efficacy, seroconversion rate at Day 26, are summarized in Table 6. Seroconversion is defined as the development of a Type 7 neutralizing antibody titer of greater or equal to 1:8 at Day 26 after vaccination in subjects whose baseline titer was less than 1:4. Table 6: Adenovirus Type 7 Seroconversion Rate (Day 26) Adenovirus Type 4 and Type 7 Vaccine, Live Oral Placebo N Seroconversion N Seroconversion n % (95% CI) n % (95% CI) 1120 1051 93.8% ( 92.4%, 95.2% ) 359 19 5.3% ( 3.0%, 7.6% ) REFERENCES 1. Van den Veyver et al. 1998. Detection of intrauterine viral infection using the polymerase chain reaction. Mol Genet Metab, 63: 85-95 2. Calvin et al. 2000. Fatal intrauterine adenoviral endomyocarditis with aortic and pulmonary valve stenosis: diagnosis by polymerase chain reaction. Hum Pathol. 31(11):1433-5 3. Ranucci-Weiss et al. 1998. Intrauterine adenoviral infection associated with fetal non-immune hydrops. Prenat. Diagn. 18(2):182-5 4. Baschat et al., 2003. Is adenovirus a fetal pathogen? Am J Obstet Gynecol. 189(3):758-63. 5. Fields Virology, Fifth Edition, 2007, p2409

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral Enteric Coated Tablets for Oral Administration DESCRIPTION Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains viable, selected strains of human adenovirus Type 4 and human adenovirus Type 7 prepared in human-diploid fibroblast cell cultures (strain WI-38). The virus strains have not been attenuated. The cells are grown and the virus growth maintained in Dulbecco's Modified Eagle's Medium, fetal bovine serum, and sodium bicarbonate. The virus is harvested, freed of particulate cellular material by filtration, formulated and dried by lyophilization. The dried virus material includes monosodium glutamate, sucrose, D-mannose, D-fructose, dextrose, human serum albumin, potassium phosphate and plasdone C. The final vaccine is composed of two tablets (one tablet of Adenovirus Type 4 and one tablet of Adenovirus Type 7) designed to pass intact through the stomach and release the live virus in the intestine. Each entericcoated tablet contains an inner core tablet containing anhydrous lactose, micro crystalline cellulose, polacrilin potassium, magnesium stearate, and live adenovirus, either Type 4 or Type 7, at a potency of no fewer than 32,000 tissue-culture infective doses (4.5 log10 TCID50) per tablet. The outer tablet layer contains microcrystalline cellulose, magnesium stearate, and anhydrous lactose, with an enteric coating consisting of cellulose acetate phthalate, alcohol, acetone, and castor oil. The Type 7 tablet also contains FD&C Yellow #6 aluminum lake dye.

INDICATIONS Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is a vaccine indicated for active immunization for the prevention of febrile acute respiratory disease caused by Adenovirus Type 4 and Type 7. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is approved for use in military populations 17 through 50 years of age. DOSAGE AND ADMINISTRATION A single vaccine dose is administered orally as two tablets: one tablet of Adenovirus Type 4 and one tablet of Adenovirus Type 7. (2) The tablets should be swallowed whole, without chewing, to avoid releasing the virus in the upper respiratory tract. [See Mechanism of Action] Postpone administration to individuals with vomiting and/or diarrhea because the effectiveness of the vaccine depends upon the multiplication of orally administered live adenovirus within the intestinal tract. [See Mechanism of Action] HOW SUPPLIED Dosage Forms And Strengths A single vaccine dose consists of two tablets: one tablet of Adenovirus Type 4 and one tablet of Adenovirus Type 7. Storage And Handling Adenovirus Type 4 and Type 7 Vaccine, Live, Oral Enteric Coated Tablets is packaged in a carton of two bottles of 100 tablets of each component of the vaccine: Adenovirus Type 4 Component of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral enteric coated tablet, a white to off-white, round, coated tablet with stylized b imprinted on one side, for oral administration NDC 51285-174-02 Adenovirus Type 7 Component of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral enteric coated tablet, a light peach, round, coated tablet with stylized b imprinted on one side, for oral administration NDC 51285-175-02 Available as a single carton containing 1 x 100 tablets Adenovirus Type 4 Component and 1 x 100 tablets Adenovirus Type 7 Component NDC 51285-138-50 Store refrigerated between 2° and 8° C (35° and 46° F). Do not freeze. Keep bottle tightly closed and protect from moisture. Do not remove desiccant canister from bottle. Manufactured by Barr Labs, Inc. Distributed by Teva Pharmaceuticals USA, Inc., Sellersville, PA 18960. Revised: March 2011

PATIENT INFORMATION Swallow each tablet whole without chewing. Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains live virus that is shed in the stool for up to 28 days following vaccination and can cause disease if transmitted. It is given to individuals, undergoing intensive military training, who have limited contact with pregnant women, children under age seven and persons with compromised immune systems. To minimize the risk for transmitting and infecting others with the virus, take the following precautions during the 28 day period following vaccination: Observe proper personal hygiene, such as, frequent hand washing, especially following bowel movements. Caution is advised when in close contact with children less than 7 years of age, immunocompromised individuals (e.g., HIV infected, has cancer, or is receiving cancer treatments) and pregnant women because they may be more vulnerable to infection if exposed to the virus. Inform women to contact their healthcare provider before receiving this vaccine if they are, or suspect they are, pregnant. Inform women to avoid becoming pregnant following vaccination for at least 6 weeks after vaccination to prevent the fetus from being exposed to adenovirus. If a pregnant woman receives Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, or a woman becomes pregnant within the 6 weeks following administration of vaccination, they should be enrolled in the Adenovirus Pregnancy Registry. [See Pregnancy] If anyone has any questions or concerns regarding this vaccine, they should speak with their healthcare provider.

