etect delayed-type hypersensitivity responses in a general population with unknown exposure to c. immitis has not been evaluated. persons with acute or disseminated coccidioidomycosis may not develop a delayed-type hypersensitivity response to spherusol ® . persons with immunodeficiency and a history of coccidioidomycosis may not develop a delayed-type hypersensitivity response to spherusol ® .( 1 )

t to manage possible anaphylactic reactions should be available for immediate use. patients should be observed for a minimum of 30 minutes following administration to assess for adverse reactions. 5.2 patients on beta blockers patients receiving beta blockers may be unresponsive to the usual doses of epinephrine used to treat serious systemic reactions, including anaphylaxis. 5.3 immunosuppression any condition or agent that impairs or attenuates delayed-type hypersensitivity reactions, including infections and use of immunosuppressive drugs, can potentially cause a false negative reaction to spherusol ® . [see drug interactions ( 7.1 )]

n at 48 hours (±4 hours) following administration. the response to the skin test should be measured by taking the mean of the orthogonal diameters of the area of induration. a mean induration of ≥ 5 mm is considered a positive delayed-type hypersensitivity response to spherusol ® . repeat administration of spherusol ® has not been evaluated.

of pulmonary coccidioidomycosis of at least 45 days duration, diagnosed by clinical findings, radiography and serological and/or mycological evidence of the disease, received a single dose of spherusol ® concomitantly with two licensed skin test extracts (candin ® and trichophyton) and two controls (product diluent [thimerosal ≤0.0001%] and saline). each intradermal injection of 0.1 ml of reagent was given at pre-determined sites on the right and left forearms. solicited local adverse reactions and systemic adverse events occurring within 7 days after injection were recorded by study subjects via diary card. these events were also recorded on case report forms (crfs) by study personnel during clinical visits 48 hours and 7 days following injections. diary cards and crfs did not record solicited local reactions by specific site. local adverse reactions and systemic adverse events that occurred within 7 days were monitored until resolution. reports of unsolicited adverse events and serious adverse events that occurred within 7 days after administration were collected on the diary cards or reported at study visits. table 1 lists the percentage of subjects reporting solicited local reactions (at any site) and solicited systemic adverse events within 7 days following the administration of spherusol ® , candin ® , trichophyton, diluent control and placebo control. table 1. frequency of solicited local reactions and systemic adverse events within 7 days of administration of spherusol ® , candin ® , trichophyton, diluent control and saline control in subjects with a history of pulmonary coccidioidomycosis (n=53) symptom frequency (%) local ∗ any mild moderate severe itching 85 36 47 2 swelling 79 36 41 2 pain 17 13 4 0 necrosis/ulceration 4 2 0 2 systemic increased heart rate 4 2 2 0 weakness 6 2 4 0 faintness 0 0 0 0 dizziness 2 2 0 0 nausea/cramps 2 2 0 0 flu-like symptoms 7 2 6 0 difficulty breathing/shortness of breath 0 0 0 0 any = percentage of subjects experiencing adverse event of any intensity; mild = barely noticeable, not bothersome; moderate = distinctly noticeable discomfort; severe = needs medical attention. ∗ local reactions occurring at any injection site of subjects with severe reactions, one subject required treatment with oral corticosteroids for ulceration and swelling. based on investigator's determination the reaction was at the site of trichophyton injection. all severe reactions resolved without sequelae. during the 7 days following administration two subjects reported unsolicited adverse events: one subject reported joint pain, fatigue, cough, sensitivity at a test site (test site not specified), and one subject with erythema immediately after administration (test site not specified). the intensities of these unsolicited adverse events were not recorded. no serious adverse events or deaths were reported during the clinical study. 6.2 to report suspected adverse reactions, contact nielsen biosciences, inc. at (855) 855-1212 or medwatch, food and drug administration (fda), 5600 fishers lane, rockville, md 20852-9782. telephone: (800) 332-1088 or www.vaers.hhs.gov .

sing woman. 8.4 pediatric use the safety and effectiveness of spherusol ® in the pediatric population have not been established. 8.5 geriatric use the safety and effectiveness of spherusol ® have not been established in individuals >65 years of age.

gonal diameters. a positive skin test was defined as a mean induration of ≥ 5 mm at 48 hours following administration of the antigens or controls. for each subject spherusol ® skin test results were considered valid if ≥ 5 mm was observed at the positive control antigen sites and no induration ≥ 5 mm was observed at the negative control sites. the use of spherusol ® to detect delayed-type hypersensitivity response in a general population with unknown exposure to c. immitis has not been evaluated. 14.1 induration response in subjects with a history of pulmonary coccidioidomycosis a multicenter, double-blinded study in endemic areas (bakersfield, ca and tucson, az) enrolled 54 adults with a history of pulmonary coccidioidomycosis diagnosed by radiography, laboratory serologies (e.g., complement fixation, immunodiffusion) and/or culture. subjects were 23-64 years of age; 28% women; 70% caucasian, 11% hispanic, 2% asian, 2% native american and 4% who did not specify race or ethnicity. of the 51 subjects with valid skin test results, 50 subjects [98.0%; 2-sided 95% ci (89.6%, 100%)] had a mean induration of ≥ 5 mm at the spherusol ® injection site. among subjects with valid skin test results the average size of induration at the spherusol ® injection site was 17 mm (range 5 mm-39 mm). the receipt of concurrent or previous antifungal therapy did not appear to interfere with or accentuate the induration response to spherusol ® . 14.2 induration response in subjects without a history of pulmonary coccidioidomycosis or known exposure to c. immitis. a single site, double-blind study conducted in a non-endemic area for c. immitis (spokane, wa) enrolled 60 adult subjects (18-56 years of age) with no known exposure to c. immitis by travel to or residency in an endemic area. subjects had negative serologies to c. immitis by complement fixation, immunodiffusion and/or elisa. subjects enrolled in the study were 65% women; 96% caucasian, 2% hispanic and 2% native american. at the 48 hour (± 4 hours) assessment, a total of 55 subjects had valid skin test results (5 subjects had negative skin test results to all reagents and were considered un-interpretable). one subject (1/55) had a 5 mm mean induration response to spherusol ® and 54 subjects with demonstrated negative responses (< 5mm mean induration) to spherusol ® . fifty-four of the 55 subjects with valid skin test responses [98.2%; 2-sided 95% ci (90.3%, > 99.9%)] demonstrated a negative induration response to spherusol ® . when the five subjects who had un-interpretable responses were analyzed as if these responses represented positive reactions to spherusol ® , 54 of 60 subjects 90.0% (ci 79.5%, 96.2%) demonstrated a negative induration response. 14.3 induration response in subjects with a history of pulmonary histoplasmosis a single site, double-blind study conducted in a non-endemic area for c. immitis , but endemic for h. capsulatum (blair, ne) enrolled 12 adult subjects (33 to 60 years of age) with no known exposure to c. immitis by travel to or residency in an endemic area. all subjects had a history of pulmonary histoplasmosis. subjects had negative serologies to c. immitis by complement fixation, immunodiffusion and/or elisa. subjects were 42% women and 100% caucasian. at the 48 hour (± 4 hours) assessment, all 12 subjects reacted to at least one of the positive controls with ≥ 5mm mean induration and demonstrated negative (< 5mm) induration responses to thimerosal and saline controls. no positive induration responses to spherusol ® were observed [1-sided 97.5% ci; (0%, 26.5%)] among subjects who had a previous history of disease caused by h. capsulatum and no history of travel to areas endemic for c. immitis . these findings support the lack of cross-reaction between the cellular immune responses induced by the two fungal species.