SOLIRIS

1 INDICATIONS AND USAGE SOLIRIS is a complement inhibitor indicated for: the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. ( 1.1 ) the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. ( 1.2 ) Limitation of Use SOLIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients six years of age and older who are anti-acetylcholine receptor (AChR) antibody positive. ( 1.3 ) the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ( 1.4 ) 1.1 Paroxysmal Nocturnal Hemoglobinuria (PNH) SOLIRIS is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. 1.2 Atypical Hemolytic Uremic Syndrome (aHUS) SOLIRIS is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of Use SOLIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). 1.3 Generalized Myasthenia Gravis (gMG) SOLIRIS is indicated for the treatment of generalized myasthenia gravis (gMG) in adult and pediatric patients six years of age and older who are anti-acetylcholine receptor (AChR) antibody positive. 1.4 Neuromyelitis Optica Spectrum Disorder (NMOSD) SOLIRIS is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

2 DOSAGE AND ADMINISTRATION For intravenous infusion only; recommended dosage for: PNH: ( 2.2 ) aHUS, gMG, and NMOSD in adults: ( 2.3 ) aHUS and gMG in pediatric patients: ( 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Vaccinate patients against meningococcal infection (serogroups A, C, W, Y and B) according to current ACIP recommendations at least 2 weeks prior to initiation of SOLIRIS [see Warnings and Precautions (5.1) ] . If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Healthcare providers who prescribe SOLIRIS must enroll in the ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2) ] . 2.2 Recommended Dosage for Adults – PNH The recommended dosage of SOLIRIS for the treatment of PNH in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Administer SOLIRIS at the recommended dosage regimen time points, or within two days of these time points [see Warnings and Precautions (5.4) ] . 2.3 Recommended Dosage for Adults – aHUS, gMG, and NMOSD The recommended dosage of SOLIRIS for the treatment of aHUS, gMG, or NMOSD in patients 18 years of age and older is administered as an intravenous infusion [see Dosage and Administration (2.7) ] as follows: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, then 1200 mg every 2 weeks thereafter. 2.4 Recommended Dosage for Pediatric Patients – aHUS and gMG The recommended dosage of SOLIRIS for the treatment of aHUS in pediatric patients less than 18 years of age or gMG in pediatric patients 6 years of age and older is administered as an intravenous infusion based upon body weight, according to the following schedule (Table 1): Table 1: Dosing Recommendations in Pediatric Patients Less Than 18 Years of Age with aHUS and Pediatric Patients 6 Years of Age and Older with gMG Patient Body Weight Induction Maintenance 40 kg and over 900 mg weekly for the first 4 weeks 1200 mg at week 5; then 1200 mg every 2 weeks 30 kg to less than 40 kg 600 mg for the first 2 weeks 900 mg at week 3; then 900 mg every 2 weeks 20 kg to less than 30 kg 600 mg for the first 2 weeks 600 mg at week 3; then 600 mg every 2 weeks 10 kg to less than 20 kg 600 mg single dose at Week 1 300 mg at week 2; then 300 mg every 2 weeks 5 kg to less than 10 kg 300 mg single dose at Week 1 300 mg at week 2; then 300 mg every 3 weeks Administer SOLIRIS at the recommended dosage regimen time points, or within two days of these time points. 2.5 Dose Adjustment in Case of Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg For adult and pediatric patients with aHUS or gMG, and adult patients with NMOSD, supplemental dosing of SOLIRIS is required in the setting of concomitant plasmapheresis or plasma exchange, or fresh frozen plasma infusion (PE/PI) (Table 2). Table 2: Supplemental Dose of SOLIRIS after Plasmapheresis/PE/PI Type of Plasma Intervention Most Recent SOLIRIS Dose Supplemental SOLIRIS Dose with Each Plasma Intervention Timing of Supplemental SOLIRIS Dose Plasmapheresis or plasma exchange 300 mg 300 mg per each plasmapheresis or plasma exchange session Within 60 minutes after each plasmapheresis or plasma exchange ≥600 mg 600 mg per each plasmapheresis or plasma exchange session Fresh frozen plasma infusion ≥300 mg 300 mg per infusion of fresh frozen plasma 60 minutes prior to each infusion of fresh frozen plasma For patients with gMG, a supplemental dose of SOLIRIS is required in the setting of concomitant use of intravenous immunoglobulin (IVIg) treatment as described in Table 3. Table 3: Supplemental Dose of SOLIRIS with concomitant IVIg IVIg Frequency Most Recent SOLIRIS Dose Supplemental Soliris Dose per IVIg Cycle Timing of