OVERDOSE No information provided. CONTRAINDICATIONS Pregnancy Adenovirus Type 4 and Type 7 Vaccine, Live, Oral should not be administered to pregnant females [See Pregnancy]. It is not known whether Adenovirus Type 4 and Type 7 Vaccine, Live, Oral can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Naturally occurring infection with adenoviruses has been associated with fetal harm. Pregnancy should be avoided for 6 weeks following receipt of vaccine. Severe Allergic Reaction Severe allergic reaction (e.g., anaphylaxis) to any component of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is a Contraindication. [See DESCRIPTION] Inability To Swallow Adenovirus Type 4 and Type 7 Vaccine, Live, Oral should not be administered to individuals incapable of swallowing each entire tablet, whole, without chewing. Chewing a tablet could expose the upper respiratory tract to live adenovirus leading to disease. [See Mechanism of Action]

SIDE EFFECTS Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to the rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. Multicenter Safety and Efficacy Trial Safety of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral was evaluated in a multicenter, double-blind, randomized, placebo-controlled study that enrolled 3031 subjects who received vaccine and 1009 subjects who received placebo (lactose tablets). The study was conducted in healthy male (63%) and female (37%) active duty US Army and Navy military recruits during their basic training. The population had a mean age of 21 years, with an age range of 17 to 42 years. Race was 62% Caucasian, 18% African-American, 11% Hispanic, 3% Asian and 6% other. Subjects in both groups were administered other vaccines concomitantly with Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. The specific vaccines that each subject received varied and were dependent on their immunization history. The vaccines that were co-administered included Hepatitis A Vaccine, Inactivated (Merck & Co., Inc.), Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine (GlaxoSmithKline Biologicals), Hepatitis B Vaccine (Recombinant) (Merck & Co., Inc.), Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant (Merck & Co., Inc.), Influenza Vaccine, Live, Intranasal (MedImmune, LLC), Influenza Virus Vaccine (Sanofi Pasteur, Inc.), Measles, Mumps, and Rubella Virus Vaccine Live (Merck & Co., Inc.), Meningococcal (Groups A, C, Y and W-135) Polysaccharide, Diphtheria Toxoid Conjugate Vaccine (Sanofi Pasteur, Inc.), Meningococcal Polysaccharide Vaccine (Groups A, C, Y and W-135 Combined) (Sanofi Pasteur, Inc.), Poliovirus Vaccine Inactivated (Sanofi Pasteur, SA), Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Sanofi Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains live viruses that are shed in the stool and can cause disease if transmitted. Pasteur, Ltd.), Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (GlaxoSmithKline Biologicals), Typhoid Vi Polysaccharide Vaccine (Sanofi Pasteur, SA), Varicella Virus Vaccine Live (Merck & Co., Inc.), Yellow Fever Vaccine (Sanofi Pasteur, Inc.). Serious Adverse Events No deaths were reported during the multicenter safety and efficacy trial. Serious adverse events in vaccine recipients included hematuria, gastroenteritis, febrile gastroenteritis, gastritis, pneumonia, and hematochezia. Fifty-seven serious adverse events (SAEs) were reported during the six month study period with 39 reported between 0 and 56 days following treatment and 18 reported during the 56 to 180 day follow-up period. Thirtyfive subjects (1.2%) who received vaccine (25 between 0 and 56 days from the date of vaccination, 10 during the 56 to 180 day follow-up period) and 12 subjects (1.2%) who received placebo (9 between 0 and 56 days from the date of treatment, 3 during the 56 to 180 day follow-up period) experienced at least one SAE. The SAEs occurring between Day 0 and Day 56 post-vaccination in the vaccine group, possibly associated with the receipt of the vaccine product as determined by the investigator, were as follows: one subject with hematuria and gastroenteritis (at 9 days post vaccination), one subject with febrile gastroenteritis (at 4 days post vaccination, one subject with gastritis (at 23 days post vaccination), and one subject with pneumonia ( at 23 days