FDA label fb54bb30-3972-4345-92d9-83cb0a3b1d13

5 WARNINGS AND PRECAUTIONS Hepatic Injury: Monitor liver function tests and signs and symptoms of hepatic injury; consider discontinuing EXTAVIA if serious hepatic injury occurs. ( 5.1 , 5.11 ) Anaphylaxis and Other Allergic Reactions: Discontinue if anaphylaxis occurs. ( 5.2 ) Depression and Suicide: Advise patients to immediately report any symptom of depression and/or suicidal ideation; consider discontinuation of EXTAVIA if depression occurs. ( 5.3 ) Congestive Heart Failure (CHF): Monitor patients with CHF for worsening of cardiac symptoms; consider discontinuation of EXTAVIA if worsening of CHF occurs. ( 5.4 ) Injection Site Reactions Including Necrosis: Do not administer EXTAVIA into affected area until fully healed; if multiple lesions occur, change injection site or discontinue EXTAVIA until healing of skin lesions. ( 5.5 ) Leukopenia: Monitor complete blood count. ( 5.6 , 5.12 ) Thrombotic Microangiopathy (TMA): Cases of TMA have been reported. Discontinue EXTAVIA if clinical symptoms and laboratory findings consistent with TMA occur and a relationship to EXTAVIA is suspected. ( 5.7 ) Pulmonary Arterial Hypertension: Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including EXTAVIA. Discontinue EXTAVIA if PAH is diagnosed. ( 5.8 ) Flu-like Symptom Complex: Consider analgesics and/or antipyretics on injection days. ( 5.9 ) Drug-induced Lupus Erythematosus: Cases of drug-induced lupus erythematosus have been reported. Discontinue EXTAVIA if patients develop new characteristic signs and symptoms. ( 5.11 ) 5.1 Hepatic Injury Severe hepatic injury, including cases of hepatic failure, some of which have been due to autoimmune hepatitis, has been rarely reported in patients taking EXTAVIA. In some cases, these events have occurred in the presence of other drugs or comorbid medical conditions that have been associated with hepatic injury. Consider the potential risk of EXTAVIA used in combination with known hepatotoxic drugs or other products (e.g., alcohol) prior to EXTAVIA administration, or when adding new agents to the regimen of patients already on EXTAVIA. Monitor patients for signs and symptoms of hepatic injury. Consider discontinuing EXTAVIA if serum transaminase levels significantly increase, or if they are associated with clinical symptoms, such as jaundice. Asymptomatic elevation of serum transaminases is common in patients treated with EXTAVIA. In controlled clinical trials, elevations of serum glutamic-pyruvic transaminase (SGPT) to greater than five times baseline value were reported in 12% of patients receiving interferon beta-1b (compared to 4% on placebo), and increases of serum glutamic-oxaloacetic transaminase (SGOT) to greater than five times baseline value were reported in 4% of patients receiving interferon beta-1b (compared to 1% on placebo), leading to dose-reduction or discontinuation of treatment in some patients [see Adverse Reactions (6.1)] . Monitor liver function tests [see Warnings and Precautions (5.11)] . 5.2 Anaphylaxis and Other Allergic Reactions Anaphylaxis has been reported as a rare complication of interferon beta-1b use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash, and urticaria [see Adverse Reactions (6.1)] . Discontinue EXTAVIA if anaphylaxis occurs. The removable rubber cap of the diluent (0.54% sodium chloride solution, USP) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals. The safe use of EXTAVIA pre-filled syringe in latex-sensitive individuals has not been studied. 5.3 Depression and Suicide Depression and suicide have been reported to occur with increased frequency in patients receiving interferon beta products, including interferon beta-1b. Advise patients to report any symptom of depression and/or suicidal ideation to their healthcare provider. If a patient develops depression, discontinuation of EXTAVIA therapy should be considered. In randomized controlled clinical trials, there were three suicides and eight suicide attempts among the 1532 patients on interferon beta-1b compared to one suicide and four suicide attempts among 965 patients on placebo. 5.4 Congestive Heart Failure Monitor patients with preexisting congestive heart failure (CHF) for worsening of their cardiac condition during initiation of and continued treatment with EXTAVIA. While beta interferons do not have any known direct-acting cardiac toxicity, cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients without known predisposition to these events, and without other known etiologies being established. In some cases, these events have been temporally related to the administration of interferon beta-1b. Recurrence upon rechallenge was observed in some patients. Consider discontinuation of EXTAVIA if worsening of CHF occurs with no other etiology. 