FDA label c9b3e182-6a7b-4e8f-a2ea-9fc6da546962

CONTRAINDICATIONS AND WARNINGS PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH LEFLUNOMIDE TABLETS. LEFLUNOMIDE TABLETS ARE CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE CONTRAINDICATIONS AND WARNINGS.) PREGNANCY MUST BE AVOIDED DURING LEFLUNOMIDE TABLET TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER LEFLUNOMIDE TABLET TREATMENT.

WARNINGS Immunosuppression Potential/Bone Marrow Suppression Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal (see PRECAUTIONS - General - Need for Drug Elimination ). Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections. Rarely, severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality. Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see PRECAUTIONS - General - Need for Drug Elimination ). In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment. Hepatotoxicity RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH LEFLUNOMIDE. MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins). (See PRECAUTIONS). At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of leflunomide under close monitoring. If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, leflunomide should be discontinued and cholestyramine or charcoal should be administered (see PRECAUTIONS - General - Need for Drug Elimination ) with close monitoring, including retreatment with cholestyramine or charcoal as indicated. In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 7 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 7. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) * Only 10% of patients in MN302 received folate. All patients in US301 received folate. US301 MN301 MN302 * LEF PL MTX LEF PL SSZ LEF MTX ALT (SGPT) >3-fold ULN 8 3 5 2 1 2 13 83 (n %) (4.4) (2.5) (2.7) (1.5) (1.1) (1.5) (2.6) (16.7) Reversed to < 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0-3 Months 6 1 1 2 1 2 7 27 4-6 Months 1 1 3 - - - 1 34 7-9 Months 1 1 1 - - - - 16 10-12 Months - - - - - - 5 6 In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added. Pre-existing Hepatic Disease Given the possible risk of increased hepatotoxicity, and the role of the liver in drug activation, elimination and recycling, the use of leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses. (See WARNINGS – Hepatoxicity ). Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving leflunomide. If a patient taking leflunomide develops any of these conditions, leflunomide therapy should be stopped, and a drug elimination procedure is recommended. (See PRECAUTIONS – General – Need for Drug Elimination ). Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppression medications. There is a potential for immunosuppression with leflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the clinical trials of leflunomide, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with leflunomide. Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating leflunomide in pregnant women. However, based on animal studies, leflunomide may increase the risk of fetal death or teratogenic effects when administered to a pregnant woman (see CONTRAINDICATIONS ). Women of childbearing potential must not be started on leflunomide until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with leflunomide, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite by instituting the drug elimination procedure described below at the first delay of menses may decrease the risk to the fetus from leflunomide. Upon discontinuing leflunomide, it is recommended that all women of childbearing potential undergo the drug elimination procedure described below. Women receiving leflunomide treatment who wish to become pregnant must discontinue leflunomide and undergo the drug elimination procedure described below which includes verification of M1 metabolite plasma levels less than 0.02 mg/L (0.02 µg/mL). Human plasma levels of the active metabolite (M1) less than 0.02 mg/L (0.02 µg/mL) are expected to have minimal risk based on available animal data. Drug Elimination Procedure The following drug elimination procedure is recommended to achieve non-detectable plasma levels (less than 0.02 mg/L or 0.02 µg/mL) after stopping treatment with leflunomide: 1. Administer cholestyramine 8 grams 3 times daily for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly.) 2. Verify plasma levels less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart. If plasma levels are higher than 0.02 mg/L, additional cholestyramine treatment should be considered. Without the drug elimination procedure, it may take up to 2 years to reach plasma M1 metabolite levels less than 0.02 mg/L due to individual variation in drug clearance.

Immunosuppression Potential/Bone Marrow Suppression Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, or severe, uncontrolled infections. In the event that a serious infection occurs, it may be necessary to interrupt therapy with leflunomide and administer cholestyramine or charcoal (see PRECAUTIONS - General - Need for Drug Elimination ). Medications like leflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections. Rarely, severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. There have been rare reports of pancytopenia, agranulocytosis and thrombocytopenia in patients receiving leflunomide alone. These events have been reported most frequently in patients who received concomitant treatment with methotrexate or other immunosuppressive agents, or who had recently discontinued these therapies; in some cases, patients had a prior history of a significant hematologic abnormality. Patients taking leflunomide should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6- to 8 weeks thereafter. If used with concomitant methotrexate and/or other potential immunosuppressive agents, chronic monitoring should be monthly. If evidence of bone marrow suppression occurs in a patient taking leflunomide, treatment with leflunomide should be stopped, and cholestyramine or charcoal should be used to reduce the plasma concentration of leflunomide active metabolite (see PRECAUTIONS - General - Need for Drug Elimination ). In any situation in which the decision is made to switch from leflunomide to another anti-rheumatic agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Leflunomide washout with cholestyramine or charcoal may decrease this risk, but also may induce disease worsening if the patient had been responding to leflunomide treatment.