post vaccination); one SAE (hematochezia) in the vaccine group occurred during the 56 to 180 day followup period and was determined to be possibly related to the vaccine product. A placebo recipient developed febrile acute respiratory disease where adenovirus Type 4 vaccine strain was detected from posterior pharyngeal and tonsillar swabbing and characterized by serotyping and polymerase chain reaction analysis. [See WARNINGS AND PRECAUTIONS: Shedding and Transmission] Overall, the percentage of subjects who experienced at least one adverse event during the 56 day study period was 91.2% in the Adenovirus Type 4 and Type 7 Vaccine, Live, Oral group compared to 93.9% in the placebo group. No subject in either treatment arm discontinued the study due to an adverse event. Adverse reactions were captured on a 2-Week Daily Diary (for a minimum of the first 780 subjects) or a 1-Week Daily Diary (for all remaining subjects) and were also reported at each study visit up to Day 56 after vaccination. Any reported AEs for Days 0-14 for the safety cohort and for Days 0-7 for the remaining subjects were defined as “solicited” because they were almost exclusively recorded directly by the subject from a pre-defined diary checklist. Although pyrexia was defined as “solicited”, it was not on the pre-defined diary checklist. Any AEs reported spontaneously as part of the regular study visit or during a spontaneous visit to the clinic, for Days 15-56 for the safety cohort and Days 8-56 for the remaining subjects were designated as “non-solicited”. Solicited Adverse Reactions The following solicited adverse reactions were collected through daily diaries: stuffy nose, cough, sore throat, stomach pain, headache, diarrhea, nausea, and joint pain (within 14 days post enrollment for subjects in the initial safety cohort (n=878) and within 7 days post enrollment all subjects (n= 4040) for the rest of safety population). Those solicited adverse reactions reported by ≥ 5 % of subjects in either the vaccine or placebo treatment groups are presented in Table 1. Table 1: Solicited Adverse Reactions, Days 0-7 for All Subjects and Days 8-14 for the Safety Cohort, Reported by ≥ 5% of Subjects in the Multicenter Safety and Efficacy Trial Adverse Reaction* Adenovirus Type 4 and Type 7 Vaccine, Live, Oral Placebo 0-7 Days N= 3031 8-14 Days N = 660 0-7 Days N= 1009 8-14 Days N = 218 n % n % n % n % Headache 894 29.5 38 6.5 310 30.7 11 5.6 Nasal Congestion (Stuffy Nose) 463 15.3 49 8.4 141 14.0 12 6.2 Pharyngolaryngeal Pain (Sore Throat) 391 12.9 72 12.3 124 12.3 24 12.3 Cough 375 12.4 59 10.1 130 12.9 14 7.2 Nausea 412 13.6 29 5.0 137 13.6 11 5.6 Diarrhea 310 10.2 18 3.1 84 8.3 10 5.1 *MedDRA Preferred Term Pyrexia (temp ≥ 100.5°F) within 7 days, was reported to occur in 1.4% (42/3030) of vaccine recipients and 0.5% (5/961) of placebo recipients who were not diagnosed with ARD. During the 8-14 days post vaccination, rates of pyrexia were 0.6% (4/659) and 1.1% (2/170) in vaccine and placebo recipients respectively. Non-Solicited Adverse Reactions Non-solicited adverse reactions, that occurred Days 15-56 in the safety cohort and Days 8-56 for all remaining subjects, reported by ≥ 5 % of subjects in either the vaccine or placebo treatment groups are presented in Table 2. Table 2: Nonsolicited Adverse Reactions, Days 15-56 for the Safety Cohort and Days 8-56 for all Remaining Subjects, Reported by ≥ 5% of Subjects in the Multicenter Safety and Efficacy Trial Adenovirus Type 4 and Type 7 Vaccine, Live Oral N=3031 Placebo N=1009 N % N % Upper Respiratory Tract Infection 1135 37.5 397 39.4 Arthralgia 524 17.3 180 17.8 Abdominal Pain Upper 443 14.6 157 15.6 Headache 330 10.9 148 14.7 Cough 257 8.5 91 9.0 Pharyngolaryngeal Pain 253 8.4 73 7.2 Nasal Congestion 229 7.6 73 7.2 Vomiting 160 5.3 55 5.5 Chills 77 2.5 51 5.1 *MedDRA Preferred Term Less common (less than 5%) adverse reactions reported in the clinical trial in military recruits receiving Adenovirus Type 4 and Type 7 Vaccine, Live, Oral, versus placebo, respectively included rhinorrhea (128 [4.22%] vs. 25 [2.48%]), pain in extremity (130 [4.29%] vs. 37 [3.67%]), and pyrexia (fever greater than or equal to100.5 °F) (126 [4.16%] vs. 49 [4.86%]). Safety and Immunogenicity Trial Five SAEs were reported among the 58 subjects in the safety and