BENLYSTA

5 WARNINGS AND PRECAUTIONS • Serious Infections: Serious and sometimes fatal infections have occurred in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA if patients develop a new infection during treatment with BENLYSTA. ( 5.1 ) • Progressive Multifocal Leukoencephalopathy (PML): Evaluate patients with new-onset or deteriorating neurological signs and symptoms for PML. If PML is suspected, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. ( 5.1 ) • Hypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. ( 5.2 ) • Stevens‑Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN): Discontinue BENLYSTA immediately if signs or symptoms of SJS/TEN occur. ( 5.3 ) • Depression and Suicidality: Depression and suicidality were reported in trials with BENLYSTA. Assess for depression and risk of suicide before treatment with BENLYSTA and monitor during treatment. Instruct patients to contact their healthcare provider if new or worsening depression, suicidal thoughts, or other mood changes occur. ( 5.4 ) • Immunization: Live vaccines should not be given concurrently with BENLYSTA. ( 5.6 ) 5.1 Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Overall, the incidence of serious infections in controlled trials was similar in subjects receiving BENLYSTA compared with placebo, whereas fatal infections occurred more frequently in subjects receiving BENLYSTA [see Adverse Reactions ( 6.1 )] . Consider the risk and benefit before initiating treatment with BENLYSTA in patients with severe or chronic infections. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while receiving it and monitor these patients closely. Progressive Multifocal Leukoencephalopathy (PML) Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with suspected PML, immunosuppressant therapy, including BENLYSTA, must be suspended until PML has been excluded. If PML is confirmed, immunosuppressant therapy, including BENLYSTA, must be discontinued. 5.2 Hypersensitivity Reactions, including Anaphylaxis Acute hypersensitivity reactions, including anaphylaxis and death, and infusion-related reactions have been reported in association with BENLYSTA [see Adverse Reactions ( 6.1 )] . These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion-related reactions in all cases. In the controlled clinical trials of BENLYSTA administered intravenously in adults with SLE, some subjects (13%) received premedication, which may have mitigated or masked a hypersensitivity response or infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions or infusion-related reaction. BENLYSTA for intravenous use should be administered by healthcare providers prepared to manage anaphylaxis and infusion-related reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion-related reactions. In the event of a serious reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. With intravenous administration, the infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Monitor patients during infusion and for an appropriate period of time after intravenous administration of BENLYSTA. Consider administering premedication as prophylaxis prior to intravenous dosing [see Dosage and Administration ( 2.1 , 2.2 )] . Inform patients receiving BENLYSTA of the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical care should a reaction occur. 5.3 Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients treated with BENLYSTA. Monitor for and advise patients about signs and symptoms of SJS/TEN during treatment with BENLYSTA. Discontinue BENLYSTA immediately if signs or symptoms suggestive of SJS/TEN occur. Early consultation with a dermatologist or other appropriate specialist is recommended to ensure greater diagnostic accuracy and appropriate management. If the etiology is considered to be associated with BENLYSTA, permanently discontinue and do not reintroduce BENLYSTA [see Contraindications ( 4 )] . 5.4 Depression and Suicidality In controlled clinical trials, depression and suicidality were reported in subjects receiving BENLYSTA [see Adverse Reactions ( 6.1 )] . Assess the risk of depression and suicide considering the patient’s medical history and current psychiatric status before treatment with BENLYSTA and continue to monitor patients during treatment. Instruct patients receiving BENLYSTA (and caregivers, if applicable) to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or behavior, or other mood changes. Consider the risk and benefit of continued treatment with BENLYSTA for patients who develop such symptoms. 5.5 Malignancy There is an increased risk of malignancies with the use of immunosuppressants. The impact of treatment with BENLYSTA on the development of malignancies is not known [see Adverse Reactions ( 6.1 )] . Consider the individual benefit-risk in patients with known risk factors for the development or reoccurrence of malignancy prior to prescribing BENLYSTA. In patients who develop malignancies, consider the risk and benefit of continued treatment with BENLYSTA. 5.6 Immunization Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. 