Tigecycline

WARNING: ALL-CAUSE MORTALITY An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. Tigecycline for injection should be reserved for use in situations when alternative treatments are not suitable [see Indications and Usage ( 1.4 ), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. WARNING: ALL-CAUSE MORTALITY See full prescribing information for complete boxed warning. All-cause mortality was higher in patients treated with tigecycline for injection than comparators in a meta-analysis of clinical trials. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. Tigecycline for injection should be reserved for use in situations when alternative treatments are not suitable ( 1.4 , 5.1 , 5.2 , 6.1 ).

5 WARNINGS AND PRECAUTIONS All-Cause Mortality: A meta-analysis of Phase 3 and 4 clinical trials demonstrated an increase in all-cause mortality in tigecycline-treated patients compared to controls with a risk difference of 0.6% (95% CI 0.1, 1.2). The cause of this increase has not been established. An increase was also seen in a meta-analysis limited to the approved indications [0.6% (95% CI 0, 1.2)]. The greatest difference in mortality was seen in tigecycline-treated patients with ventilator-associated pneumonia. ( 5.1 , 5.2 ) Anaphylactic Reactions: have been reported with tigecycline for injection, and may be life-threatening. Avoid use in patients with known hypersensitivity to tetracyclines. ( 5.3 ) Hepatic Adverse Effects: have been reported with tigecycline for injection. Patients who develop abnormal liver function tests during tigecycline for injection therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. ( 5.4 ) Pancreatitis: including fatalities, has been reported with tigecycline for injection. If pancreatitis is suspected, then consider stopping tigecycline for injection. ( 5.5 ) Monitoring Blood Coagulation Parameters: Hypofibrinogenemia has been reported with tigecycline for injection. Monitor blood coagulation parameters, including fibrinogen, at baseline and regularly during treatment with tigecycline for injection. ( 5.6 ) Tooth Discoloration and Enamel Hypoplasia: The use of tigecycline for injection during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. ( 5.7 ) Inhibition of Bone Growth: The use of tigecycline for injection during the second and third trimester of pregnancy, infancy, and childhood up to the age of 8 years may cause reversible inhibition of bone growth. ( 5.8 ) Clostridioides difficile associated Diarrhea (CDAD): evaluate if diarrhea occurs. (5.9 ) 5.1 All-Cause Mortality An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4% (150/3,788) of patients receiving tigecycline for injection and 3% (110/3,646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline for injection and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2,640) for tigecycline and 1.8% (48/2,628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0, 1.2). The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Tigecycline for injection should be reserved for use in situations when alternative treatments are not suitable [see Boxed Warning, Indications and Usage ( 1.4 ), Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . 5.2 Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of tigecycline for injection. In this trial, patients were randomized to receive tigecycline for injection (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline for injection had lower cure rates (47.9% versus 70.1% for the clinically evaluable population). In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received tigecycline for injection (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients) [see Adverse Reactions ( 6.1 )] . Particularly high mortality was seen among tigecycline-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50%] versus 1/13 [7.7%] in comparator-treated patients). 5.3 Anaphylactic Reactions Anaphylactic reactions have been reported with nearly all antibacterial agents, including tigecycline for injection, and may be life-threatening. Tigecycline for injection is structurally similar to tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. 5.4 Hepatic Adverse Effects Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued. 5.5 Pancreatitis Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis [see Adverse Reactions ( 6.2 )] . 5.6 Monitoring of Blood Coagulation Parameters Hypofibrinogenemia has been reported in patients treated with tigecycline for injection [see Adverse Reactions ( 6.2 )] . Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with tigecycline for injection. 5.7 Tooth Discoloration and Enamel Hypoplasia The use of tigecycline for injection during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of tetracyclines, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations (8.1, 8.4 )]. 5.8 Inhibition of Bone Growth The use of tigecycline for injection during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the tetracycline was discontinued. Advise the patient of the potential risk to the fetus if tigecycline for injection is used during the second or third trimester of pregnancy [see Use in Specific Populations ( 8.1 , 8.4)]. 5.9 Clostridioides difficile Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.10 Sepsis/Septic Shock in Patients With Intestinal Perforation Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1,642), 6 patients treated with tigecycline for injection and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline for injection had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established. 5.11 Tetracycline-Class Adverse Effects Tigecycline for injection is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse effects. Such effects may include: photosensitivity, fixed drug eruption, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). Discontinue tigecycline for injection if any of these adverse reactions are suspected. 