immunogenicity trial. Two SAEs occurred among the vaccine recipients: one case of pneumonia reported on Day 33 of the follow-up period, and a report of appendicitis occurring on Day 118 of follow-up period. Three SAEs were reported among placebo recipients: one case of pneumonia on Day 10 and one case of upper respiratory infection reported on Day 14, and a right thigh abscess reported at Day 91. DRUG INTERACTIONS Concomitant Vaccine Administration In clinical studies Adenovirus Type 4 and Type 7 Vaccine, Live, Oral was administered concurrently with other vaccines [See ADVERSE REACTIONS]. Data were not available to assess whether Adenovirus Type 4 and Type 7 Vaccine, Live, Oral interferes with the immune response to the other vaccines. Immunosuppressive Therapies There are no data regarding the use of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral concomitantly with immunosuppressive therapies, e.g., irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses). [See Altered Immunocompetence]

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Altered Immunocompetence The safety and effectiveness of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral in immunocompromised individuals has not been evaluated. Shedding And Transmission People who come in close contact with those who were vaccinated, including other vaccinees, may be exposed to the virus present in the stool and may develop disease. [See Pharmacodynamics] Persons vaccinated with Adenovirus Type 4 and Type 7 Vaccine, Live, Oral should exercise caution when in close contact with children less than 7 years of age and immunocompromised individuals such as those with HIV infection and cancer, or those receiving immunosuppressive therapy during the 28 day period of viral shedding following the vaccination. [See Use in Specific Populations and Pharmacodynamics] Vaccinees should exercise caution when in close contact with pregnant women during the 28 day period of shedding because fetal harm may result if pregnant women are exposed to adenovirus. [See Pregnancy and Pharmacodynamics] Human Serum Albumin Adenovirus Type 4 and Type 7 Vaccine, Live, Oral contains albumin, a derivative of human blood. It is present at concentrations of < 0.3 mg/tablet. Based on effective donor screening, and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeld-Jakob disease (CJD) also is considered extremely remote. No cases of transmissions of viral diseases or CJD have ever been identified for human albumin. Use In Specific Populations Pregnancy Pregnancy Category: Contraindication [See CONTRAINDICATIONS] Five pregnancies were reported among women enrolled in the multicenter safety and efficacy trial of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral. Four of the subjects (3 vaccine recipients and 1 placebo recipient) were estimated to have conceived 2 to 13 days prior to vaccination. One subject (vaccine recipient) conceived approximately 21 weeks after vaccination. The deliveries to all five of the subjects were of healthy infants at estimated gestational ages between 36 and 40 weeks. All cases in which a woman receives Adenovirus Type 4 and Type 7 Vaccine, Live, Oral during pregnancy or becomes pregnant (conception occurs) within 6 weeks following vaccination should be reported to the Adenovirus Pregnancy Registry by calling 1-866-790-4549. Labor And Delivery There is no information regarding the affect of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral on labor and delivery. Fecal shedding during delivery may result in vaccine virus transmission to the newborn infant. Nursing Mothers It is not known whether Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is excreted in human milk. Because many viruses are excreted in human milk, caution should be exercised when Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is administered to a nursing woman. [See WARNINGS AND PRECAUTIONS] Pediatric Use The safety and effectiveness of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral has not been evaluated in the age groups from birth through age 16. Geriatric Use Clinical studies of Adenovirus Type 4 and Type 7 Vaccine, Live, Oral did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. There are no data to support use of this vaccine in geriatric (person ≥ 65 years) populations.