Additions and/or revisions underlined:

…

Because of the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called ULTOMIRIS and SOLIRIS REMS [see Warnings and Precautions (5.2)].

Additions and/or revisions underlined:

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.

  …

• Healthcare settings and pharmacies that dispense SOLIRIS must be certified in the REMS and must verify prescribers are certified.

  …

Additions and/or revisions underlined:

…

ULTOMIRIS and SOLIRIS REMS

SOLIRIS is available only through a restricted program called ULTOMIRIS and SOLIRIS REMS

[see Warnings and Precautions (5.2)].

…

Additions and/or revisions underlined:

RNING: SERIOUS MENINGOCOCCAL INFECTIONS

SOLIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis [see Warnings and Precautions (5.1)]. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

• Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying therapy with SOLIRIS outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by meningococcal bacteria.

• Patients receiving SOLIRIS are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.

Because of the risk of serious meningococcal infections, SOLIRIS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called SOLIRIS REMS [see Warnings and Precautions (5.2)].

Additions and/or revisions underlined:

SOLIRIS is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis

infection [see Warnings and Precautions (5.1)].

Additions and/or revisions underlined:

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)].

New subsection added:

SOLIRIS is available only through a restricted program under a REMS called SOLIRIS REMS, because of the risk of serious meningococcal infections [see Warnings and Precautions (5.1)].

Notable requirements of the SOLIRIS REMS include the following:

• Prescribers must enroll in the REMS.

• Prescribers must counsel patients about the risk of 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.

• 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.solirisrems.com or 1-888-765-4747

Additions and/or revisions underlined:

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.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

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.

SOLIRIS REMS

SOLIRIS is available only through a restricted program called 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.

   

  …

  MEDICATION GUIDE

  Additions and/or revisions underlined:

  What is the most important information I should know about SOLIRIS?

  …

• Meningococcal vaccines do not prevent all meningococcal infections. Call your healthcare provider or get emergency medical care right away if you get any of these signs and symptoms of a serious meningococcal infection:

  …

• fever with high heart rate

…

How should I receive SOLIRIS?

…

• After each infusion, you should be monitored for at least 1 hour for infusion-related reactions. See “What are the possible side effects of SOLIRIS?” If you have an infusion-related reaction during your SOLIRIS infusion, your healthcare provider may decide to give SOLIRIS more slowly or stop your infusion.

  …

Additions underlined

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.

Addition underlined

…

• Infusion-Related Reactions [see Warnings and Precautions (5.5)]

Additions underlined

…

How should I receive SOLIRIS?

• SOLIRIS is given through a vein (I.V. or intravenous infusion) usually over 35 minutes in adults and 1 to 4 hours in pediatric patients. If you have an infusion-related reaction during your SOLIRIS infusion, your doctor may decide to give SOLIRIS more slowly or stop your infusion.

• If you are an adult, you will usually receive a SOLIRIS infusion by your doctor:

  • weekly for five weeks, then

  • every 2 weeks

• If you are less than 18 years of age, your doctor will decide how often you will receive SOLIRIS depending on your age and body weight

  After each infusion, you should be monitored for one hour for infusion-related reactions. See “What are the possible side effects of SOLIRIS?”

  …

  What are the possible side effects of SOLIRIS? SOLIRIS can cause serious side effects including:

• See “What is the most important information I should know about SOLIRIS?”

• Serious infusion-related reactions. Serious infusion-related reactions can happen during your SOLIRIS infusion. Tell your doctor or nurse right away if you get any of these symptoms during your SOLIRIS infusion:

  • chest pain

  • trouble breathing or shortness of breath o swelling of your face, tongue, or throat o feel faint or pass out

    If you have an infusion-relatedreaction to SOLIRIS, your doctor may need to infuse SOLIRIS more slowly, or stop SOLIRIS.

    …

Additions underlined

…

Infusion-Related Reactions

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

(additions underlined)

…

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. Patients were 19 to 75 years of age (mean 44 years of age), and 91% were female. Table 9 displays the most common adverse reactions from NMOSD Study 1 that occurred in greater than or equal to 5% of Soliris-treated patients and at a greater frequency than on placebo.

(please refer to label to view Table 9)

(additions underlined)

…

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.

(addition underlined)

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

(additions and revisions underlined)

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.