5.12 Development of Drug-Resistant Bacteria Prescribing tigecycline for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: All-Cause Mortality [see Boxed Warning and Warnings and Precautions ( 5.1 )] Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia [see Warnings and Precautions ( 5.2 )] Anaphylaxis [Warning and Precautions ( 5.3 )] Hepatic Adverse Effects [Warnings and Precautions ( 5.4 )] Pancreatitis [Warnings and Precautions ( 5.5 )] The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex at 1-800-706-5575 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, 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 practice. In clinical trials, 2,514 patients were treated with tigecycline for injection. Tigecycline for injection was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials. Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies Body System Tigecycline for injection Comparators a Adverse Reactions (N=2,514) (N=2,307) a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid. b LFT abnormalities in tigecycline-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. Body as a Whole Abdominal pain 6 4 Abscess 2 2 Asthenia 3 2 Headache 6 7 Infection 7 5 Cardiovascular System Phlebitis 3 4 Digestive System Diarrhea 12 11 Dyspepsia 2 2 Nausea 26 13 Vomiting 18 9 Hemic and Lymphatic System Anemia 5 6 Metabolic and Nutritional Alkaline Phosphatase Increased 3 3 Amylase Increased 3 2 Bilirubinemia 2 1 BUN Increased 3 1 Healing Abnormal 3 2 Hyponatremia 2 1 Hypoproteinemia 5 3 SGOT Increased b 4 5 SGPT Increased b 5 5 Respiratory System Pneumonia 2 2 Nervous System Dizziness 3 3 Skin and Appendages Rash 3 4 In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4% (150/3,788) of patients receiving tigecycline for injection and 3% (110/3,646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline for injection and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Table 2. Patients with Outcome of Death by Infection Type Tigecycline for injection Comparator Risk Difference* Infection Type n/N % n/N % % (95% CI) CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in tigecycline for injection and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction. ** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI. a These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis). cSSSI 12/834 1.4 6/813 0.7 0.7 (-0.3, 1.7) cIAI 42/1,382 3.0 31/1,393 2.2 0.8 (-0.4, 2.0) CAP 12/424 2.8 11/422 2.6 0.2 (-2.0, 2.4) HAP 66/467 14.1 57/467 12.2 1.9 (-2.4, 6.3) Non-VAP a 41/336 12.2 42/345 12.2 0.0 (-4.9, 4.9) VAP a 25/131 19.1 15/122 12.3 6.8 (-2.1, 15.7) RP 11/128 8.6 2/43 4.7 3.9 (-4.0, 11.9) DFI 7/553 1.3 3/508 0.6 0.7 (-0.5, 1.8) Overall Adjusted 150/3,788 4.0 110/3,646 3.0 0.6 (0.1, 1.2)** An analysis of mortality in all trials conducted for approved indications -cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) - showed an adjusted mortality rate of 2.5% (66/2,640) for tigecycline and 1.8% (48/2,628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0, 1.2). In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with tigecycline for injection (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with tigecycline for injection (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see Warnings and Precautions ( 5.10 )]. The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 to 2 days of therapy. The majority of cases of nausea and vomiting associated with tigecycline for injection and comparators were either mild or moderate in severity. In patients treated with tigecycline for injection, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe). In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for tigecycline for injection and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline for injection and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline for injection and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline for injection and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline for injection and 8% for levofloxacin; vomiting incidence was 16% for tigecycline for injection and 6% for levofloxacin. Discontinuation from tigecycline for injection was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%). The following adverse reactions were reported (<2%) in patients receiving tigecycline for injection in clinical studies: Body as a Whole : injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia Special Senses: taste perversion Hemic and Lymphatic System : prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of tigecycline for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. anaphylactic reactions acute pancreatitis hepatic cholestasis, and jaundice severe skin reactions, including Stevens-Johnson Syndrome symptomatic hypoglycemia in patients with and without diabetes mellitus hypofibrinogenemia [see Warnings and Precautions ( 5.6 )]

<table ID="t1" width="100%"><caption ID="G543c8624-2d9a-4991-aa38-670fcecc7eac">Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in &#x2265; 2% of Patients Treated in Clinical Studies </caption><colgroup><col align="left" width="50%"/><col align="center" width="25%"/><col align="center" width="25%"/></colgroup><thead><tr><th><content styleCode="bold">Body System </content></th><th>Tigecycline for injection</th><th>Comparators^a</th></tr><tr><td>Adverse Reactions</td><td>(N=2,514)</td><td>(N=2,307)</td></tr></thead><tfoot><tr><td colspan="3">^a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.