Omnitrope

5 WARNINGS AND PRECAUTIONS • Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk ( 5.1 ) • Prader-Willi Syndrome in children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment. Discontinue treatment if these signs occur ( 5.2 ) • Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin - in particular meningiomas in patients treated with radiation to the head for their first neoplasm ( 5.3 ) • Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment ( 5.4 ) • Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction ( 5.5 ) • Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention ( 5.6 ) • Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome - especially in adults): May occur frequently. Reduce dose as necessary ( 5.7 ) • Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism ( 5.8 ) • Hypothyroidism: May first become evident or worsen ( 5.9 ) • Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the onset of a limp or hip/knee pain ( 5.10 ) • Progression of Preexisting Scoliosis: May develop ( 5.11 ) • Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain (5.15) 5.1 Acute Critical Illness Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications ( 4 )] . Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk. 5.2 Prader-Willi Syndrome in Children There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi Syndrome should be evaluated for signs of upper airway obstruction (including onset of or increased snoring) and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi Syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications ( 4 )] . 5.3 Neoplasms In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications ( 4 )] . Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor [see Contraindications ( 4 )] . Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. 5.4 Impaired Glucose Tolerance and Diabetes Mellitus Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner Syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients [see Drug Interactions ( 7.5 )]. 5.5 Intracranial Hypertension (IH) Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropins. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by fundoscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner Syndrome and Prader-Willi Syndrome may be at increased risk for the development of IH. 5.6 Hypersensitivity Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications ( 4 )]. 5.7 Fluid Retention Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) are usually transient and dose dependent. 5.8 Hypoadrenalism Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see Drug Interactions ( 7.1 )]. 5.9 Hypothyroidism Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner Syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism and should have their thyroid function checked prior to initiation of somatropin therapy. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated. 5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner Syndrome) or in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during OMNITROPE therapy should be evaluated for slipped capital femoral epiphysis and osteonecrosis and managed accordingly. 5.11 Progression of Preexisting Scoliosis in Pediatric Patients Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner Syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi Syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy . 5.12 Otitis Media and Cardiovascular Disorders in Turner Syndrome Patients with Turner Syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner Syndrome. In addition, patients with Turner Syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions. 5.13 Lipoatrophy When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration ( 2.3 )] . 5.14 Laboratory Tests Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-1 may increase after somatropin therapy. 5.15 Pancreatitis Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner Syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin treated patient, especially a child, who develops persistent severe abdominal pain. 5.16 Benzyl Alcohol Benzyl alcohol, a component of OMNITROPE Cartridge 5 mg/1.5 mL and the diluent for OMNITROPE for injection 5.8 mg/vial, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

6 ADVERSE REACTIONS Other common somatropin-related adverse reactions include injection site reactions/rashes and lipoatrophy ( 6.1 ) and headaches ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch The following important adverse reactions are also described elsewhere in labeling: • Increased mortality in patients with acute critical illness [see Warnings and Precautions ( 5.1 )] • Fatalities in children with Prader-Willi Syndrome [see Warnings and Precautions ( 5.2 )] • Neoplasms [see Warnings and Precautions ( 5.3 )] • Glucose intolerance and diabetes mellitus [see Warnings and Precautions ( 5.4 )] • Intracranial hypertension [see Warnings and Precautions ( 5.5 )] • Severe hypersensitivity [see Warnings and Precautions ( 5.6 )] • Fluid retention [see Warnings and Precautions ( 5.7 )] • Hypoadrenalism [see Warnings and Precautions ( 5.8 )] • Hypothyroidism [see Warnings and Precautions ( 5.9 )] • Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions ( 5.10 )] • Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions ( 5.11 )] • Otitis media and cardiovascular disorders in patients with Turner Syndrome [see Warnings and Precautions ( 5.12 )] • Lipoatrophy [see Warnings and Precautions ( 5.13 )] • Pancreatitis [see Warnings and Precautions ( 5.15 )] • Benzyl Alcohol [see Warnings and Precautions ( 5.16 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice. Clinical Trials in Pediatric GHD Patients The following events were observed during clinical studies with OMNITROPE Cartridge conducted in children with GHD: Table 1. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE Cartridge (N=86) Adverse Event n (%) N=number of patients receiving treatment n=number of patients who reported the event during study period %=percentage of patients who reported the event during study period Elevated HbA1c 12 (14%) Eosinophilia 10 (12%) Hematoma 8 (9%) The following events were observed during clinical studies with OMNITROPE for injection conducted in children with GHD: Table 2. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE for Injection (N=44) Adverse Event n (%) N=number of patients receiving treatment n=number of patients who reported the event during study period %= percentage of patients who reported the event during study period Hypothyroidism 7 (16%) Eosinophilia 5 (11%) Elevated HbA1c 4 (9%) Hematoma 4 (9%) Headache 3 (7%) Hypertriglyceridemia 2 (5%) Leg Pain 2 (5%) Clinical Trials in PWS In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia. Clinical Trials in Children with SGA In clinical studies of 273 pediatric patients born small for gestational age treated with another somatropin product, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Clinical Trials in Children with Idiopathic Short Stature In two open-label clinical studies conducted with another somatropin product in pediatric patients with ISS, the most commonly encountered adverse events were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies during treatment with this other somatropin product, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0.23 and the 0.47 mg/kg/week groups respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD. Clinical Trials in Children with Turner Syndrome In two clinical studies with another somatropin product in pediatric patients with Turner Syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain. Clinical Trials in Adults with GHD In clinical trials with another somatropin product in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction. Table 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with another somatropin product. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials. Table 3. Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment Double Blind Phase Open Label Phase Another Somatropin Product Adverse Event Placebo 0–6 mo. (n = 572) % Patients Another Somatropin Product 0–6 mo. (n = 573) % Patients 6–12 mo. (n = 504) % Patients 12–18 mo. (n = 63) % Patients 18–24 mo. (n = 60) % Patients n=number of patients receiving treatment during the indicated period %=percentage of patients who reported the event during the indicated period Swelling, peripheral 5.1 17.5 Increased significantly when compared to placebo, P ≤ .025: Fisher’s Exact Test (one-sided) 5.6 0 1.7 Arthralgia 4.2 17.3 6.9 6.3 3.3 Upper respiratory infection 14.5 15.5 13.1 15.9 13.3 Pain, extremities 5.9 14.7 6.7 1.6 3.3 Edema, peripheral 2.6 10.8 3.0 0 0 Paresthesia 1.9 9.6 2.2 3.2 0 Headache 7.7 9.9 6.2 0 0 Stiffness of extremities 1.6 7.9 2.4 1.6 0 Fatigue 3.8 5.8 4.6 6.3 1.7 Myalgia 1.6 4.9 2.0 4.8 6.7 Back pain 4.4 2.8 3.4 4.8 5.0 Post-Trial Extension Studies in Adults In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with another somatropin product. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving this other somatropin product. Of the 3,031 patients receiving this other somatropin product, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of somatropin or OMNITROPE. Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse events reported during postmarketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins [see Warnings and Precautions ( 5.6 )]. Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] . The following additional adverse reactions have been observed during the use of somatropin: headaches (children and adults), gynecomastia (children), osteonecrosis (children), and pancreatitis (children and adults) [see Warnings and Precautions ( 5.16 )] . New-onset type 2 diabetes mellitus has been reported.