Hepatotoxicity RARE CASES OF SEVERE LIVER INJURY, INCLUDING CASES WITH FATAL OUTCOME, HAVE BEEN REPORTED DURING TREATMENT WITH LEFLUNOMIDE. MOST CASES OF SEVERE LIVER INJURY OCCUR WITHIN 6 MONTHS OF THERAPY AND IN A SETTING OF MULTIPLE RISK FACTORS FOR HEPATOTOXICITY (liver disease, other hepatotoxins). (See PRECAUTIONS). At minimum, ALT (SGPT) must be performed at baseline and monitored initially at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if leflunomide and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing monthly. Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of leflunomide under close monitoring. If elevations between 2- and 3-fold ULN persist despite dose reduction or if ALT elevations of >3-fold ULN are present, leflunomide should be discontinued and cholestyramine or charcoal should be administered (see PRECAUTIONS - General - Need for Drug Elimination ) with close monitoring, including retreatment with cholestyramine or charcoal as indicated. In clinical trials, leflunomide treatment as monotherapy or in combination with methotrexate was associated with elevations of liver enzymes, primarily ALT and AST, in a significant number of patients; these effects were generally reversible. Most transaminase elevations were mild (≤2-fold ULN) and usually resolved while continuing treatment. Marked elevations (>3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment. Table 7 shows liver enzyme elevations seen with monthly monitoring in clinical trials US301 and MN301. It was notable that the absence of folate use in MN302 was associated with a considerably greater incidence of liver enzyme elevation on methotrexate. Table 7. Liver Enzyme Elevations >3-fold Upper Limits of Normal (ULN) * Only 10% of patients in MN302 received folate. All patients in US301 received folate. US301 MN301 MN302 * LEF PL MTX LEF PL SSZ LEF MTX ALT (SGPT) >3-fold ULN 8 3 5 2 1 2 13 83 (n %) (4.4) (2.5) (2.7) (1.5) (1.1) (1.5) (2.6) (16.7) Reversed to < 2-fold ULN: 8 3 5 2 1 2 12 82 Timing of Elevation 0-3 Months 6 1 1 2 1 2 7 27 4-6 Months 1 1 3 - - - 1 34 7-9 Months 1 1 1 - - - - 16 10-12 Months - - - - - - 5 6 In a 6 month study of 263 patients with persistent active rheumatoid arthritis despite methotrexate therapy, and with normal LFTs, leflunomide was added to a group of 130 patients starting at 10 mg per day and increased to 20 mg as needed. An increase in ALT greater than or equal to three times the ULN was observed in 3.8% of patients compared to 0.8% in 133 patients continued on methotrexate with placebo added.

Pre-existing Hepatic Disease Given the possible risk of increased hepatotoxicity, and the role of the liver in drug activation, elimination and recycling, the use of leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses. (See WARNINGS – Hepatoxicity ).

