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.

1.3 Generalized Myasthenia Gravis (gMG)

SOLIRIS is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients 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.

2.1 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 Regimen – PNH

For patients 18 years of age and older, SOLIRIS therapy consists of:

• 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 Regimen – aHUS

For patients 18 years of age and older, SOLIRIS therapy consists of:

• 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.

For patients less than 18 years of age, administer SOLIRIS based upon body weight, according to the following schedule (Table 1):

Administer SOLIRIS at the recommended dosage regimen time points, or within two days of these time points.

2.4 Recommended Dosage Regimen – gMG and NMOSD

For adult patients with generalized myasthenia gravis or neuromyelitis optica spectrum disorder, SOLIRIS therapy consists of:

• 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.

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, or Fresh Frozen Plasma Infusion

For adult and pediatric patients with aHUS, and adult patients with gMG or 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).

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 3).

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°-25° C, 64°-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°-8° C (36°-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.

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

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.

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)].

6.2 Immunogenicity

As with all proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to eculizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of SOLIRIS has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS, gMG, and NMOSD indications, as well as for additional patients with PNH. In the PNH population, antibodies to SOLIRIS were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay. In the aHUS population, antibodies to SOLIRIS were detected in 3/100 (3%) patients using the ECL assay. None of the 62 patients with gMG had antibodies to SOLIRIS detected following the 26-week active treatment. Two of the 96 (2%) SOLIRIS-treated patients with NMOSD had antibodies to SOLIRIS detected during the entire treatment period.

An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 5 patients with PNH, the 3 patients with aHUS, and the 2 patients with NMOSD with anti-eculizumab antibody positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%), and none of the 96 patients with NMOSD had low positive values for neutralizing antibodies.

No apparent correlation of antibody development to clinical response was observed.

6.3 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.

Fatal or serious infections: Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, Neisseria spp unspecified

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of SOLIRIS for the treatment of PNH, gMG, or NMOSD in pediatric patients have not been established.

The safety and effectiveness of SOLIRIS for the treatment of aHUS have been established in pediatric patients. Use of SOLIRIS in pediatric patients for this indication is supported by evidence from four adequate and well-controlled clinical studies assessing the safety and effectiveness of SOLIRIS for the treatment of aHUS. The studies included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of SOLIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)].

Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to ACIP guidelines [see Warnings and Precautions (5.1, 5.3)].

8.5 Geriatric Use

Fifty-one patients 65 years of age or older (15 with PNH, 4 with aHUS, 26 with gMG, and 6 with NMOSD) were treated with SOLIRIS in clinical trials in the approved indications. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.

12.1 Mechanism of Action

Eculizumab, the active ingredient in SOLIRIS, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9.

SOLIRIS inhibits terminal complement-mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

The precise mechanism by which eculizumab exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction.

The precise mechanism by which eculizumab exerts its therapeutic effect in NMOSD is unknown, but is presumed to involve inhibition of aquaporin-4-antibody induced terminal complement C5b-9 deposition.

12.2 Pharmacodynamics

In the placebo-controlled clinical study (PNH Study 1), SOLIRIS when administered as recommended reduced serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L) in patients with PNH. In the single arm clinical study (PNH Study 2), the effect was maintained through week 52 [see Clinical Studies (14)].

In patients with PNH, aHUS, gMG, and NMOSD, free C5 concentrations of < 0.5 mcg/mL was correlated with complete blockade of terminal complement activity.

12.3 Pharmacokinetics

Following intravenous maintenance doses of 900 mg once every 2 weeks in patients with PNH, the week 26 observed mean ± SD serum eculizumab maximum concentration (Cmax) was 194 ± 76 mcg/mL and the trough concentration (Ctrough) was 97 ± 60 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with aHUS, the week 26 observed mean ± SD Ctrough was 242 ± 101 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with gMG, the week 26 observed mean ± SD Cmax was 783 ± 288 mcg/mL and the Ctrough was 341 ± 172 mcg/mL. Following intravenous maintenance doses of 1200 mg once every 2 weeks in patients with NMOSD, at week 24, the observed mean±SD Cmax was 877±331 and the Ctrough was 429±188 mcg/mL.

Steady state was achieved 4 weeks after starting eculizumab treatment, with accumulation ratio of approximately 2-fold in all studied indications. Population pharmacokinetic analyses showed that eculizumab pharmacokinetics were dose-linear and time-independent over the 600 mg to 1200 mg dose range, with inter-individual variability of 21% to 38%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies of eculizumab have not been conducted.