(additions underlined)

…

SOLIRIS is only available through a program called the SOLIRIS REMS. Before you can receive SOLIRIS, your doctor must:

…

• make sure that you are vaccinated with the meningococcal vaccine and, if needed, get revaccinated with the meningococcal vaccine. Ask your doctor if you are not sure if you need to be revaccinated.

…

What is SOLIRIS?

…

• adults with a disease called neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.

It is not known if SOLIRIS is safe and effective in children with PNH, gMG, or NMOSD.

…

What are the possible side effects of SOLIRIS?

…

The most common side effects in people with NMOSD treated with SOLIRIS include:

• common cold (upper respiratory infection)    

• joint pain (arthralgia)

• pain or swelling of your nose or throat (nasopharyngitis)      

• throat irritation (pharyngitis)

• diarrhea          

• bruising (contusion)

• back pain

• dizziness

• flu like symptoms (influenza) including fever, headache, tiredness, cough, sore throat, and body aches

...

(Additions and/or revisions are underlined)

Risk and Prevention

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. The use of Soliris increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis). Soliris is associated with an approximate 2,000-fold increased risk of meningococcal disease in comparison to the general U.S. population annual rate (0.14 per 100,000 population in 2015).

Vaccinate for meningococcal disease according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complementdeficiencies.  Revaccinate patients in accordance with ACIP recommendations, considering the duration of Soliris therapy.

Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris.  If urgent Soliris therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with two weeks of antibacterial drug prophylaxis.

(Additions and/or revisions are underlined)

Serious infections with Neisseria species (other than N. meningitides), including disseminated gonococcal infections, have been reported.

(Additions and/or revisions are underlined)

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

(Additions and/or revisions are underlined)

Other Infections

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

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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.

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Although limited published data does not report detectable levels of eculizumab in human milk, maternal IgG is known to be present in human milk. Available information is insufficient to inform the effect of eculizumab on the breastfed infant. There are no data on the effects of eculizumab on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Soliris and any potential adverse effects on the breastfed child from eculizumab or from the underlying maternal condition.

(Additions and/or revisions are underlined)

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)…

Table 4: Adverse Reactions Reported in 5% or More of Soliris Treated Patients with PNH and Greater than Placebo in the Controlled Clinical Study

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 Studies C08-002A/B, C08-003A/B and C10-004All patients received the recommended dosage of Soliris. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in Studies C08- 002A/B, C08-003A/B and C10-004  combined.

Table 5: Per Patient Incidence of Adverse Events in 10% or More Adult and Adolescent Patients Enrolled in Studies C08-002A/B, C08-003A/B and C10-004Separately and in Total

In Studies C08-002A/B, C08-003A/B and C10-004 combined, 60% (47/78) of patients experienced a serious adverse event (SAE)…

Study C10-003 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age…

Table 6: Per Patient Incidence of Adverse Reactions in 10% or More Patients Enrolled in StudyC10-003

In C10-003, 59% (13/22) of patients experienced a serious adverse event (SAE)…

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 (2:15%) adverse events occurring in pediatric patients are presented in Table 7.

Table 7: Adverse Reactions Occurring in at Least 15% of Patients Less than 18 Years of Age Enrolled in Study C09-001r

(Newly added)

Generalized Myasthenia Gravis (gMG)

In a 26-week placebo-controlled trial evaluating the effect of Soliris for the treatment of gMG (gMG Study 1), 62 patients received Soliris at the recommended dosage regimen and 63 patients received placebo. Patients were 19 to 79 years of age, and 66% were female. Table 8 displays the most common adverse reactions from gMG Study 1 that occurred in 2:5% of Soliris-treated patients and at a greater frequency than placebo.

(Newly added table-see label)

Table 8:  Adverse Reactions Reported in 5% or More of Soliris-Treated Patients in gMG Study 1 and at a Greater Frequency than in Placebo-Treated Patients

(Newly added)

The most common adverse reactions (2:10%) that occurred in Soliris-treated patients in the long-term extension to gMG Study 1, Study ECU-MG-302, that are not included in Table 8 were headache (26%), nasopharyngitis (24%), diarrhea (15%), arthralgia (12%), upper respiratory tract infection (11%), and nausea (10%).

(Additions and/or revisions are underlined)

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.

…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. An ECL based neutralizing assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 3 patients with aHUS and the 5 patients with PNH with positive samples using the ECL assay. Two of 161 patients with PNH (1.2%) and 1 of 100 patients with aHUS (1%) had low positive values for neutralizing antibodies. None of 62 patients with gMG had antibodies to Soliris detected immediately following the 26-week active treatment.