ADVERSE REACTIONS Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See Table 8.) Table 8. Percentage Of Patients With Adverse Events ≥3% In Any Leflunomide Treated Group * Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate. 1 Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months). 2 Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials. 3 In a meta-analysis of all phase II and III studies, during the first 6 months in patients receiving leflunomide, 10% lost 10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs (4 cases/100 patient years). Of patients receiving leflunomide, 4% lost 10% of their baseline weight during the first 6 months of treatment. All RA Studies Placebo-Controlled Trials Active-Controlled Trials MN 301 and US 301 MN 302 * LEF (N=1339) 1 LEF (N=315) PBO (N=210) SSZ (N=133) MTX (N=182) LEF (N=501) MTX (N=498) BODY AS A WHOLE Allergic Reaction 2% 5% 2% 0% 6% 1% 2% Asthenia 3% 6% 4% 5% 6% 3% 3% Flu Syndrome 2% 4% 2% 0% 7% 0% 0% Infection, upper respiratory 4% 0% 0% 0% 0% 0% 0% Injury Accident 5% 7% 5% 3% 11% 6% 7% Pain 2% 4% 2% 2% 5% 1% <1% Abdominal Pain 6% 5% 4% 4% 8% 6% 4% Back Pain 5% 6% 3% 4% 9% 8% 7% CARDIOVASCULAR Hypertension 2 10% 9% 4% 4% 3% 10% 4% - New onset of hypertension 1% <1% 0% 2% 2% <1% Chest Pain 2% 4% 2% 2% 4% 1% 2% GASTROINTESTINAL Anorexia 3% 3% 2% 5% 2% 3% 3% Diarrhea 17% 27% 12% 10% 20% 22% 10% Dyspepsia 5% 10% 10% 9% 13% 6% 7% Gastroenteritis 3% 1% 1% 0% 6% 3% 3% Abnormal Liver Enzymes 5% 10% 2% 4% 10% 6% 17% Nausea 9% 13% 11% 19% 18% 13% 18% Gl/Abdominal Pain 5% 6% 4% 7% 8% 8% 8% Mouth Ulcer 3% 5% 4% 3% 10% 3% 6% Vomiting 3% 5% 4% 4% 3% 3% 3% METABOLIC AND NUTRITIONAL Hypokalemia 1% 3% 1% 1% 1% 1% <1% Weight Loss 3 4% 2% 1% 2% 0% 2% 2% MUSCULO-SKELETAL SYSTEM Arthralgia 1% 4% 3% 0% 9% <1% 1% Leg Cramps 1% 4% 2% 2% 6% 0% 0% Joint Disorder 4% 2% 2% 2% 2% 8% 6% Synovitis 2% <1% 1% 0% 2% 4% 2% Tenosynovitis 3% 2% 0% 1% 2% 5% 1% NERVOUS SYSTEM Dizziness 4% 5% 3% 6% 5% 7% 6% Headache 7% 13% 11% 12% 21% 10% 8% Paresthesia 2% 3% 1% 1% 2% 4% 3% RESPIRATORY SYSTEM Bronchitis 7% 5% 2% 4% 7% 8% 7% Increased Cough 3% 4% 5% 3% 6% 5% 7% Respiratory Infection 15% 21% 21% 20% 32% 27% 25% Pharyngitis 3% 2% 1% 2% 1% 3% 3% Pneumonia 2% 3% 0% 0% 1% 2% 2% Rhinitis 2% 5% 2% 4% 3% 2% 2% Sinusitis 2% 5% 5% 0% 10% 1% 1% SKIN AND APPENDAGES Alopecia 10% 9% 1% 6% 6% 17% 10% Eczema 2% 1% 1% 1% 1% 3% 2% Pruritus 4% 5% 2% 3% 2% 6% 2% Rash 10% 12% 7% 11% 9% 11% 10% Dry Skin 2% 3% 2% 2% 0% 3% 1% UROGENITAL SYSTEM Urinary Tract Infection 5% 5% 7% 4% 2% 5% 6% Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. In addition, the following adverse events have been reported in 1% to <3% of the RA patients in the leflunomide treatment group in controlled clinical trials. Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain; Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation; Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder; Endocrine: diabetes mellitus, hyperthyroidism; Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis; Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema; Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture; Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo; Respiratory System: asthma, dyspnea, epistaxis, lung disorder; Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin; Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion; Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis. Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia <2000 WBC/mm3 (rare). Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence. In post-marketing experience, the following have been reported rarely: Body as a Whole: opportunistic infections, severe infections including sepsis that may be fatal; Gastrointestinal: pancreatitis; Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia; Hypersensitivity: angioedema; Hepatic: hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal; Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; Nervous System: peripheral neuropathy; Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis including cutaneous necrotizing vasculitis. Adverse Reactions (Pediatric Patients) Adverse event information for pediatric patients is approved for Aventis Pharmaceuticals’ leflunomide tablets. However, due to Aventis Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Adverse Reactions (Pediatric Patients) Adverse event information for pediatric patients is approved for Aventis Pharmaceuticals’ leflunomide tablets. However, due to Aventis Pharmaceuticals’ marketing exclusivity rights, this drug product is not labeled with that pediatric information.

