FDA label 96a21827-46ee-4299-88ee-1b983e3e5e43

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis may occur with collagenase clostridium histolyticum. If a serious hypersensitivity reaction occurs, initiate appropriate therapy. ( 5.1 ) Injection Site Bruising: Bruising occurs frequently after QWO administration. Use with caution in patients with bleeding abnormalities or who are currently being treated with antiplatelet (except those taking ≤ 150 mg aspirin daily) or anticoagulant therapy. ( 5.2 ) Substitution: QWO must not be substituted for other injectable collagenase products. QWO is not indicated for the treatment of Peyronie’s disease or Dupuytren’s contracture. ( 5.3 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions including anaphylaxis have been reported with the use of collagenase clostridium histolyticum. If such a reaction occurs, further injection of QWO should be discontinued and appropriate medical therapy immediately instituted. 5.2 Injection Site Bruising In clinical trials, 84% of subjects treated with QWO experienced injection site bruising [see Adverse Reactions ( 6.1 )] . Subjects with coagulation disorders or using anticoagulant or antiplatelet medications (except those taking ≤ 150 mg aspirin daily) were excluded from participating in Trials 1 and 2. QWO should be used with caution in patients with bleeding abnormalities or who are currently being treated with antiplatelet (except those taking ≤ 150 mg aspirin daily) or anticoagulant therapy. 5.3 Substitution of Collagenase Products QWO must not be substituted with other injectable collagenase products. QWO is not intended for the treatment of Peyronie’s Disease or Dupuytren’s Contracture

6 ADVERSE REACTIONS The following adverse reactions to QWO for injection are discussed in greater detail in other sections of the labeling: Hypersensitivity [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Injection Site Bruising [see Warnings and Precautions ( 5.2 )] . The most common adverse reactions (≥ 1%) were related to the injection site (bruising, pain, nodule, pruritus, erythema, discoloration, swelling, and warmth). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo Pharmaceuticals Inc. at 1-800-462-3636 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In two double-blind, placebo-controlled clinical trials (Trials 1 and 2) of identical design, 424 female subjects with cellulite in the buttocks received QWO and 419 female subjects with cellulite received placebo. Enrolled subjects were adults age 18 to 78 years with moderate to severe cellulite (graded as 3 or 4 on a 0 to 4 scale) and without excessive skin laxity. The majority were White (78%) or African American (18%). Subjects completed up to 3 treatment visits separated by 21 days and were followed for up to 6 months after the last treatment visit in a separate open-label extension trial (Trial 3). Table 3 shows the incidence of adverse reactions that were reported in ≥ 1% of subjects who received QWO-and at a frequency greater than subjects who received placebo in Trials 1 and 2 through Day 71. Generally, adverse reactions had a duration of less than 21 days. Table 3: Adverse Reactions Occurring in ≥ 1% of Subjects in Trials 1 and 2 Through Day 71 Adverse Reactions at Injection Site QWO N=424 % Placebo N=419 % Bruising 84 21 Pain 48 10 Nodule 33 1 Pruritus 15 1 Erythema 9 5 Discoloration 8 1 Swelling Warmth 8 3 1 0 Pooled terms: Bruising - injection site bruising, injection site hematoma, and injection site hemorrhage (refers to verbatim term injection site ecchymosis) Pain - injection site pain, injection site discomfort, and injection site dysesthesia Swelling - injection site swelling, injection site edema, injection site induration Discoloration - injection site discoloration Nodule- injection site mass and injection site nodule Four hundred seventy-nine (479) subjects from Trials 1 and 2 completed a 6-month observation phase in the ongoing open-label safety extension (Trial 3). No long-term safety signals have been identified. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handing, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products, including other collagenase clostridium histolyticum products, may be misleading. By Day 22, approximately 53% (203/383) and 26% (101/383) of subjects who completed the first treatment visit of QWO at the recommended dose in Trials 1 and 2 developed anti-AUX-I and anti-AUX-II antibodies, respectively. The majority (> 96%) of subjects developed antibodies for AUX-I and AUX-II after second and third treatment visits. Antibody titers suggested that antibodies were retained for up to 360 days after receiving the first recommended dose. By Day 71, approximately 68% and 83% of subjects developed antibodies to AUX-I and AUX-II which were classified as neutralizing, respectively. Antibodies to AUX-I and AUX-II including those classified as neutralizing were not associated with changes in clinical response or adverse reactions at injection site. 6.3 Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reaction was reported during post approval use of a collagenase product: Immune system disorders: serious hypersensitivity reactions including anaphylaxis [see Warnings and Precautions ( 5.1 )] .

<table width="75%"><caption>Table 3: Adverse Reactions Occurring in &#x2265; 1% of Subjects in Trials 1 and 2 Through Day 71</caption><col/><col/><col/><thead><tr><th> Adverse Reactions at Injection Site</th><th>QWO N=424 % </th><th>Placebo N=419 % </th></tr></thead><tbody><tr><td> Bruising</td><td align="center">84</td><td align="center">21</td></tr><tr><td> Pain</td><td align="center">48</td><td align="center">10</td></tr><tr><td> Nodule</td><td align="center">33</td><td align="center">1</td></tr><tr><td> Pruritus</td><td align="center">15</td><td align="center">1</td></tr><tr><td> Erythema</td><td align="center">9</td><td align="center">5</td></tr><tr><td> Discoloration</td><td align="center">8</td><td align="center">1</td></tr><tr><td><paragraph> Swelling</paragraph><paragraph> Warmth</paragraph></td><td align="center"><paragraph>8</paragraph><paragraph>3</paragraph></td><td align="center"><paragraph>1</paragraph><paragraph>0</paragraph></td></tr></tbody></table>