Supplemental SOLIRIS Dose Acute rescue therapy No supplemental SOLIRIS dose needed Equal to or more frequent than every 4 weeks 900 mg or more 600 mg At the same time as scheduled SOLIRIS dose 600 mg or less 300 mg Less frequent than every 4 weeks 900 mg or more 600 mg At the next scheduled SOLIRIS dose after the last IVIg cycle 600 mg or less 300 mg 2.6 Preparation Dilute SOLIRIS to a final admixture concentration of 5 mg/mL using the following steps: Withdraw the required amount of SOLIRIS from the vial into a sterile syringe. Transfer the recommended dose to an infusion bag. Dilute SOLIRIS to a final concentration of 5 mg/mL by adding the appropriate amount (equal volume of diluent to drug volume) of 0.9% Sodium Chloride Injection, USP; 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, USP; or Ringer's Injection, USP to the infusion bag. The final admixed SOLIRIS 5 mg/mL infusion volume is 60 mL for 300 mg doses, 120 mL for 600 mg doses, 180 mL for 900 mg doses or 240 mL for 1200 mg doses (Table 4). Table 4: Preparation and Reconstitution of SOLIRIS SOLIRIS Dose Diluent Volume Final Volume 300 mg 30 mL 60 mL 600 mg 60 mL 120 mL 900 mg 90 mL 180 mL 1200 mg 120 mL 240 mL Gently invert the infusion bag containing the diluted SOLIRIS solution to ensure thorough mixing of the product and diluent. Discard any unused portion left in a vial, as the product contains no preservatives. Prior to administration, the admixture should be allowed to adjust to room temperature [18°C to 25°C, 64°F to 77°F]. The admixture must not be heated in a microwave or with any heat source other than ambient air temperature. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 2.7 Administration Only administer as an intravenous infusion. Do not administer as an intravenous push or bolus injection. Administer the SOLIRIS admixture by intravenous infusion over 35 minutes in adults and 1 to 4 hours in pediatric patients via gravity feed, a syringe-type pump, or an infusion pump. Admixed solutions of SOLIRIS are stable for 24 h at 2°C to 8°C (36°F to 46°F) and at room temperature. If an adverse reaction occurs during the administration of SOLIRIS, the infusion may be slowed or stopped at the discretion of the physician. If the infusion is slowed, the total infusion time should not exceed two hours in adults. Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion-related reaction.

4 CONTRAINDICATIONS SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection. ( 4 )

5 WARNINGS AND PRECAUTIONS Use caution when administering SOLIRIS to patients with any other systemic infection. ( 5.3 ) Infusion-Related Reactions: Monitor patients during infusion, interrupt for reactions, and institute appropriate supportive measures. ( 5.6 ) 5.1 Serious Meningococcal Infections SOLIRIS, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of SOLIRIS treatment is contraindicated in patients with unresolved serious Neisseria meningitidis infection. Complete or update meningococcal vaccination (for serogroups A, C, W, Y and B) at least 2 weeks prior to administration of the first dose of SOLIRIS, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with SOLIRIS. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent SOLIRIS therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including SOLIRIS. The benefits and risks of treatment with SOLIRIS, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis . Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of SOLIRIS in patients who are undergoing treatment for serious meningococcal infection depending on the risks of interrupting treatment in the disease being treated. SOLIRIS is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 ULTOMIRIS and SOLIRIS REMS SOLIRIS is available only through a restricted program under a REMS called ULTOMIRIS and SOLIRIS REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1) ]. Notable requirements of the ULTOMIRIS and SOLIRIS REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious meningococcal infection. Prescribers must provide the patients with the REMS educational materials. Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of SOLIRIS. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of SOLIRIS. Healthcare settings and pharmacies that dispense SOLIRIS must be certified in the REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection. Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with SOLIRIS. Further information is available at www.UltSolREMS.com or 1-888-765-4747. 