Spherusol

WARNING The expected response to Spherusol ® is a local area of inflammation at the site of the skin test. The reaction is usually dime to quarter size reaching maximum diameter between 24 and 48 hours. Larger accelerated reactions can occur, which may require treatment with local cold compresses and anti-inflammatory medication. ( 2.3 , 6.1 ) Systemic reactions can occur with skin test antigens and in certain individuals these reactions may be life-threatening or cause death. Emergency measures and personnel trained in their use should be immediately available. Patients should be observed for at least 20 minutes following the administration of a skin test. ( 6.2 ) Spherusol ® should never be given intravenously. ( 5 ) 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 . ( 6.2 ) WARNING See full prescribing information for complete boxed warning The expected response to Spherusol ® is a local area of inflammation at the site of the skin test. The reaction is usually dime to quarter size reaching maximum diameter between 24 and 48 hours. Larger accelerated reactions can occur, which may require treatment with local cold compresses and anti-inflammatory medication. ( 2.3 , 6.1 ) Systemic reactions can occur with skin test antigens and in certain individuals these reactions may be life-threatening or cause death. Emergency measures and personnel trained in their use should be immediately available. Patients should be observed for at least 20 minutes following the administration of a skin test. ( 5.3 , 6.2 ) Spherusol ® should never be given intravenously. ( 5 ) 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 . ( 6.2 )

5 WARNINGS AND PRECAUTIONS Acute hypersensitivity reactions and anaphylaxis have occurred following the administration of other skin test antigens and may occur in individuals following the administration of Spherusol ® . ( 5.1 ) Patients receiving beta-blocking drugs may be refractive to the usual dose of epinephrine in cases of hypersensitivity. ( 5.2 ) 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 ® . ( 5.3 ) 5.1 Prevention and Management of Acute Hypersensitivity Reactions Prior to administration, the healthcare provider should review the medical history for possible skin test sensitivity and previous skin test related adverse reactions to assess the risks and benefits. Immediate hypersensitivity, to include severe systemic reactions, may occur following administration of skin test antigens. Medications and equipment 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 )]

6 ADVERSE REACTIONS The most commonly reported local adverse reactions were itching and swelling (>75%) and pain (>15%) within 7 days of administration.( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nielsen Biosciences, Inc. at (855) 855-1212 or Food and Drug Administration (FDA) at 1-800-332-1088 or www.vaers.hhs.gov . ( 6.3 ) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a skin test antigen cannot be directly compared to rates in the clinical trials of another skin test antigen, and may not reflect the rates observed in practice. As with any skin test antigen, there is the possibility that broad use of Spherusol ® could reveal adverse reactions not observed in clinical trials. In a double-blinded placebo-controlled clinical trial conducted in areas of the U.S. endemic for C. immitis (Bakersfield, CA and Tucson, AZ), 54 adults (23-64 years of age) with a history 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 .

<table border="1" width="100%" ID="table1"><caption>Table 1. Frequency of Solicited Local Reactions and Systemic Adverse Events within 7 days of Administration of Spherusol ^&#xAE;, Candin ^&#xAE;, Trichophyton, Diluent Control and Saline Control in Subjects with a History of Pulmonary Coccidioidomycosis (N=53) </caption><col width="40%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th align="left" styleCode="Lrule Rrule">Symptom</th><th colspan="4" styleCode="Rrule">Frequency (%)</th></tr><tr styleCode="Botrule"><th align="left" styleCode="Lrule Rrule">Local &#x2217;</th><th styleCode="Rrule">Any</th><th styleCode="Rrule">Mild</th><th styleCode="Rrule">Moderate</th><th styleCode="Rrule">Severe</th></tr></thead><tbody><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Itching</td><td styleCode="Rrule">85</td><td styleCode="Rrule">36</td><td styleCode="Rrule">47</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Swelling</td><td styleCode="Rrule">79</td><td styleCode="Rrule">36</td><td styleCode="Rrule">41</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Pain</td><td styleCode="Rrule">17</td><td styleCode="Rrule">13</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Necrosis/Ulceration</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule"><content styleCode="bold">Systemic</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Increased heart rate</td><td styleCode="Rrule">4</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Weakness</td><td styleCode="Rrule">6</td><td styleCode="Rrule">2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Faintness</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Nausea/cramps</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Flu-like symptoms</td><td styleCode="Rrule">7</td><td styleCode="Rrule">2</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td align="left" styleCode="Lrule Rrule">Difficulty breathing/shortness of breath</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr><th colspan="5" align="left">Any = Percentage of subjects experiencing adverse event of any intensity; Mild = Barely noticeable, not bothersome; Moderate = Distinctly noticeable discomfort; Severe = Needs medical attention. &#x2217; Local reactions occurring at any injection site </th></tr></tbody></table>