5.7 Concomitant Use with Other Biologic Therapies Available data do not support the safety and efficacy of concomitant use of BENLYSTA with rituximab in patients with SLE. An increased incidence of serious infections and post-injection systemic reactions in subjects receiving BENLYSTA concomitantly with rituximab compared to subjects receiving BENLYSTA alone has been observed [see Adverse Reactions ( 6.1 )] . The safety and efficacy of BENLYSTA concomitantly with other biologic therapies, including B-cell-targeted therapies, have not been established. Caution should be exercised if BENLYSTA is administered in combination with other biologic therapies [see Warnings and Precautions ( 5 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and in the Warnings and Precautions section: • Serious Infections [see Warnings and Precautions ( 5.1 )] • Hypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions ( 5.2 )] • Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions ( 5.3 )] • Depression and Suicidality [see Warnings and Precautions ( 5.4 )] • Malignancy [see Warnings and Precautions ( 5.5 )] Common adverse reactions (≥5%): nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, pharyngitis, and injection site reactions (subcutaneous administration). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-877-423-6597 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Intravenous Administration in Adult Subjects with Active SLE The data described in Table 2 reflect exposure to BENLYSTA administered intravenously plus standard therapy compared with placebo plus standard therapy in 2,133 adult subjects with active SLE in 3 controlled trials (Trials 1, 2, and 3). Subjects received BENLYSTA plus standard therapy at doses of 1 mg/kg (n = 673), 4 mg/kg (n = 111; Trial 1 only), or 10 mg/kg (n = 674), or placebo plus standard therapy (n = 675) intravenously over a 1‑hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks [see Clinical Studies ( 14.2 )] . Because there was no apparent dose‑related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 intravenous doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended intravenous dose of 10 mg/kg compared with placebo. In Trials 1, 2, and 3, 93% of subjects treated with BENLYSTA plus standard therapy reported an adverse event compared with 92% treated with placebo plus standard therapy. The most common serious adverse events were serious infections (6% and 5.2% in the groups receiving BENLYSTA and placebo plus standard therapy, respectively), some of which were fatal. The most commonly reported adverse events, occurring in ≥5% of subjects in Trials 1, 2, and 3 were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. The proportion of subjects who discontinued treatment due to any adverse reaction during Trials 1, 2, and 3 was 6.2% for subjects receiving BENLYSTA plus standard therapy and 7.1% for subjects receiving placebo plus standard therapy. The most common adverse reactions resulting in discontinuation of treatment (≥1% of subjects receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1% placebo). Table 2 lists adverse reactions, regardless of causality, occurring in at least 3% of subjects with active SLE who received BENLYSTA 10 mg/kg plus standard therapy and at an incidence at least 1% greater than that observed with placebo plus standard therapy in 3 controlled trials (Trials 1, 2, and 3). Table 2. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Subjects with Active SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Subjects Receiving Placebo plus Standard Therapy (Trials 1, 2, and 3) Adverse Reactions BENLYSTA 10 mg/kg + Standard Therapy (n = 674) % Placebo + Standard Therapy (n = 675) % Nausea 15 12 Diarrhea 12 9 Pyrexia 10 8 Nasopharyngitis 9 7 Bronchitis 9 5 Insomnia 7 5 Pain in extremity 6 4 Depression 5 4 Migraine 5 4 Pharyngitis 5 3 Cystitis 4 3 Leukopenia 4 2 Gastroenteritis viral 3 1 Specific Adverse Reactions in Adult Subjects with Active SLE (Intravenous Administration) Infections: In Trials 1, 2, and 3, the overall incidence of infections was 71% in subjects receiving BENLYSTA compared with 67% in subjects receiving placebo. The most frequent infections (>5% of subjects receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Infections leading to discontinuation of treatment occurred in 0.7% of subjects receiving BENLYSTA and 1.0% of subjects receiving placebo. Serious Infections: In Trials 1, 2, and 3, the incidence of serious infections was 6.0% in subjects receiving BENLYSTA and 5.2% in subjects receiving placebo. The most frequent serious infections included pneumonia, urinary tract infections, cellulitis, and bronchitis. Fatal infections occurred in 0.3% (4/1,458) of subjects receiving BENLYSTA and in 0.1% (1/675) of subjects receiving placebo. In a randomized, double‑blind, placebo‑controlled, 52‑week, postmarketing safety trial of BENLYSTA administered intravenously in adults with active SLE (N = 4,003), the incidence of serious infections was 3.7% in subjects receiving BENLYSTA compared with 4.1% in subjects receiving placebo. Serious infections leading to discontinuation of treatment occurred in 1.0% of subjects receiving BENLYSTA and in 0.9% of subjects receiving placebo. Fatal infections occurred in 0.45% (9/2,002) of subjects receiving BENLYSTA and in 0.15% (3/2,001) of