5.3 Other Infections Serious infections with Neisseria species (other than Neisseria meningitidis ), including disseminated gonococcal infections, have been reported. SOLIRIS blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria such as infections with Neisseria meningitidis but also Streptococcus pneumoniae , Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with SOLIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving SOLIRIS are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. 5.4 Monitoring Disease Manifestations after SOLIRIS Discontinuation Treatment Discontinuation for PNH Monitor patients after discontinuing SOLIRIS for at least 8 weeks to detect hemolysis. Treatment Discontinuation for aHUS After discontinuing SOLIRIS, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued SOLIRIS treatment. TMA complications occurred following a missed dose in 5 patients, and SOLIRIS was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during SOLIRIS treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during SOLIRIS treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during SOLIRIS treatment. If TMA complications occur after SOLIRIS discontinuation, consider reinstitution of SOLIRIS treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. 5.5 Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management. 5.6 Infusion-Related Reactions Administration of SOLIRIS may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of SOLIRIS. Interrupt SOLIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

7 DRUG INTERACTIONS 7.1 Plasmapheresis, Plasma Exchange, Fresh Frozen Plasma Infusion or IVIg Concomitant use of SOLIRIS with plasma exchange (PE), plasmapheresis (PP) , fresh frozen plasma infusion (PE/PI), or in patients with gMG on concomitant IVIg treatment can reduce serum eculizumab concentrations and requires a supplemental dose of SOLIRIS [see Dosage and Administration (2.5) ]. 7.2 Neonatal Fc Receptor Blockers Concomitant use of SOLIRIS with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of SOLIRIS. Closely monitor for reduced effectiveness of SOLIRIS.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Infections [see Warnings and Precautions (5.3) ] Monitoring Disease Manifestations after SOLIRIS Discontinuation [see Warnings and Precautions (5.4) ] Thrombosis Prevention and Management [see Warnings and Precautions (5.5) ] Infusion-Related Reactions [see Warnings and Precautions (5.6) ] The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea. ( 6.1 ) The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia. ( 6.1 ) The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) in adult patients is musculoskeletal pain. ( 6.1 ) The most frequently reported adverse reactions in the NMOSD placebo- controlled trial (≥10%) are: upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Meningococcal infections are the most important adverse reactions experienced by patients receiving SOLIRIS. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period [see Warnings and Precautions (5.1) ] . PNH The data described below reflect exposure to SOLIRIS in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. SOLIRIS was studied in a placebo-controlled clinical study (PNH Study 1, in which 43 patients received SOLIRIS and 44, placebo); a single arm clinical study (PNH Study 2); and a long term extension study (E05-001). 182 patients were exposed for greater than one year. All patients received the recommended SOLIRIS dose regimen. Table 5 summarizes the adverse reactions that occurred at a numerically higher rate in the SOLIRIS group than the placebo group and at a rate of 5% or more among patients treated with SOLIRIS. Table 5: Adverse Reactions Reported in 5% or More of SOLIRIS Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study Reaction SOLIRIS (N=43) N (%) Placebo (N=44) N (%) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving SOLIRIS and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving SOLIRIS experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with SOLIRIS in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). aHUS The safety of SOLIRIS therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (Studies C08-002A/B, C08-003A/B, and C10-004), one in pediatric and adolescent patients (Study C10-003), and one retrospective study (Study C09-001r). The data described below were derived from 78 adult and adolescent patients with aHUS in Studies C08-002A/B, C08-003A/B and C10-004. All patients received the recommended dosage of SOLIRIS. Median exposure was 67 weeks (range: 2-145 weeks). Table 6 summarizes all adverse events reported in at least 10% of patients in Studies C08-002A/B, C08-003A/B and C10-004 combined. Table 6: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004 Separately and in Total Number (%) of Patients C08-002A/B (N=17) C08-003A/B (N=20) C10-004 (N=41) Total (N=78) Vascular Disorders Hypertension includes the preferred terms hypertension, accelerated hypertension, and malignant hypertension. 