SOLIRIS
Generic: ECULIZUMAB
Basic Information
Manufacturer
Alexion Pharmaceuticals Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
ebcd67fa-b4d1-4a22-b33d-ee8bf6b9c722
Indications & Usage
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.
( 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.
Adverse Reactions
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.
( 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.