subjects receiving placebo, where the incidence of all‑cause mortality was 0.50% (10/2,002) in subjects receiving BENLYSTA and 0.40% (8/2,001) in subjects receiving placebo. Hypersensitivity Reactions, including Anaphylaxis: In Trials 1, 2, and 3, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of subjects receiving BENLYSTA and 11% (76/675) of subjects receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of subjects receiving BENLYSTA and 0.4% (3/675) of subjects receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Infusion ‑ Related Reactions: In Trials 1, 2, and 3, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of subjects receiving BENLYSTA and 15% (99/675) of subjects receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of subjects receiving BENLYSTA and 0.4% of subjects receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥3% of subjects receiving BENLYSTA) were headache, nausea, and skin reactions. Depression and Suicidality: In Trials 1, 2, and 3, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), primarily related to depression‑related events (6.3% BENLYSTA; 4.7% placebo), insomnia (6% BENLYSTA; 5.3% placebo), and anxiety (3.9% BENLYSTA; 2.8% placebo). Serious psychiatric events were reported in 0.8% (12/1,458) of subjects receiving BENLYSTA and 0.4% (3/675) of subjects receiving placebo. Serious depression was reported in 0.4% (6/1,458) of subjects receiving BENLYSTA and 0.1% (1/675) of subjects receiving placebo. Two suicides (0.1%) were reported in subjects receiving BENLYSTA (one with 10 mg/kg and one with 1 mg/kg). In a 52-week postmarketing safety trial of BENLYSTA (N = 4,003), serious psychiatric events were reported in 1% (20/2,002) of subjects receiving BENLYSTA and 0.3% (6/2,001) of subjects receiving placebo. Serious depression was reported in 0.3% (7/2,002) of subjects receiving BENLYSTA and in <0.1% (1/2,001) receiving placebo. The overall incidence of serious suicidal ideation or behavior or self‑injury without suicidal intent was 0.7% (15/2,002) of subjects receiving BENLYSTA and 0.2% (5/2,001) of subjects receiving placebo. On the Columbia‑Suicide Severity Rating Scale (C‑SSRS), 2.4% (48/1,974) of subjects receiving BENLYSTA reported suicidal ideation or behavior compared with 2% (39/1,988) of subjects receiving placebo. No suicide was reported in either group. The intravenous trials above did not exclude subjects with a history of psychiatric disorders. Malignancy: In Trials 1, 2, and 3, malignancies (including non‑melanoma skin cancers) were reported in 0.4% of subjects receiving BENLYSTA and 0.4% of subjects receiving placebo. In the intravenous controlled clinical trials, malignancies, excluding non‑melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of subjects receiving BENLYSTA and placebo, respectively. Intravenous Administration in Black/African-American Subjects with Active SLE The safety of BENLYSTA 10 mg/kg administered intravenously in adults plus standard therapy (n = 331) compared with placebo plus standard therapy (n = 165) in Black subjects with active SLE (Trial 4) was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in the overall population [see Clinical Studies ( 14.2 )] . Intravenous Administration in Adult Subjects with Active Lupus Nephritis The safety of BENLYSTA 10 mg/kg administered intravenously plus standard therapy (n = 224) compared with placebo plus standard therapy (n = 224) was evaluated in adults with active lupus nephritis for up to 104 weeks (Trial 5) [see Clinical Studies ( 14.3 )] . The adverse reactions observed were consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy in patients with active SLE. Cases of myelosuppression, including febrile neutropenia, leukopenia, and pancytopenia, were observed in subjects who received induction therapy with cyclophosphamide followed by maintenance therapy with azathioprine, or mycophenolate. Specific Adverse Reactions in Adult Subjects with Active Lupus Nephritis (Intravenous Administration) Infections: In Trial 5, the overall incidence of infections was 82% in subjects receiving BENLYSTA compared with 76% in subjects receiving placebo. Serious Infections: In Trial 5, serious infections occurred in 14% of subjects receiving BENLYSTA and in 17% of subjects receiving placebo. Fatal infections occurred in 0.9% (2/224) of subjects receiving BENLYSTA and in 0.9% (2/224) of subjects receiving placebo. Intravenous Administration in Pediatric Subjects 5 Years of Age and Older with Active SLE The safety of BENLYSTA administered intravenously plus standard therapy (n = 53) compared with placebo plus standard therapy (n = 40) was evaluated in 93 pediatric subjects with active SLE (Trial 6). The adverse reactions observed were consistent with those observed in adults with SLE [see Clinical Studies ( 14.4 )] . Subcutaneous Administration in Adult Subjects with Active SLE The data described below reflect exposure to BENLYSTA administered subcutaneously plus standard therapy compared with placebo plus standard therapy in 836 adult subjects with active SLE in a controlled trial (Trial 7). In addition to standard therapy, subjects received BENLYSTA 200 mg (n = 556) or placebo (n = 