10 (59) 9 (45) 7 (17) 26 (33) Hypotension 2 (12) 4 (20) 7 (17) 13 (17) Infections and Infestations Bronchitis 3 (18) 2 (10) 4 (10) 9 (12) Nasopharyngitis 3 (18) 11 (55) 7 (17) 21 (27) Gastroenteritis 3 (18) 4 (20) 2 (5) 9 (12) Upper respiratory tract infection 5 (29) 8 (40) 2 (5) 15 (19) Urinary tract infection 6 (35) 3 (15) 8 (20) 17 (22) Gastrointestinal Disorders Diarrhea 8 (47) 8 (40) 12 (32) 29 (37) Vomiting 8 (47) 9 (45) 6 (15) 23 (30) Nausea 5 (29) 8 (40) 5 (12) 18 (23) Abdominal pain 3 (18) 6 (30) 6 (15) 15 (19) Nervous System Disorders Headache 7 (41) 10 (50) 15 (37) 32 (41) Blood and Lymphatic System Disorders Anemia 6 (35) 7 (35) 7 (17) 20 (26) Leukopenia 4 (24) 3 (15) 5 (12) 12 (15) Psychiatric Disorders Insomnia 4 (24) 2 (10) 5 (12) 11 (14) Renal and Urinary Disorders Renal Impairment 5 (29) 3 (15) 6 (15) 14 (18) Proteinuria 2 (12) 1 (5) 5 (12) 8 (10) Respiratory, Thoracic and Mediastinal Disorders Cough 4 (24) 6 (30) 8 (20) 18 (23) General Disorders and Administration Site Conditions Fatigue 3 (18) 4 (20) 3 (7) 10 (13) Peripheral edema 5 (29) 4 (20) 9 (22) 18 (23) Pyrexia 4 (24) 5 (25) 7 (17) 16 (21) Asthenia 3 (18) 4 (20) 6 (15) 13 (17) Eye Disorder 5 (29) 2 (10) 8 (20) 15 (19) Metabolism and Nutrition Disorders Hypokalemia 3 (18) 2 (10) 4 (10) 9 (12) Neoplasms benign, malignant, and unspecified (including cysts and polyps) 1 (6) 6 (30) 1 (20) 8 (10) Skin and Subcutaneous Tissue Disorders Rash 2 (12) 3 (15) 6 (15) 11 (14) Pruritus 1 (6) 3 (15) 4 (10) 8 (10) Musculoskeletal and Connective Tissue Disorders Arthralgia 1 (6) 2 (10) 7 (17) 10 (13) Back pain 3 (18) 3 (15) 2 (5) 8 (10) In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued SOLIRIS due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningococcal meningitis. Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of SOLIRIS. Median exposure was 44 weeks (range: 1 dose-87 weeks). Table 7 summarizes all adverse events reported in at least 10% of patients enrolled in Study C10-003. Table 7: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in Study C10-003 1 month to <12 yrs (N=18) Total (N=22) Eye Disorders 3 (17) 3 (14) Gastrointestinal Disorders Abdominal pain 6 (33) 7 (32) Diarrhea 5 (28) 7 (32) Vomiting 4 (22) 6 (27) Dyspepsia 0 3 (14) General Disorders and Administration Site Conditions Pyrexia 9 (50) 11 (50) Infections and Infestations Upper respiratory tract infection 5 (28) 7 (32) Nasopharyngitis 3 (17) 6 (27) Rhinitis 4 (22) 4 (18) Urinary Tract infection 3 (17) 4 (18) Catheter site infection 3 (17) 3 (14) Musculoskeletal and Connective Tissue Disorders Muscle spasms 2 (11) 3 (14) Nervous System Disorders Headache 3 (17) 4 (18) Renal and Urinary Disorders 3 (17) 4 (18) Respiratory, Thoracic and Mediastinal Disorders Cough 7 (39) 8 (36) Oropharyngeal pain 1 (6) 3 (14) Skin and Subcutaneous Tissue Disorders Rash 4 (22) 4 (18) Vascular Disorders Hypertension 4 (22) 4 (18) In Study C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued SOLIRIS due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in Study C09-001r (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. Study C09-001r included 19 pediatric patients less than 18 years of age. Overall, the safety of SOLIRIS in pediatric patients with aHUS enrolled in Study C09-001r appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 8. Table 8: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r Number (%) of Patients < 2 yrs (N=5) 2 to < 12 yrs (N=10) 12 to <18 yrs (N=4) Total (N=19) General Disorders and Administration Site Conditions Pyrexia 4 (80) 4 (40) 1 (25) 9 (47) Gastrointestinal Disorders Diarrhea 1 (20) 4 (40) 1 (25) 6 (32) Vomiting 2 (40) 1 (10) 1 (25) 4 (21) Infections and Infestations Upper respiratory tract infection includes the preferred terms upper respiratory tract infection and nasopharyngitis. 2 (40) 3 (30) 1 (25) 6 (32) Respiratory, Thoracic and Mediastinal Disorders Cough 3 (60) 2 (20) 0 (0) 5 (26) Nasal congestion 2 (40) 2 (20) 0 (0) 4 (21) Cardiac Disorders Tachycardia 2 (40) 2 (20) 0 (0) 4 (21) Generalized Myasthenia Gravis (gMG) Adults In a 26-week placebo-controlled trial evaluating the effect of SOLIRIS for the treatment of adult patients with gMG (Study ECU-MG-301), 62 patients received SOLIRIS at the recommended dosage regimen and 63 patients received placebo [see Clinical Studies (14.3) ] . Patients were 19 to 79 years of age, and 66% were female. Table 9 displays the most common adverse reactions from gMG Study 1 that occurred in ≥5% of SOLIRIS-treated patients and at a greater frequency than on placebo. Table 