<table ID="_RefID7D038DDF1E2E470A96892B2E38CF16CB" styleCode="Noautorules" width="100%"><caption>Table 1. Incidence of Adverse Reactions Reported in &#x2265; 5% Pediatric Patients with GHD During Treatment with OMNITROPE Cartridge (N=86)</caption><col width="50%"/><col width="50%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Event</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">n (%)</content></th></tr></thead><tfoot><tr><td align="left" colspan="2" valign="top">N=number of patients receiving treatment n=number of patients who reported the event during study period %=percentage of patients who reported the event during study period</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Elevated HbA1c</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12 (14%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Eosinophilia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 (12%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Hematoma</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>8 (9%)</paragraph></td></tr></tbody></table>

<table ID="_RefID285B626BA6B34D0483C200D72542F4AE" styleCode="Noautorules" width="100%"><caption>Table 2. Incidence of Adverse Reactions Reported in &#x2265; 5% Pediatric Patients with GHD During Treatment with OMNITROPE for Injection (N=44)</caption><col width="50%"/><col width="50%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Event</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">n (%)</content></th></tr></thead><tfoot><tr><td align="left" colspan="2" valign="top">N=number of patients receiving treatment n=number of patients who reported the event during study period %= percentage of patients who reported the event during study period</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypothyroidism</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7 (16%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Eosinophilia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 (11%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Elevated HbA1c</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 (9%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hematoma</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 (9%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (7%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertriglyceridemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2 (5%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Leg Pain</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2 (5%)</paragraph></td></tr></tbody></table>

<table ID="_RefID6D742D84D08440F5BEFEB3E07288D834" styleCode="Noautorules" width="100%"><caption>Table 3. Adverse Events Reported by &#x2265; 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment</caption><col width="23%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold"> Double Blind Phase</content></th><th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Open Label Phase</content> <content styleCode="bold">Another Somatropin Product</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold"> Adverse Event</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">0&#x2013;6 mo.</content> <content styleCode="bold">(n = 572)</content> <content styleCode="bold">% Patients</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><content styleCode="bold">Another</content> <content styleCode="bold">Somatropin</content> <content styleCode="bold">Product</content> <content styleCode="bold">0&#x2013;6 mo.</content> <content styleCode="bold">(n = 573)</content> <content styleCode="bold">% Patients</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">6&#x2013;12 mo.</content> <content styleCode="bold">(n = 504)</content> <content styleCode="bold">% Patients</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">12&#x2013;18 mo.</content> <content styleCode="bold">(n = 63)</content> <content styleCode="bold">% Patients</content></th><th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"> <content styleCode="bold">18&#x2013;24 mo.</content> <content styleCode="bold">(n = 60)</content> <content styleCode="bold">% Patients</content></th></tr></thead><tfoot><tr><td align="left" colspan="6" valign="top">n=number of patients receiving treatment during the indicated period %=percentage of patients who reported the event during the indicated period</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Swelling, peripheral</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17.5<footnote ID="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622">Increased significantly when compared to placebo, <content styleCode="italics">P </content>&#x2264; .025: Fisher&#x2019;s Exact Test (one-sided)</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Arthralgia</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17.3<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Upper respiratory infection</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pain, extremities</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.7<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Edema, peripheral</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10.8<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Paresthesia</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9.6<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Headache</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Stiffness of extremities</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.9<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Fatigue</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Myalgia</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.9<footnoteRef IDREF="_RefIDDB36D769FD51449B8A1FFAA6C2D4C622"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.7</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Back pain</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>4.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.8</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5.0</paragraph></td></tr></tbody></table>