5.5 Injection Site Reactions Including Necrosis Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including EXTAVIA. Injection site necrosis (ISN) was reported in 4% of interferon beta-1b-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions (6.1)] . Typically, ISN occurs within the first four months of therapy, although postmarketing reports have been received of ISN occurring over one year after initiation of therapy. The necrotic lesions are typically 3 cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat, but has extended to the fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions, debridement, and/or skin grafting have been required. In most cases, healing was associated with scarring. In controlled clinical trials, injection site reactions occurred in 78% of patients receiving interferon beta-1b with injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%), and nonspecific reactions were significantly associated with interferon beta-1b treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies. Injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including EXTAVIA. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating injection sites with each dose. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with EXTAVIA after injection site necrosis has occurred, avoid administration of EXTAVIA into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs. 5.6 Leukopenia In controlled clinical trials, leukopenia was reported in 18% of patients receiving interferon beta-1b (compared to 6% on placebo), leading to a reduction of the dose of interferon beta-1b in some patients [see Adverse Reactions (6.1)] . Monitoring of complete blood and differential white blood cell counts is recommended. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. 5.7 Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including EXTAVIA. Cases have been reported several weeks to years after starting interferon beta products. If clinical symptoms and laboratory findings consistent with TMA occur and a relationship to EXTAVIA is suspected, discontinue treatment and manage as clinically indicated. 5.8 Pulmonary Arterial Hypertension Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including EXTAVIA. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment. Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated. 5.9 Flu-like Symptom Complex In controlled clinical trials, the rate of flu-like symptom complex for patients on interferon beta-1b was 57% [see Adverse Reactions (6.1)] . The incidence decreased over time, with 10% of patients reporting flu-like symptom complex at the end of the studies. The median duration of flu-like symptom complex in Study 1 was 7.5 days [see Clinical Studies (14)] . Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with EXTAVIA use. 5.10 Seizures Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing safety surveillance. It is not known whether these events were related to a primary seizure disorder, the effects of MS alone, the use of beta interferons, other potential precipitants of seizures (e.g., fever), or to some combination of these. 5.11 Drug-induced Lupus Erythematosus Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including EXTAVIA. Signs and symptoms of drug-induced lupus reported in EXTAVIA-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded DNA antibody testing). If EXTAVIA-treated patients develop new signs and symptoms characteristic of this syndrome, EXTAVIA therapy should be stopped. 5.12 Monitoring for Laboratory Abnormalities In addition to those laboratory tests normally required for monitoring patients with MS, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of EXTAVIA therapy, and then periodically thereafter in the absence of clinical symptoms.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more details in other sections of labeling: Hepatic Injury [see Warnings and Precautions (5.1)] Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.2)] Depression and Suicide [see Warnings and Precautions (5.3)] Congestive Heart Failure [see Warnings and Precautions (5.4)] Injection Site Reactions Including Necrosis [see Warnings and Precautions (5.5)] Leukopenia [see Warnings and Precautions (5.6)] Thrombotic Microangiopathy [see Warnings and Precautions (5.7)] Pulmonary Arterial Hypertension [see Warnings and Precautions (5.8)] Flu-like Symptom Complex [see Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Drug-induced Lupus Erythematosus [see Warnings and Precautions (5.11)] In controlled clinical trials, the most common adverse reactions (at least 5% more frequent on interferon beta-1b than on placebo) were: injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 and over varying lengths of time, adverse reaction rates observed in the clinical trials of interferon beta-1b cannot be directly compared to rates in clinical trials of other drugs, and may not reflect the rates observed in practice. Among 1407 patients with MS treated with interferon beta-1b 0.25 mg every other day (including 1261 patients treated for greater than one year), the most commonly reported adverse reactions (at least 5% more frequent on interferon beta-1b than on placebo) were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of interferon beta-1b, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction symptom) were depression, flu-like symptom complex, injection site reactions, leukopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia. Table 2 enumerates adverse reactions and laboratory abnormalities that occurred among patients treated with 0.25 mg of interferon beta-1b every other day by subcutaneous injection in the pooled placebo-controlled trials (Studies 1-4) at an incidence that was at least 2% more than that observed in the placebo-treated patients [see Clinical Studies (14)] . Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4 Abbreviations: SGPT, serum glutamic-pyruvic transaminase; SGOT, serum glutamic-oxaloacetic transaminase. a "Injection site reaction" comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy. b "Flu-like symptom (complex)" denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. Adverse Reaction Placebo (N = 965) Interferon beta-1b (N = 1407) Blood and lymphatic system disorders Lymphocytes count decreased (< 1500/mm 3 ) 66% 86% Absolute neutrophil count decreased (< 1500/mm 3 ) 5% 13% White blood cell count decreased (< 3000/mm 3 ) 4% 13% Lymphadenopathy 3% 6% Nervous system disorders Headache 43% 50% Insomnia 16% 21% Incoordination 15% 17% Vascular disorders Hypertension 4% 6% Respiratory, thoracic, and mediastinal disorders Dyspnea 3% 6% Gastrointestinal disorders Abdominal pain 11% 16% Hepatobiliary disorders Alanine aminotransferase increased (SGPT > 5 times baseline) 4% 12% Aspartate aminotransferase increased (SGOT > 5 times baseline) 1% 4% Skin and subcutaneous tissue disorders Rash 15% 21% Skin disorder 8% 10% Musculoskeletal and connective tissue disorders Hypertonia 33% 40% Myalgia 14% 23% Renal and urinary disorders Urinary urgency 8% 11% Reproductive system and breast disorders Metrorrhagia 7% 9% Impotence 6% 8% General disorders and administration-site conditions Injection site reaction a 26% 78% Asthenia 48% 53% Flu-like symptoms (complex) b 37% 57% Pain 35% 42% Fever 19% 31% Chills 9% 21% Peripheral edema 10% 12% Chest pain 6% 9% Malaise 3% 6% Injection site necrosis 0% 4% In addition to the adverse reactions listed in Table 2, the following adverse reactions occurred more frequently on interferon beta-1b than on placebo, but with a difference smaller than 2%: alopecia, anxiety, arthralgia, constipation, diarrhea, dizziness, dyspepsia, dysmenorrhea, leg cramps, menorrhagia, myasthenia, nausea, nervousness, palpitations, peripheral vascular disorder, prostatic disorder, tachycardia, urinary frequency, vasodilatation, and weight increase. Laboratory Abnormalities In the four clinical trials (Studies 1, 2, 3, and 4), leukopenia was reported in 18% and 6% of patients in interferon beta-1b- and placebo-treated groups, respectively. No patients were withdrawn or dose-reduced for neutropenia in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose-reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of interferon beta-1b patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1 to 4, nine (0.6%) patients were withdrawn from treatment with interferon beta-1b for any laboratory abnormality, including four (0.3%) patients following dose reduction. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples were monitored for the development of antibodies to interferon beta-1b during Study 1. In patients receiving 0.25 mg every other day, 56/124 (45%) were found to have serum neutralizing activity at one or more of the time points tested. In Study 4, neutralizing activity was measured every 6 months and at end of study. At individual visits after start of therapy, activity was observed in 17% up to 25% of the interferon beta-1b-treated patients. Such neutralizing activity was measured at least once in 75 (30%) out of 251 interferon beta-1b patients who provided samples during treatment phase; of these, 17 (23%) converted to negative status later in the study. Based on all the available evidence, the relationship between antibody formation and clinical safety or efficacy is not known. These data reflect the percentage of patients whose test results were considered positive for antibodies to interferon beta-1b using a biological neutralization assay that measures the ability of immune sera to inhibit the production of the interferon-inducible protein, MxA. Neutralization assays are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to interferon beta-1b with the incidence of antibodies to other products may be misleading. Anaphylactic reactions have been reported with the use of interferon beta-1b [see Warnings and Precautions (5.2)]. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of interferon beta-1b. 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. Blood and lymphatic system disorders: Anemia, Thrombocytopenia, Hemolytic anemia Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase Psychiatric disorders: Anxiety, Confusion, Emotional lability Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia Vascular disorders: Vasodilatation Respiratory, thoracic, and mediastinal disorders: Bronchospasm, Pulmonary Arterial Hypertension Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting Hepatobiliary disorders: Hepatitis, Gamma GT increased Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria Musculoskeletal and connective tissue disorders: Arthralgia, Drug-induced lupus erythematosus Reproductive system and breast disorder: Menorrhagia General disorders and administration site conditions: Fatal capillary leak syndrome* *The administration of cytokines to patients with a preexisting monoclonal gammopathy has been associated with the development of this syndrome.