9: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in Study ECU-MG-301 and at a Greater Frequency than in Placebo-Treated Patients SOLIRIS (N=62) N (%) Placebo (N=63) N (%) Gastrointestinal Disorders Abdominal pain 5 (8) 3 (5) General Disorders and Administration Site Conditions Peripheral edema 5 (8) 3 (5) Pyrexia 4 (7) 2 (3) Infections and Infestations Herpes simplex virus infections 5 (8) 1 (2) Injury, Poisoning, and Procedural Complications Contusion 5 (8) 2 (3) Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 (15) 5 (8) The most common adverse reactions (≥10%) that occurred in SOLIRIS-treated patients in the long-term extension to Study ECU-MG-301, Study ECU-MG-302, and that are not included in Table 9 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%). Pediatric Patients 6 Years of Age and Older In a 26-week, single arm study evaluating the safety of SOLIRIS in 11 pediatric patients with gMG 12 to 17 years of age (Study ECU-MG-303), adverse reactions were consistent with those observed in adult patients with gMG [see Use in Specific Populations (8.4) ]. The safety of SOLIRIS in pediatric patients 6 to less than 12 years of age is expected to be similar to that of adults and pediatric patients 12 years of age and older treated with SOLIRIS. Neuromyelitis Optica Spectrum Disorder (NMOSD) In a placebo-controlled trial evaluating the effect of SOLIRIS for the treatment of NMOSD (NMOSD Study 1), 96 patients received SOLIRIS at the recommended dosage regimen and 47 patients received placebo [see Clinical Studies (14.4) ] . Patients were 19 to 75 years of age (mean 44 years of age), and 91% were female. Table 10 displays the most common adverse reactions from NMOSD Study 1 that occurred in ≥5% of SOLIRIS-treated patients and at a greater frequency than on placebo. Table 10: Adverse Reactions Reported in 5% or More of SOLIRIS-Treated Patients in NMOSD Study 1 and at a Greater Frequency than in Placebo-Treated Patients SOLIRIS (N=96) N (%) Placebo (N=47) N (%) Events/Patients 1295/88 617/45 Blood and lymphatic system disorders Leukopenia 5 (5) 1 (2) Lymphopenia 5 (5) 0 (0) Eye disorders Cataract 6 (6) 2 (4) Gastrointestinal disorders Diarrhea 15 (16) 7 (15) Constipation 9 (9) 3 (6) General disorders and administration site conditions Asthenia 5 (5) 1 (2) Infections and infestations Upper respiratory tract infection 28 (29) 6 (13) Nasopharyngitis 20 (21) 9 (19) Influenza 11 (11) 2 (4) Pharyngitis 10 (10) 3 (6) Bronchitis 9 (9) 3 (6) Conjunctivitis 9 (9) 4 (9) Cystitis 8 (8) 1 (2) Hordeolum 7 (7) 0 (0) Sinusitis 6 (6) 0 (0) Cellulitis 5 (5) 1 (2) Injury, poisoning and procedural complications Contusion 10 (10) 2 (4) Metabolism and nutrition disorders Decreased appetite 5 (5) 1 (2) Musculoskeletal and connective tissue disorders Back pain 14 (15) 6 (13) Arthralgia 11 (11) 5 (11) Musculoskeletal pain 6 (6) 0 (0) Muscle spasms 5 (5) 2 (4) Nervous system disorders Dizziness 14 (15) 6 (13) Paraesthesia 8 (8) 3 (6) Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 7 (7) 2 (4) Skin and subcutaneous tissue disorders Alopecia 5 (5) 2 (4) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of SOLIRIS. 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 SOLIRIS exposure. Adverse Reactions from Postmarketing Spontaneous Reports Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified. Cases of cholestatic or mixed pattern liver injury with increased serum liver enzymes and bilirubin levels have been reported in adult and pediatric patients with aHUS who were treated with Soliris. These events occurred within 3 to 27 days after starting treatment. The median time to resolution (or return to baseline) was approximately 3 weeks.

8.1 Pregnancy Risk Summary Limited data on outcomes of pregnancies that have occurred following SOLIRIS use in pregnant women have not identified a concern for specific adverse developmental outcomes ( see Data ). There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) in pregnancy ( see Clinical Considerations ). Animal studies using a mouse analogue of the SOLIRIS molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or fetal/neonatal risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. aHUS in pregnancy is associated with adverse maternal outcomes, including pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight. Data Human Data A pooled analysis of prospectively (50.3%) and retrospectively (49.7%) collected data in more than 300 pregnant women with live births following exposure to SOLIRIS have not suggested safety concerns. However, these data cannot definitively exclude any drug-associated risk during pregnancy, because of the limited sample size. Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function.