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

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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.

(Pregnancy and Lactation Labeling Rule Conversion - additions and/or revisions are underlined)

Pregnancy Exposure Registry

Alexion's PNH and aHUS disease registries collect pregnancy outcomes in women exposed to Soliris during pregnancy. To enroll or to obtain information, contact www.pnhregistry.com or www.ahusregistry.com, or call (215)-616-3558. In cases where gMG patients become pregnant, call (215)-616-3558.

Risk Summary

There are no available data on Soliris use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Soliris, a recombinant IgG molecule (humanized anti-C5 antibody), is expected to cross the placenta. 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. Advise pregnant women of the potential risk to a fetus.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

(Pregnancy and Lactation Labeling Rule Conversion - additions and/or revisions are underlined)

Risk Summary

There is no information regarding the presence of eculizumab in human milk, the effects on the breastfed infant, or the effects on milk production. IgG is excreted in human milk, so it is expected that eculizumab will be present in human milk. However, published data suggest that antibodies in human milk do not enter the neonatal and infant circulation in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Soliris and any potential adverse effects on the breastfed child from Soliris or from the underlying maternal condition.

(Additions and/or revisions are underlined)

Forty-five patients 65 years of age or older (15 with PNH, 4 with aHUS, and 26 with gMG) were treated with Soliris in clinical trials in the approved indications. ..

(Additions and/or revisions are underlined)

…The safety and effectiveness of Soliris for the treatment of aHUS appear similar in pediatric and adult patients. The safety and effectiveness of Soliris for the treatment of generalized Myasthenia Gravis in pediatric patients have not been established…

(addition underlined)

WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

• Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
• Immunize patients with meningococcal vaccines least 2 weeks prior to administering the first dose of Soliris, unless the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection.
• Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.

Soliris is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris REMS, prescribers must enroll in the program. Enrollment in the Soliris REMS

program and additional information are available by telephone: 1-888-SOLIRIS (1-

888-765-4747) or at solirisrems.com.

(additions underlined)

Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris.The use of Soliris increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis).

Vaccinate for meningococcal disease according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of Soliris therapy.

Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris. If urgent Soliris therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible.

In prospective clinical studies, 75/100 patients with aHUS were treated with Soliris less than 2 weeks after meningococcal vaccination and 64 of these 75 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established.

…

(additions underlined)

The safety and effectiveness of Soliris for the treatment of PNH 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.

Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenza type b (Hib) according to ACIP guidelines.

(section revised, additions underlined)

Advise the patient to read FDA-approved patient labeling (Medication Guide).

Meningococcal Infection

Prior to treatment, patients should fully understand the risks and benefits of Soliris, in particular the risk of meningococcal infection. Ensure that patients receive the Medication Guide.

Inform patients that they are required to receive meningococcal vaccination at least 2 weeks prior to receiving the first dose of Soliris, if they have not previously been vaccinated. They are required to be revaccinated according to current medical guidelines for meningococcal vaccine use while on Soliris therapy. Inform patients that vaccination may not prevent meningococcal infection.

Signs and Symptoms of Meningococcal Infection

Inform patients s about the signs and symptoms of meningococcal infection, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:

•         headache with nausea or vomiting

•         headache and a fever

•         headache with a stiff neck or stiff back

•         fever and a rash

•         confusion

•         muscle aches with flu-like symptoms

•         eyes sensitive to light

Inform patients that they will be given a Soliris Patient Safety Information Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation.

Other Infections

Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Additionally, Aspergillus infections have occured 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 influenza type b (Hib) according to current medical guidelines.

Discontinuation

Inform patients with PNH that they may develop 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 Soliris Patient

Safety Information 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.

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Meningococcal infections may quickly become life-threatening and cause death if not recognized and treated early.

1.  You must receive meningococcal vaccination at least 2 weeks before your first dose of Soliris unless you have already had this vaccine. If your doctor decided that urgent treatment with Soliris is needed, you should receive meningococcal vaccination as soon as possible.

1.  If you had a meningococcal vaccine in the past, you might need additional vaccination before starting Soliris. Your doctor will decide if you need additional meningococcal vaccination.

1. Meningococcal vaccines do not prevent all meningococcal infections.

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