Genotoxicity studies have not been conducted with eculizumab.

Effects of eculizumab upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of SOLIRIS had no adverse effects on mating or fertility.

14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)

The safety and efficacy of SOLIRIS in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (PNH Study 1, NCT00122330); PNH patients were also treated with SOLIRIS in a single arm 52 week study (PNH Study 2, NCT00122304) and in a long-term extension study (E05-001, NCT00122317). Patients received meningococcal vaccination prior to receipt of SOLIRIS. In all studies, the dose of SOLIRIS was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. SOLIRIS was administered as an intravenous infusion over 25 - 45 minutes.

14.2 Atypical Hemolytic Uremic Syndrome (aHUS)

Five single-arm studies [four prospective: C08-002A/B (NCT00844545 and NCT00844844), C08-003A/B (NCT00838513 and NCT00844428), C10-003 (NCT01193348), and C10-004 (NCT01194973); and one retrospective: C09-001r (NCT01770951)] evaluated the safety and efficacy of SOLIRIS for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of SOLIRIS or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of SOLIRIS in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in Study C09-001r and Study C10-003 was based on body weight [see Dosage and Administration (2.3)]. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints.

Endpoints related to TMA included the following:

• platelet count change from baseline
• hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks)
• complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks)
• TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement)
• Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day).

14.3 Generalized Myasthenia Gravis (gMG)

The efficacy of SOLIRIS for the treatment of gMG was established in gMG Study 1 (NCT01997229), a 26-week randomized, double-blind, parallel-group, placebo-controlled, multi-center trial that enrolled patients who met the following criteria at screening:

1. Positive serologic test for anti-AChR antibodies,
2. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV,
3. MG-Activities of Daily Living (MG-ADL) total score ≥6,
4. Failed treatment over 1 year or more with 2 or more immunosuppressive therapies (ISTs) either in combination or as monotherapy, or failed at least 1 IST and required chronic plasmapheresis or plasma exchange (PE) or intravenous immunoglobulin (IVIg).

A total of 62 patients were randomized to receive SOLIRIS treatment and 63 were randomized to receive placebo. Baseline characteristics were similar between treatment groups, including age at diagnosis (38 years in each group), gender [66% female (eculizumab) versus 65% female (placebo)], and duration of gMG [9.9 (eculizumab) versus 9.2 (placebo) years]. Over 95% of patients in each group were receiving acetylcholinesterase (AchE) inhibitors, and 98% were receiving immunosuppressant therapies (ISTs). Approximately 50% of each group had been previously treated with at least 3 ISTs.

SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

The primary efficacy endpoint for gMG Study 1 was a comparison of the change from baseline between treatment groups in the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function (total score 0-24). A statistically significant difference favoring SOLIRIS was observed in the mean change from baseline to Week 26 in MG-ADL total scores [-4.2 points in the SOLIRIS-treated group compared with -2.3 points in the placebo-treated group (p=0.006)].

A key secondary endpoint in gMG Study 1 was the change from baseline in the Quantitative Myasthenia Gravis (QMG) total score at Week 26. The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness (total score 0-39). A statistically significant difference favoring SOLIRIS was observed in the mean change from baseline to Week 26 in QMG total scores [-4.6 points in the SOLIRIS-treated group compared with -1.6 points in the placebo-treated group (p=0.001)].

The results of the analysis of the MG-ADL and QMG from gMG Study 1 are shown in Table 21.

In gMG Study 1, a clinical response was defined in the MG-ADL total score as at least a 3-point improvement and in QMG total score as at least a 5-point improvement. The proportion of clinical responders at Week 26 with no rescue therapy was statistically significantly higher for SOLIRIS compared to placebo for both measures. For both endpoints, and also at higher response thresholds (≥4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥6-, 7-, 8-, 9-, or 10-point improvement on QMG), the proportion of clinical responders was consistently greater for SOLIRIS compared to placebo. Available data suggest that clinical response is usually achieved by 12 weeks of SOLIRIS treatment.

