Adverse reactions : תופעות לוואי

6   ADVERSE REACTIONS
PI: Intravenous: The most common adverse reactions observed at a rate ≥ 5% in subjects with intravenous treatment in the clinical trials were cough increased, rhinitis, pharyngitis, headache, asthma, nausea, fever, diarrhea, and sinusitis.


PI: Subcutaneous: The most common adverse reactions observed at a rate ≥5% of subjects with subcutaneous treatment in the clinical trials were local infusion site reactions, fatigue, headache, upper respiratory tract infection, arthralgia, diarrhea, nausea, sinusitis, bronchitis, depression, allergic dermatitis, erythema, migraine, myalgia, viral infection, and pyrexia.

ITP: The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trials were headache, ecchymosis, vomiting, fever, nausea, rash, abdominal pain, back pain and dyspepsia.

CIDP: The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trial were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia.

6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in clinical practice.

PI: Intravenous Administration

The most serious adverse event observed in clinical study subjects receiving GAMUNEX-C IV for PI was an exacerbation of autoimmune pure red cell aplasia in one subject.

In four different clinical trials to study PI, out of 157 subjects treated with GAMUNEX-C, 4 subjects discontinued due to the following adverse events: Coombs negative hypochromic anemia, autoimmune pure red cell aplasia, arthralgia/hyperhidrosis/fatigue/myalgia/nausea and migraine.

In a study of 87 subjects, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion, such as diphenhydramine and acetaminophen.

Table 2 lists the adverse reactions reported by at least 5% of subjects during the 9-month treatment.

Table 2: Adverse Reactions Occurring in ≥ 5% of Subjects
GAMUNEX®-C                                GAMIMUNE® N, 10%
No. of subjects: 87                           No. of subjects: 85
No. of subjects with adverse                  No. of subjects with adverse reaction (percentage of all                   reaction (percentage of all Adverse Reactions                               subjects)                                     subjects) Cough increased                                         27 (31.0%)                                     25 (29.4%) Rhinitis                                                21 (24.1%)                                     24 (28.2%) Headache                                                13 (14.9%)                                     17 (20.0%) Pharyngitis                                             14 (16.1%)                                     16 (18.8%) Asthma                                                  13 (14.9%)                                     10 (11.8%) Fever                                                     6 (6.9%)                                     10 (11.8%) Nausea                                                  10 (11.5%)                                      9 (10.6%) Diarrhea                                                  6 (6.9%)                                      9 (10.6%) Sinusitis                                                 5 (5.7%)                                       6 (7.1%) *An adverse reaction is an adverse event that meets any of the following 3 criteria: (a) that began during or within 72 hours of the end of product infusion, (b) that was considered at least possibly related by either the investigator or the applicant, and/or (c) whose causality assessment by the investigator was missing or indeterminate.

Table 3 lists the frequency of adverse reactions (as defined for Table 2), which were reported by at least 5% of subjects.


Table 3: Adverse Reactions Frequency

GAMUNEX®-C                         GAMIMUNE® N, 10%
No. of infusions: 825                 No. of infusions: 865
Number (percentage of all             Number (percentage of all
Adverse Reactions                         infusions)                            infusions) 
Cough increased                                      40 (4.8%)                         47 (5.4%) 
Rhinitis                                             34 (4.1%)                         44 (5.1%) 
Headache                                             17 (2.1%)                         24 (2.8%) 
Pharyngitis                                          20 (2.4%)                         24 (2.8%) 
Fever                                                8 (1.0%)                          20 (2.3%) 
Asthma                                               17 (2.1%)                         12 (1.4%) 
Diarrhea                                             10 (1.2%)                         10 (1.2%) 
Nausea                                               10 (1.2%)                         10 (1.2%) 
Sinusitis                                            6 (0.7%)                           7 (0.8%) 
The mean number of adverse reactions per infusion that occurred during or within 72 hours of the end of product infusion was 0.33 for the GAMUNEX-C and 0.39 for the GAMIMUNE® N, 10% [Immune Globulin Intravenous (Human), 10%] treatment group.

In all three trials in primary humoral immunodeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The infusion rate was reduced for 11 of 222 exposed subjects (7 GAMUNEX-C, 4 GAMIMUNE N, 10%) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills.
There were no anaphylactic or anaphylactoid reactions to GAMUNEX-C or GAMIMUNE N, 10% in clinical trials.

In the IV efficacy and safety study, serum samples were drawn to monitor the virus safety at baseline and one week after the first infusion of IGIV (for parvovirus B19), eight weeks after first and fifth infusion of IGIV (for hepatitis C, hepatitis B, and HIV-1), 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study (for hepatitis C, hepatitis B, HIV-1, and parvovirus B19). Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction [PCR]) and serological testing. There were no treatment-related emergent findings of virus transmission for either GAMUNEX-C or GAMIMUNE N, 10%.

