Oraqix

5 WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. ( 5.1 ) DO NOT INJECT ( 5.2 ) Allergic and anaphylactic reactions can occur ( 5.3 ) Avoid contact with eyes ( 5.4 ) Use with caution in patients with severe hepatic disease ( 5.6 ) 5.1 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ORAQIX and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.2 DO NOT INJECT Oraqix should not be used with standard dental syringes. Only use this product with the Oraqix blunt-tipped applicator and the dispenser which is available from DENTSPLY Pharmaceutical. 5.3 Allergic/anaphylactic reactions Allergic and anaphylactic reactions associated with lidocaine or prilocaine in Oraqix can occur. These reactions may be characterized by urticaria, angioedema, bronchospasm, and shock. If these reactions occur they should be managed by conventional means. 5.4 Avoid Contact with Eyes Oraqix coming in contact with the eye should be avoided because animal studies have demonstrated severe eye irritation. A loss of protective reflexes may allow corneal irritation and potential abrasion. If eye contact occurs, immediately rinse the eye with water or saline and protect it until normal sensation returns. In addition, the patient should be evaluated by an ophthalmologist, as indicated. 5.5 History of Drug Sensitivity Patients allergic to paraminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine and/or prilocaine. However, Oraqix should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. 5.6 Severe Hepatic Disease Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

6 ADVERSE REACTIONS Most common adverse reactions (incidence >15%) are application site reactions including pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact DENTSPLY Pharmaceutical at 1-800-989- 8826 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Although no major differences in adverse events between Oraqix and placebo-treated subjects were observed, all patients in the placebo-controlled studies received either Oraqix or a placebo gel (consisting of the vehicle in Oraqix without lidocaine or prilocaine). Therefore, it is not possible to determine if adverse events in each treatment group were attributable to the inactive ingredients comprising the Oraqix or vehicle or if adverse event rates were higher than expected background rates. Therefore, a causal relationship between the reported adverse reactions and Oraqix could neither be established nor ruled out. Following SRP treatment with Oraqix in 391 patients, the most frequent adverse events were local reactions in the oral cavity (see following table ). These events, which occurred in approximately 15% of patients, included pain, soreness, irritation, numbness, vesicles, ulcerations, edema and/or redness in the treated area. Of the 391 patients treated with Oraqix, five developed ulcerative lesions and two developed vesicles of mild to moderate severity near the site of SRP. In addition, ulcerative lesions in or near the treated area were also reported for three out of 168 patients who received placebo. Other symptoms reported in more than one patient were headache, taste perversion, nausea, fatigue, flu, respiratory infection, musculoskeletal pain and accident/injury. Table 1. Number (percent) of patients with adverse events occurring in more than one patient in any of the treatment groups. Each patient is counted only once per adverse event. The occurrence in a single patient is included in this table if the same symptom has been seen in at least one patient in another group. System Organ Class PreferredTerm Oraqix gel in a cross-over study, 170 subjects received either Oraqix or lidocaine injection 2% in each test period (N=391)n (%) Placebo gel (N=168)n (%) Lidocaine injection (N=170)n (%) Muscular-Skeletal System Disorders Myalgia 1(0) 2(1) Arthralgia and/or Arthropathy 1(0) 1(1) Central & Peripheral Nervous System Disorders Headache 8(2) 3(2) 5(3) Dizziness 1(0) 1(1) 1(1) Special Senses Other, Disorders Taste Perversion includes complaints of bad or bitter taste lasting for up to 4 hours after administration of Oraqix 8(2) 1(1) Gastro-Intestinal System Disorders Nausea 3(1) 1(1) Respiratory System Disorders Respiratory Infection 2(1) 1(1) Rhinitis 2(1) Body as a whole-General Disorders Accident and/or Injury 2(1) 2(1) Fatigue 3(1) 2(1) Flu-Like Disorder 2(1) Pain (remote from application site) 1(0) 1(1) 1(1) Application Site Disorders i.e. symptoms in the oral cavity Anesthesia Local 2(1) Application Site Reaction includes pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness in the treated area 52(13) 20(12)

<table width="85%" styleCode="Noautorules" ID="Table1"><caption>Table 1. Number (percent) of patients with adverse events occurring in more than one patient in any of the treatment groups.</caption><col width="45%" align="left" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th align="left" colspan="4">Each patient is counted only once per adverse event. The occurrence in a single patient is included in this table if the same symptom has been seen in at least one patient in another group.</th></tr><tr styleCode="Toprule Botrule"><th styleCode="Lrule Rrule">System Organ Class PreferredTerm</th><th styleCode="Rrule">Oraqix gel<footnote ID="ft1">in a cross-over study, 170 subjects received either Oraqix or lidocaine injection 2% in each test period</footnote> (N=391)n (%)</th><th styleCode="Rrule">Placebo gel<footnoteRef IDREF="ft1"/> (N=168)n (%)</th><th styleCode="Rrule">Lidocaine injection<footnoteRef IDREF="ft1"/> (N=170)n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Muscular-Skeletal System Disorders</content> Myalgia</td><td styleCode="Rrule"><content styleCode="bold">1(0)</content></td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia and/or Arthropathy</td><td styleCode="Rrule"><content styleCode="bold">1(0)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Central &amp; Peripheral Nervous System</content> Disorders</td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule"><content styleCode="bold">8(2)</content></td><td styleCode="Rrule"><content styleCode="bold">3(2)</content></td><td styleCode="Rrule"><content styleCode="bold">5(3)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule"><content styleCode="bold">1(0)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Special Senses Other, Disorders</content> Taste Perversion<footnote>includes complaints of bad or bitter taste lasting for up to 4 hours after administration of Oraqix</footnote></td><td styleCode="Rrule"><content styleCode="bold">8(2)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastro-Intestinal System Disorders</content> Nausea</td><td styleCode="Rrule"><content styleCode="bold">3(1)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory System Disorders</content> Respiratory Infection</td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rhinitis</td><td styleCode="Rrule"/><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Body as a whole-General Disorders</content> Accident and/or Injury</td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule"><content styleCode="bold">3(1)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flu-Like Disorder</td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain (remote from application site)</td><td styleCode="Rrule"><content styleCode="bold">1(0)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td><td styleCode="Rrule"><content styleCode="bold">1(1)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Application Site Disorders</content><footnote>i.e. symptoms in the oral cavity</footnote> Anesthesia Local</td><td styleCode="Rrule"><content styleCode="bold">2(1)</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Application Site Reaction<footnote>includes pain, soreness, irritation, numbness, ulcerations, vesicles, edema, abscess and/or redness in the treated area</footnote></td><td styleCode="Rrule"><content styleCode="bold">52(13)</content></td><td styleCode="Rrule"><content styleCode="bold">20(12)</content></td><td styleCode="Rrule"/></tr></tbody></table>