<table><caption>Table 2: Adverse Reactions and Laboratory Abnormalities in Patients with MS in Pooled Studies 1, 2, 3, and 4</caption><col width="200"/><col width="125"/><col width="175"/><tfoot><tr><td styleCode="Toprule " colspan="3">Abbreviations: SGPT, serum glutamic-pyruvic transaminase; SGOT, serum glutamic-oxaloacetic transaminase. ^a&quot;Injection site reaction&quot; comprises all adverse reactions occurring at the injection site (except injection site necrosis), that is, the following terms: injection site reaction, injection site hemorrhage, injection site hypersensitivity, injection site inflammation, injection site mass, injection site pain, injection site edema and injection site atrophy. ^b&quot;Flu-like symptom (complex)&quot; denotes flu syndrome and/or a combination of at least two adverse reactions from fever, chills, myalgia, malaise, sweating. </td></tr></tfoot><tbody><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Placebo</content> (N = 965)</td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Interferon beta-1b</content> (N = 1407)</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Lymphocytes count decreased (&lt; 1500/mm³) </td><td styleCode="Toprule Lrule Rrule " align="center">66%</td><td styleCode="Toprule Lrule Rrule " align="center">86%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Absolute neutrophil count decreased (&lt; 1500/mm³) </td><td styleCode="Toprule Lrule Rrule " align="center">5%</td><td styleCode="Toprule Lrule Rrule " align="center">13%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">White blood cell count decreased (&lt; 3000/mm³) </td><td styleCode="Toprule Lrule Rrule " align="center">4%</td><td styleCode="Toprule Lrule Rrule " align="center">13%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Lymphadenopathy </td><td styleCode="Toprule Lrule Rrule " align="center">3%</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Headache</td><td styleCode="Toprule Lrule Rrule " align="center">43%</td><td styleCode="Toprule Lrule Rrule " align="center">50%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Insomnia</td><td styleCode="Toprule Lrule Rrule " align="center">16%</td><td styleCode="Toprule Lrule Rrule " align="center">21%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Incoordination</td><td styleCode="Toprule Lrule Rrule " align="center">15%</td><td styleCode="Toprule Lrule Rrule " align="center">17%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Vascular disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Hypertension</td><td styleCode="Toprule Lrule Rrule " align="center">4%</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Respiratory, thoracic, and mediastinal disorders </content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Dyspnea</td><td styleCode="Toprule Lrule Rrule " align="center">3%</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Abdominal pain</td><td styleCode="Toprule Lrule Rrule " align="center">11%</td><td styleCode="Toprule Lrule Rrule " align="center">16%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Hepatobiliary disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Alanine aminotransferase increased (SGPT &gt; 5 times baseline) </td><td styleCode="Toprule Lrule Rrule " align="center">4%</td><td styleCode="Toprule Lrule Rrule " align="center">12%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Aspartate aminotransferase increased (SGOT &gt; 5 times baseline) </td><td styleCode="Toprule Lrule Rrule " align="center">1%</td><td styleCode="Toprule Lrule Rrule " align="center">4%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Rash</td><td styleCode="Toprule Lrule Rrule " align="center">15%</td><td styleCode="Toprule Lrule Rrule " align="center">21%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Skin disorder</td><td styleCode="Toprule Lrule Rrule " align="center">8%</td><td styleCode="Toprule Rrule" align="center">10%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Hypertonia</td><td styleCode="Toprule Lrule Rrule " align="center">33%</td><td styleCode="Toprule Lrule Rrule " align="center">40%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Myalgia</td><td styleCode="Toprule Lrule Rrule " align="center">14%</td><td styleCode="Toprule Lrule Rrule " align="center">23%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Renal and urinary disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Urinary urgency</td><td styleCode="Toprule Lrule Rrule " align="center">8%</td><td styleCode="Toprule Rrule" align="center">11%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Reproductive system and breast disorders</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Metrorrhagia</td><td styleCode="Toprule Lrule Rrule " align="center">7%</td><td styleCode="Toprule Lrule Rrule " align="center">9%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Impotence</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td><td styleCode="Toprule Lrule Rrule " align="center">8%</td></tr><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">General disorders and administration-site conditions</content></td><td styleCode="Toprule Lrule Rrule " align="center"/><td styleCode="Toprule Lrule Rrule " align="center"/></tr><tr><td styleCode="Toprule Lrule Rrule ">Injection site reaction^a</td><td styleCode="Toprule Lrule Rrule " align="center">26%</td><td styleCode="Toprule Lrule Rrule " align="center">78%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Asthenia</td><td styleCode="Toprule Lrule Rrule " align="center">48%</td><td styleCode="Toprule Lrule Rrule " align="center">53%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Flu-like symptoms (complex)^b</td><td styleCode="Toprule Lrule Rrule " align="center">37%</td><td styleCode="Toprule Lrule Rrule " align="center">57%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Pain</td><td styleCode="Toprule Lrule Rrule " align="center">35%</td><td styleCode="Toprule Lrule Rrule " align="center">42%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Fever</td><td styleCode="Toprule Lrule Rrule " align="center">19%</td><td styleCode="Toprule Lrule Rrule " align="center">31%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Chills</td><td styleCode="Toprule Lrule Rrule " align="center">9%</td><td styleCode="Toprule Lrule Rrule " align="center">21%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Peripheral edema</td><td styleCode="Toprule Lrule Rrule " align="center">10%</td><td styleCode="Toprule Lrule Rrule " align="center">12%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Chest pain</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td><td styleCode="Toprule Lrule Rrule " align="center">9%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Malaise</td><td styleCode="Toprule Lrule Rrule " align="center">3%</td><td styleCode="Toprule Lrule Rrule " align="center">6%</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Injection site necrosis</td><td styleCode="Toprule Lrule Rrule " align="center">0%</td><td styleCode="Toprule Lrule Rrule " align="center">4%</td></tr></tbody></table>