PI: Subcutaneous Administration (PK and Safety Study

Adverse reactions were divided into 2 types: 1( Local infusion site reactions, and 2) Non-infusion site adverse reactions. Table 4 lists those adverse reactions (as defined for Table 2) occurring in ≥ 2% of infusions during the SC phase of the pharmacokinetic (PK) crossover and safety trial. [see Clinical Pharmacology (12.3)]

Table 4: Most Frequent Adverse Reactions (≥ 2% of infusions) by Infusion in the SC Phase 
Adverse Reactions                        Number (Rate*)
Non-infusion Site Adverse Reactions
Headache                                            25 (0.03)
Abdominal Pain                                      1 (<0.01)
Local Infusion Site   Reactions†, ‡
Mild                                               389 (0.54)
Moderate                                                           29 (0.04) Severe                                                              9 (0.01) * Rate is calculated by the total number of events divided by the number of infusions received (725) † All local infusion site reactions were a priori considered drug-related.
‡
At each level of summation (Preferred Term), local infusion site reactions are counted only once if they occur at the same infusion visit.
Mild – usually transient in nature and generally not interfering with normal activities.
Moderate – sufficiently discomforting to interfere with normal activities.
Severe – prevents normal activities.


Table 5 lists the adverse reactions occurring in ≥ 5% of subjects and the frequency of adverse reactions (as defined for Table 2) per infusion.

Table 5: Most Frequent Adverse Reactions (≥ 5% of subjects) by Subject and Infusion in the SC phase

No. of Adverse
No. of Subjects                    Reactions
Adverse Reaction                                n=32 (%)                          (Rate*) Local Infusion Site Reaction†,‡                                24 (75.0%)                      427 (0.59) Fatigue                                                         5 (15.6%)                       6 (0.01) Headache                                                        4 (12.5%)                       25 (0.03) Upper respiratory tract infection                               4 (12.5%)                       5 (0.01) Arthralgia                                                       3 (9.4%)                       6 (0.01) Diarrhea                                                         3 (9.4%)                       6 (0.01) Nausea                                                           3 (9.4%)                       4 (0.01) Sinusitis                                                        3 (9.4%)                       4 (0.01) Bronchitis                                                       2 (6.3%)                       2 (<0.01) Depression                                                       2 (6.3%)                       2 (<0.01) Dermatitis allergic                                              2 (6.3%)                       2 (<0.01) Erythema                                                         2 (6.3%)                       2 (<0.01) Migraine                                                         2 (6.3%)                       2 (<0.01) Myalgia                                                          2 (6.3%)                       2 (<0.01) Pyrexia                                                          2 (6.3%)                       2 (<0.01) Viral infection                                                  2 (6.3%)                       2 (<0.01) *   Rate is calculated by the total number of events divided by the number of infusions received (725) † All local infusion site reactions were a priori considered drug-related ‡ At each level of summation (Preferred Term), infusion site reactions are counted only once if they occur at the same infusion visit.

There were no serious bacterial infections in the SC phase of the PK and safety trial.

Local Infusion Site Reactions
Local infusion site reactions with SC GAMUNEX-C consisted of erythema, pain and swelling. The majority of local infusion site reactions resolved within 3 days. The number of subjects experiencing an infusion site reaction and the number of infusion site reactions decreased over time as subjects received continued weekly SC infusions. At the beginning of the SC phase (week 1), a rate of approximately 1 infusion site reaction per infusion was reported, whereas at the end of the study (week 24) this rate was reduced to 0.5 infusion site reactions per infusion, a reduction of 50%.

ITP
In two different clinical trials to study ITP, out of 76 subjects treated with GAMUNEX-C, 2 subjects discontinued due to the following adverse reactions: Hives and Headache/Fever/Vomiting.

One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX-C. The death was judged to be unrelated to GAMUNEX-C.

No pre-medication with corticosteroids was permitted by the protocol. Twelve ITP subjects treated in each treatment group were pretreated with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug-related adverse events were of mild to moderate severity and of transient nature.

The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMUNEX-C, 3 GAMIMUNE N, 10%) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons.

Table 6 lists the adverse reactions (as defined for Table 2) reported by at least 5% of subjects during the 3-month efficacy and safety study.

Table 6: Adverse Reactions Occurring in ≥ 5% of Subjects

GAMUNEX®-C                     GAMIMUNE® N, 10%
No. of subjects: 48               No. of subjects: 49
Number                            Number
Adverse Reaction              (percentage of all subjects)      (percentage of all subjects) 
Headache                                       25 (52.1%)                         26 (53.1%) 
Vomiting                                        6 (12.5%)                         8 (16.3%) 
Ecchymosis                                      7 (14.6%)                          2 (4.1%) 
Fever                                           6 (12.5%)                         6 (12.2%) 
Nausea                                          6 (12.5%)                         5 (10.2%) 
Rash                                             4 (8.3%)                              0 
Abdominal pain                                   3 (6.3%)                          3 (6.1%) 
Back pain                                        3 (6.3%)                          2 (4.1%) 
Dyspepsia                                        3 (6.3%)                              0 
Asthenia                                         2 (4.2%)                          3 (6.1%) 
Dizziness                                        2 (4.2%)                          3 (6.1%) 
Serum samples were drawn to monitor the virus safety of the ITP subjects at baseline, nine days after the first infusion (for parvovirus B19), and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment-related emergent findings of virus transmission for either GAMUNEX®-C, or GAMIMUNE® N, 10%.