<paragraph>^b LFT abnormalities in tigecycline-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. </paragraph></td></tr></tfoot><tbody><tr><td><content styleCode="bold">Body as a Whole</content></td><td align="center"> </td><td> </td></tr><tr><td> Abdominal pain </td><td align="center">6 </td><td align="center">4 </td></tr><tr><td> Abscess </td><td align="center">2 </td><td align="center">2 </td></tr><tr><td> Asthenia </td><td align="center">3 </td><td align="center">2 </td></tr><tr><td> Headache </td><td align="center">6 </td><td align="center">7 </td></tr><tr><td> Infection </td><td align="center">7 </td><td align="center">5 </td></tr><tr><td><content styleCode="bold">Cardiovascular System</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Phlebitis </td><td align="center">3 </td><td align="center">4 </td></tr><tr><td><content styleCode="bold">Digestive System</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Diarrhea </td><td align="center">12 </td><td align="center">11 </td></tr><tr><td> Dyspepsia </td><td align="center">2 </td><td align="center" valign="middle">2 </td></tr><tr><td> Nausea </td><td align="center">26 </td><td align="center">13 </td></tr><tr><td> Vomiting </td><td align="center">18 </td><td align="center">9 </td></tr><tr><td><content styleCode="bold">Hemic and Lymphatic System</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Anemia </td><td align="center">5 </td><td align="center">6 </td></tr><tr><td><content styleCode="bold">Metabolic and Nutritional</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Alkaline Phosphatase Increased </td><td align="center">3 </td><td align="center">3 </td></tr><tr><td> Amylase Increased </td><td align="center">3 </td><td align="center">2 </td></tr><tr><td> Bilirubinemia </td><td align="center">2 </td><td align="center">1 </td></tr><tr><td> BUN Increased </td><td align="center">3 </td><td align="center">1 </td></tr><tr><td> Healing Abnormal </td><td align="center">3 </td><td align="center">2 </td></tr><tr><td> Hyponatremia </td><td align="center">2</td><td align="center">1</td></tr><tr><td> Hypoproteinemia </td><td align="center">5 </td><td align="center">3 </td></tr><tr><td> SGOT Increased^b</td><td align="center">4 </td><td align="center">5 </td></tr><tr><td> SGPT Increased^b</td><td align="center">5 </td><td align="center">5 </td></tr><tr><td><content styleCode="bold">Respiratory System</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Pneumonia</td><td align="center">2 </td><td align="center">2 </td></tr><tr><td><content styleCode="bold">Nervous System</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td> Dizziness </td><td align="center">3 </td><td align="center" valign="middle">3 </td></tr><tr><td><content styleCode="bold">Skin and Appendages</content></td><td align="center"> </td><td align="center"> </td></tr><tr><td styleCode="BOTRULE"> Rash </td><td align="center" styleCode="BOTRULE">3 </td><td align="center" styleCode="BOTRULE">4 </td></tr></tbody></table>

<table ID="t2a" width="100%"><caption ID="G562aa03e-5937-4875-ba8e-78c212d0b081">Table 2. Patients with Outcome of Death by Infection Type</caption><colgroup><col align="left" width="20%"/><col align="center" width="15%"/><col align="center" width="15%"/><col align="center" width="15%"/><col align="center" width="15%"/><col align="center" width="20%"/></colgroup><thead><tr><th/><th colspan="2">Tigecycline for injection</th><th colspan="2">Comparator</th><th>Risk Difference*</th></tr><tr><th><content styleCode="none">Infection Type</content></th><th><content styleCode="none">n/N</content></th><th>%</th><th><content styleCode="none">n/N</content></th><th>%</th><th>% (95% CI)</th></tr></thead><tfoot><tr><td colspan="6">CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.<paragraph>* The difference between the percentage of patients who died in tigecycline for injection and comparator treatment groups. The 95% CI for each infection type was calculated using the normal approximation method without continuity correction.</paragraph><paragraph>** Overall adjusted (random effects model by trial weight) risk difference estimate and 95% CI.</paragraph><paragraph>^a These are subgroups of the HAP population. </paragraph><paragraph>Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis). </paragraph></td></tr></tfoot><tbody><tr><td> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td>cSSSI</td><td align="center">12/834</td><td align="center">1.4</td><td align="center">6/813</td><td align="center">0.7</td><td align="center">0.7 (-0.3, 1.7)</td></tr><tr><td>cIAI</td><td align="center">42/1,382</td><td align="center">3.0</td><td align="center">31/1,393</td><td align="center">2.2</td><td align="center">0.8 (-0.4, 2.0)</td></tr><tr><td>CAP</td><td align="center">12/424</td><td align="center">2.8</td><td align="center">11/422</td><td align="center">2.6</td><td align="center">0.2 (-2.0, 2.4)</td></tr><tr><td> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td>HAP</td><td align="center">66/467</td><td align="center">14.1</td><td align="center">57/467</td><td align="center">12.2</td><td align="center">1.9 (-2.4, 6.3)</td></tr><tr><td> Non-VAP^a</td><td align="center">41/336</td><td align="center">12.2</td><td align="center">42/345</td><td align="center">12.2</td><td align="center">0.0 (-4.9, 4.9)</td></tr><tr><td> VAP^a</td><td align="center">25/131</td><td align="center">19.1</td><td align="center">15/122</td><td align="center">12.3</td><td align="center">6.8 (-2.1, 15.7)</td></tr><tr><td>RP</td><td align="center">11/128</td><td align="center">8.6</td><td align="center">2/43</td><td align="center">4.7</td><td align="center">3.9 (-4.0, 11.9)</td></tr><tr><td>DFI</td><td align="center">7/553</td><td align="center">1.3</td><td align="center">3/508</td><td align="center">0.6</td><td align="center">0.7 (-0.5, 1.8)</td></tr><tr><td> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td><td align="center"> </td></tr><tr><td>Overall Adjusted</td><td align="center">150/3,788</td><td align="center">4.0</td><td align="center">110/3,646</td><td align="center">3.0</td><td align="center">0.6 (0.1, 1.2)**</td></tr></tbody></table>