14.4 Neuromyelitis Optica Spectrum Disorder (NMOSD)

The efficacy of SOLIRIS for the treatment of NMOSD was established in NMOSD Study 1 (NCT01892345), a randomized, double-blind, placebo-controlled trial that enrolled 143 patients with NMOSD who were anti-AQP4 antibody positive and met the following criteria at screening:

1. History of at least 2 relapses in last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to screening,
2. Expanded Disability Status Scale (EDSS) score ≤ 7 (consistent with the presence of at least limited ambulation with aid),
3. If on immunosuppressive therapy (IST), on a stable dose regimen,
4. The use of concurrent corticosteroids was limited to 20 mg per day or less,
5. Patients were excluded if they had been treated with rituximab or mitoxantrone within 3 months or with IVIg within 3 weeks prior to screening.

A total of 96 patients were randomized to receive SOLIRIS treatment and 47 were randomized to receive placebo.

The baseline demographic and disease characteristics were balanced between treatment groups. During the treatment phase of the trial, 76% percent of patients received concomitant IST, including chronic corticosteroids; 24% of patients did not receive concomitant IST or chronic corticosteroids during the treatment phase of the trial.

SOLIRIS was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

The primary endpoint for NMOSD Study 1 was the time to the first adjudicated on-trial relapse. The time to the first adjudicated on-trial relapse was significantly longer in SOLIRIS-treated patients compared to placebo-treated patients (relative risk reduction 94%; hazard ratio 0.058; p < 0.0001) (Figure 1).

Figure 1: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse – Full Analysis Set

Note: Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. Abbreviations: CI = confidence interval

SOLIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment. SOLIRIS-treated patients had a 96% relative reduction in the adjudicated on-trial annualized relapse rate (ARR) compared to patients on placebo, as shown in Table 22.

Compared to placebo-treated patients, SOLIRIS-treated patients had reduced annualized rates of hospitalizations (0.04 for SOLIRIS versus 0.31 for placebo), of corticosteroid administrations to treat acute relapses (0.07 for SOLIRIS versus 0.42 for placebo), and of plasma exchange treatments (0.02 for SOLIRIS versus 0.19 for placebo).

Store SOLIRIS vials refrigerated at 2°-8° C (36°-46° F) in the original carton to protect from light until time of use. SOLIRIS vials may be stored in the original carton at controlled room temperature (not more than 25° C/77° F) for only a single period up to 3 days. Do not use beyond the expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of SOLIRIS.

DO NOT FREEZE. DO NOT SHAKE.

Serious Meningococcal Infections

Advise patients of the risk of serious meningococcal infection. Inform patients of the need to complete or update their meningococcal vaccinations at least 2 weeks prior to receiving the first dose of SOLIRIS or receive antibacterial drug prophylaxis if SOLIRIS treatment must be initiated immediately and they have not been previously vaccinated. Inform patients of the requirement to be revaccinated according to current ACIP recommendations for meningococcal infection while on SOLIRIS therapy [see Warnings and Precautions (5.1)].

Inform patients that vaccination may not prevent serious meningococcal infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)]:

• fever
• fever and a rash
• fever with high heart rate
• headache with nausea or vomiting
• headache and a fever
• headache with a stiff neck or stiff back
• confusion
• muscle aches with flu-like symptoms
• eyes sensitive to light

Inform patients that they will be given a Patient Safety Card for SOLIRIS that they should carry with them at all times during and for 3 months following treatment with SOLIRIS. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.

ULTOMIRIS and SOLIRIS REMS

SOLIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].

Inform the patient of the following notable requirements:

• Patients must receive counseling about the risk of serious meningococcal infections.
• Patients must receive written educational materials about this risk.
• Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with SOLIRIS.
• Patients must be instructed to complete or update meningococcal vaccines for serogroups A, C, W, Y and B per ACIP recommendations as directed by the prescriber prior to treatment with SOLIRIS.
• Patients must receive antibiotics as directed by the prescriber if they are not up to date with meningococcal vaccines and have to start SOLIRIS right away.

Other Infections

Counsel patients about gonorrhea prevention and advise regular testing for patients at-risk.

Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria.

Aspergillus infections have occurred in immunocompromised and neutropenic patients.

Inform parents or caregivers of children receiving SOLIRIS for the treatment of aHUS that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) according to current medical guidelines.

Infusion-Related Reactions

Advise patients that administration of SOLIRIS may result in infusion-related reactions.

Discontinuation

Inform patients with PNH that they may develop serious hemolysis due to PNH when SOLIRIS is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following SOLIRIS discontinuation.

Inform patients with aHUS that there is a potential for TMA complications due to aHUS when SOLIRIS is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following SOLIRIS discontinuation. Inform patients who discontinue SOLIRIS to keep the Patient Safety Card with them for three months after the last SOLIRIS dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of SOLIRIS.