<table ID="inv-f90fadb4-ea31-4278-8143-9f0196a20535" frame="border" border="1"> <caption ID="inv-21020cd1-970f-4555-95ad-ec0c28eb6e8a">Table 8. Percentage Of Patients With Adverse Events &#x2265;3% In Any Leflunomide Treated Group</caption> <col width="207px"/> <col width="93px"/> <col width="55px"/> <col width="53px"/> <col width="53px"/> <col width="53px"/> <col width="53px"/> <col width="53px"/> <tfoot> <tr> <td colspan="8"> <paragraph styleCode="footnote" ID="inv-76dd32d3-e973-40b1-972e-9ff55129b63e"> ^* Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate.</paragraph> <paragraph styleCode="footnote" ID="inv-b01d153b-0c83-4048-b901-f8014c4236cf"> ¹ Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).</paragraph> <paragraph styleCode="footnote" ID="inv-a46b9b69-1f61-4b4f-b0c3-97851b03a159"> ² Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials.</paragraph> <paragraph styleCode="footnote" ID="inv-583d0dc7-b406-4853-85a4-0250b0f11cba"> ³ In a meta-analysis of all phase II and III studies, during the first 6 months in patients receiving leflunomide, 10% lost 10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs (4 cases/100 patient years). Of patients receiving leflunomide, 4% lost 10% of their baseline weight during the first 6 months of treatment.</paragraph> </td> </tr> </tfoot> <tbody> <tr> <td valign="middle" rowspan="3" styleCode="Botrule Lrule Rrule"/> <td align="center" valign="middle" styleCode="Botrule Rrule">All RA Studies</td> <td align="center" valign="middle" colspan="4" styleCode="Botrule Rrule">Placebo-Controlled Trials</td> <td align="center" valign="middle" colspan="2" styleCode="Botrule Rrule">Active-Controlled Trials</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule"/> <td align="center" valign="middle" colspan="4" styleCode="Botrule Rrule">MN 301 and US 301</td> <td align="center" valign="middle" colspan="2" styleCode="Botrule Rrule">MN 302<footnote ID="inv-7e780cfe-b1a7-43f7-945a-3737820b5b2e">*</footnote> </td> </tr> <tr> <td align="center" valign="middle" styleCode="Botrule Lrule Rrule">LEF (N=1339)<footnote ID="inv-15557a48-78b4-4ca3-96a5-de6d1c265005">1</footnote> </td> <td align="center" valign="middle" styleCode="Botrule Rrule">LEF (N=315)</td> <td align="center" valign="middle" styleCode="Botrule Rrule">PBO (N=210)</td> <td align="center" valign="middle" styleCode="Botrule Rrule">SSZ (N=133)</td> <td align="center" valign="middle" styleCode="Botrule Rrule">MTX (N=182)</td> <td align="center" valign="middle" styleCode="Botrule Rrule">LEF (N=501)</td> <td align="center" valign="middle" styleCode="Botrule Rrule">MTX (N=498)</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">BODY AS A WHOLE</content> </td> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Allergic Reaction</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Asthenia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Flu Syndrome</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Infection, upper respiratory</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Injury Accident</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">11%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Pain</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Abdominal Pain</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Back Pain</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">CARDIOVASCULAR</content> </td> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> <td valign="middle" styleCode="Botrule Rrule"/> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Hypertension<footnote ID="inv-b80f96ad-25fb-48dc-8948-66d9b739cd82">2</footnote> </td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">- New onset of hypertension</td> <td align="center" valign="middle" styleCode="Botrule Rrule"/> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Chest Pain</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">GASTROINTESTINAL</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Anorexia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Diarrhea</td> <td align="center" valign="middle" styleCode="Botrule Rrule">17%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">27%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">12%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">20%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">22%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Dyspepsia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">13%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Gastroenteritis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Abnormal Liver Enzymes</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">17%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Nausea</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">13%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">11%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">19%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">18%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">13%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">18%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Gl/Abdominal Pain</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Mouth Ulcer</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Vomiting</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">METABOLIC AND NUTRITIONAL</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Hypokalemia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Weight Loss<footnote ID="inv-0703da28-5bba-46d6-a984-be5a21060ce0">3</footnote> </td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">MUSCULO-SKELETAL SYSTEM</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Arthralgia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Leg Cramps</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Joint Disorder</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Synovitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">&lt;1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Tenosynovitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">NERVOUS SYSTEM</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Dizziness</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Headache</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">13%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">11%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">12%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">21%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Paresthesia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">RESPIRATORY SYSTEM</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Bronchitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">8%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Increased Cough</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Respiratory Infection</td> <td align="center" valign="middle" styleCode="Botrule Rrule">15%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">21%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">21%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">20%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">32%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">27%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">25%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Pharyngitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Pneumonia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Rhinitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Sinusitis</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">SKIN AND APPENDAGES</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Alopecia</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">17%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Eczema</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Pruritus</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Rash</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">12%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">11%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">9%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">11%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">10%</td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Dry Skin</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">0%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">3%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">1%</td> </tr> <tr> <td valign="middle" colspan="2" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">UROGENITAL SYSTEM</content> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> <td valign="middle" styleCode="Botrule Rrule"> <content styleCode="bold"> </content> </td> </tr> <tr> <td valign="middle" styleCode="Botrule Lrule Rrule">Urinary Tract Infection</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">7%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">4%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">2%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">5%</td> <td align="center" valign="middle" styleCode="Botrule Rrule">6%</td> </tr> </tbody> </table>