280) (2:1 randomization) once weekly for up to 52 weeks [see Clinical Studies ( 14.5 )] . In the trial, 81% of subjects treated with BENLYSTA plus standard therapy reported an adverse event compared with 84% treated with placebo plus standard therapy. The proportion of subjects who discontinued treatment due to any adverse reaction during the controlled clinical trial was 7.2% of subjects receiving BENLYSTA plus standard therapy and 8.9% of subjects receiving placebo plus standard therapy. The safety profile observed for BENLYSTA administered subcutaneously plus standard therapy was consistent with the known safety profile of BENLYSTA administered intravenously plus standard therapy, with the exception of local injection site reactions. Infections: In Trial 7, the overall incidence of infections was 55% in subjects receiving BENLYSTA compared with 57% in subjects receiving placebo. The most commonly reported infections with BENLYSTA administered subcutaneously were similar to those reported with BENLYSTA administered intravenously. Serious Infections: In Trial 7, the incidence of serious infections was 4.1% in subjects receiving BENLYSTA and 5.4% in subjects receiving placebo. Fatal infections occurred in 0.5% (3/556) of subjects receiving BENLYSTA and in none of the subjects receiving placebo (0/280). Depression and Suicidality: In Trial 7, which excluded subjects with a history of psychiatric disorders, psychiatric events were reported in 6% of subjects receiving BENLYSTA and 11% of subjects receiving placebo. Depression‑related events were reported in 2.7% (15/556) of subjects receiving BENLYSTA and 3.6% (10/280) of subjects receiving placebo. Serious psychiatric events were reported in 0.2% (1/556) of subjects receiving BENLYSTA and in no subjects receiving placebo. There were no serious depression‑related events or suicides reported in either group. On the C‑SSRS, 1.3% (7/554) of subjects receiving BENLYSTA reported suicidal ideation or behavior compared with 0.7% (2/277) of subjects receiving placebo. Malignancy: In Trial 7, the reports of malignancies were similar to those reported with BENLYSTA administered intravenously. Injection Site Reactions: In Trial 7, the frequency of injection site reactions was 6.1% (34/556) for subjects receiving BENLYSTA plus standard therapy and 2.5% (7/280) for subjects receiving placebo plus standard therapy. These injection site reactions (most commonly pain, erythema, hematoma, pruritus, and induration) were mild to moderate in severity. The majority (94%) did not necessitate discontinuation of treatment. Concomitant Use of Subcutaneous BENLYSTA and Intravenous Rituximab in Adult Subjects with Active SLE BENLYSTA administered subcutaneously in combination with intravenous rituximab was studied in a Phase 3, randomized, double‑blind, placebo‑controlled, 104‑week trial in adult subjects with active SLE. Subjects were randomized to 1 of the 3 treatment arms: BENLYSTA with a single cycle of rituximab (n = 144); BENLYSTA with placebo (n = 72); BENLYSTA plus standard therapy (n = 76). In general, adverse reactions were consistent with the known safety profile of BENLYSTA and rituximab. When compared with BENLYSTA and placebo or BENLYSTA plus standard therapy, BENLYSTA in combination with rituximab was associated with higher frequency of serious adverse events (13.9%, 19.7%, 22.2%, respectively), serious infections (2.8%, 5.3%, 9.0%, respectively), and post‑injection systemic reactions (9.7%, 5.3%, 13.2%, respectively). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of BENLYSTA. Because these 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. • Fatal anaphylaxis [see Warnings and Precautions ( 5.2 )] . • Stevens‑Johnson syndrome and toxic epidermal necrolysis [see Warnings and Precautions ( 5.3 )] .

<table ID="_RefTable_2" width="100%"><caption>Table 2. Incidence of Adverse Reactions Occurring in at Least 3% of Adult Subjects with Active SLE Treated with BENLYSTA 10 mg/kg plus Standard Therapy and at Least 1% More Frequently than in Subjects Receiving Placebo plus Standard Therapy (Trials 1, 2, and 3)</caption><col width="43%"/><col width="29%"/><col width="27%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BENLYSTA </content></paragraph><paragraph><content styleCode="bold">10 mg/kg + </content></paragraph><paragraph><content styleCode="bold">Standard Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 674)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo + </content></paragraph><paragraph><content styleCode="bold">Standard Therapy</content></paragraph><paragraph><content styleCode="bold">(n = 675)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nasopharyngitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Bronchitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Pain in extremity</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Depression</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Migraine</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Pharyngitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Cystitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Gastroenteritis viral</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>