CIDP

In the CIDP efficacy and safety study, 113 subjects were exposed to GAMUNEX-C and 95 were exposed to Placebo. (see Clinical Studies [14]) As a result of the study design, the drug exposure with GAMUNEX- C was almost twice that of Placebo, with 1096 GAMUNEX-C infusions versus 575 Placebo infusions.
Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day. Infusions were administered in the mean over 2.7 hours.

Table 7 shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events:

Table 7: Reasons for Discontinuation Due to Adverse Events:
Number of Subjects
Number of Subjects               Discontinued due to Adverse                       Adverse Event Events
Urticaria, Dyspnea,
GAMUNEX®-C               113                      3 (2.7%)
Bronchopneumonia
Cerebrovascular Accident,
Placebo                   95                      2 (2.1%)
Deep Vein Thrombosis


The most common adverse reactions with GAMUNEX-C were headache and pyrexia. Table 8 lists adverse reactions (as defined for Table 2) reported by at least 5% of subjects in any treatment group.

Table 8: Adverse Reactions Occurring in ≥ 5% of Subjects

GAMUNEX®-C                              Placebo
No. of subjects: 113                 No. of subjects: 95
MedDRA
No. of       No. of                  No. of       No. of
Preferred term a                                    Incidence                           Incidence Subjects      Adverse              b  Subjects    Adverse
Density                             Density b
(%)      Reactions                   (%)     Reactions
35
Headache                              50          0.046    7 (7.4%)        9          0.016 (31.0%)
15
Pyrexia                              27          0.025      0             0 (13.3%)
10
Hypertension                           19          0.017    3 (3.2%)        3          0.005 (8.8%)
Chills              9 (8.0%)        10          0.009      0             0 Nausea               7 (6.2%)         9          0.008    3 (3.2%)        3          0.005 Rash                7 (6.2%)        10          0.009    1 (1.1%)        1          0.002 Arthralgia            6 (5.3%)         7          0.006      0             0 1
Asthenia             6 (5.3%)         6          0.005                    2          0.003 (1.1%) a
Reported in ≥5% of subjects in any treatment group.
b
Calculated by the total number of adverse reactions divided by the number of infusions received (1096 for GAMUNEX-C and 575 for Placebo).

The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX-C for CIDP was pulmonary embolism (PE) in one subject with a history of PE.


Laboratory Abnormalities
During the course of the clinical program, ALT and AST elevations were identified in some subjects.
•   For ALT, in the IV PI study treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMUNEX-C group versus 5/88 (6%) of subjects in the GAMIMUNE N, 10% group (p = 0.026).
•   In the SC PI study treatment emergent laboratory abnormalities during the SC phase occurred in several subjects. Four subjects (4/32, 13%) had elevated Alkaline Phosphatase. One subject (1/32, 3%) had an elevated ALT and three subjects (3/32, 9%) had an elevated AST. No elevations were >1.6 times the upper limit of normal.
•   In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding for elevation of ALT was observed among 3/44 (7%) of subjects in the GAMUNEX-C group versus 8/43 (19%) of subjects in the GAMIMUNE N, 10% group (p = 0.118).
•   In the CIDP study, 15/113 (13%) of subjects in the GAMUNEX-C group and 7/95 (7%) in the Placebo group (p=0.168) had a treatment emergent transient elevation of ALT.

Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction.

GAMUNEX-C may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 class.
Direct antiglobulin tests (DAT or direct Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily. There were 2 cases of hemolytic anemia across these clinical trials. One hemolytic event not associated with positive DAT findings was observed in the IV PI study in a woman with common variable immune deficiency and B12 deficiency (pernicious anemia) at a dose of 450 mg/kg. The other hemolytic event occurred in the CIDP study in a subject with positive DAT at a dose of 1g/kg.

6.2 Postmarketing Experience
Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequencies or establish a causal relationship to product exposure.
The following adverse reactions have been identified during post-approval use of IGIV products8,20 including GAMUNEX-C:

• Infusion Reactions:       Hypersensitivity (e.g., anaphylaxis), tachycardia, malaise, flushing, or other skin reactions, chest discomfort, rigors, and changes in blood pressure
• Renal:                    Acute renal dysfunction/failure, osmotic nephropathy • Respiratory:               Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm
• Cardiovascular:            Cardiac arrest, thromboembolism, vascular collapse, hypotension • Neurological:             Coma, loss of consciousness, seizures/convulsions, tremor, aseptic meningitis
• Integumentary:             Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
• Hematologic:               Pancytopenia, leukopenia, hemolysis, hemolytic anemia, positive direct antiglobulin (Coombs test)
• General/Body as a Whole: Rigors
• Gastrointestinal:          Hepatic dysfunction

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il. Additionally, you can also report to Padagis via the following address: Padagis.co.il.