Adverse reactions : תופעות לוואי

6      ADVERSE REACTIONS

The following are described in greater detail in the Warnings and Precautions section.
• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Seizure Potential [see Warnings and Precautions (5.2)]
• Interaction with Valproic Acid [see Warnings and Precautions (5.3)]
• Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)]
• Caution with Intramuscular Administration [see Warnings and Precautions (5.5)]
• Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6)]
• Laboratory Tests [see Warnings and Precautions (5.7)]

6.1    Clinical Trials 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.
Adults Receiving Ertapenem as a Treatment Regimen
Clinical trials enrolled 1954 patients treated with Ertapenem; in some of the clinical trials, parenteral therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14)]. Most adverse experiences reported in these clinical trials were described as mild to moderate in severity.
Ertapenem was discontinued due to adverse experiences in 4.7% of patients.
Table 3 shows the incidence of adverse experiences reported in 2.0% of patients in these trials. The most common drug-related adverse experiences in patients treated with Ertapenem, including those who were switched to therapy with an oral antimicrobial, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%).
Table 3
Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in      2.0% of Adult Patients Treated With Ertapenem in Clinical Trials


Ertapenem *           Piperacillin/           Ertapenem†           Ceftriaxone† 1 g daily           Tazobactam*              1 g daily            1 or 2 g daily Adverse Events                 (N=802)              3.375 g q6h            (N=1152)                (N=942) (N=774)
Local:
Infused vein complication              7.1                      7.9                   5.4                   6.7 Systemic:
Death                                  2.5                      1.6                   1.3                   1.6 Edema/swelling                         3.4                      2.5                   2.9                   3.3 Fever                                  5.0                      6.6                   2.3                   3.4 Abdominal pain                         3.6                      4.8                   4.3                   3.9 Hypotension                            2.0                      1.4                   1.0                   1.2 Constipation                           4.0                      5.4                   3.3                   3.1 Diarrhea                               10.3                   12.1                    9.2                   9.8 Nausea                                 8.5                      8.7                   6.4                   7.4 Vomiting                               3.7                      5.3                   4.0                   4.0 Altered mental status‡                 5.1                      3.4                   3.3                   2.5 Dizziness                              2.1                      3.0                   1.5                   2.1 Headache                               5.6                      5.4                   6.8                   6.9 Insomnia                               3.2                      5.2                   3.0                   4.1 Dyspnea                                2.6                      1.8                   1.0                   2.4 Pruritus                               2.0                      2.6                   1.0                   1.9 Rash                                   2.5                      3.1                   2.3                   1.5 Vaginitis                              1.4                      1.0                   3.3                   3.7 * Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials
†   Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials ‡    Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor 

In        patients       treated      for       complicated              intra-abdominal           infections,         death occurred in 4.7% (15/316) of patients receiving Ertapenem and 2.6% (8/307) of patients receiving comparator drug. These deaths occurred in patients with significant           co-morbidity           and/or        severe          baseline        infections.         Deaths       were considered unrelated to study drugs by investigators.
In clinical trials, seizure was reported during study therapy plus 14-day follow-up period in 0.5% of patients treated with Ertapenem , 0.3% of patients treated            with      piperacillin/tazobactam                      and   0%        of      patients      treated      with ceftriaxone [see Warnings and Precautions (5.2)].
Additional adverse experiences that were reported with Ertapenem.with an incidence 0.1% within each body system are listed below
Body as a Whole: abdominal distention, pain, chills, septicemia, septic shock, dehydration, gout, malaise, asthenia/fatigue, necrosis, candidiasis, weight loss, facial edema, injection site induration, injection site pain, extravasation, phlebitis/thrombophlebitis, flank pain, syncope
Cardiovascular                   System:             heart           failure,        hematoma,             chest       pain, hypertension, tachycardia, cardiac arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, subdural hemorrhage
Digestive                  System:         acid      regurgitation,             oral         candidiasis,           dyspepsia, gastrointestinal                hemorrhage,            anorexia,              flatulence,         C.   difficile-associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, pyloric stenosis Musculoskeletal System: leg pain
Nervous System & Psychiatric: anxiety, nervousness, seizure [see Warnings and Precautions (5.2)], tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, vertigo
Respiratory System: cough, pharyngitis, rales/rhonchi, respiratory distress,           pleural      effusion,          hypoxemia,              bronchoconstriction,                pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, hiccups, voice disturbance
Skin & Skin Appendage: erythema, sweating, dermatitis, desquamation,
flushing, urticaria
Special Senses: taste perversion

Urogenital System: renal impairment, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, vulvovaginitis.
In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with Ertapenem, the adverse experience profile was generally similar to that seen in previous clinical trials.

Pediatric Patients Receiving Ertapenem as a Treatment Regimen
Clinical trials enrolled 384 patients treated with Ertapenem; in some of the clinical trials, parenteral therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14)]. The overall adverse experience profile in pediatric patients is comparable to that in adult patients. Table 5 shows the incidence of adverse experiences reported in 2.0% of pediatric patients in clinical trials. The most common drug-related adverse experiences in pediatric patients treated with Ertapenem, including those who were switched to therapy with an oral antimicrobial, were diarrhea (6.5%), infusion site pain (5.5%), infusion site erythema (2.6%), vomiting (2.1%).
Table 5
Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in        2.0% of Pediatric Patients Treated With Ertapenem in Clinical Trials

Ertapene            Ceftriaxone*            Ticarcillin/ m *,†
Adverse Events                                     (N=384)                (N=100)             Clavulanate† (N=24)
Local:
Infusion Site Erythema                            3.9                    3.0                   8.3 Infusion Site Pain                                7.0                    4.0                  20.8 Systemic:
Abdominal Pain                                    4.7                    3.0                   4.2 Constipation                                      2.3                    0.0                   0.0 Diarrhea                                         11.7                   17.0                   4.2 Loose Stools                                      2.1                    0.0                   0.0 Vomiting                                         10.2                   11.0                   8.3 Pyrexia                                           4.9                    6.0                   8.3 Upper Respiratory Tract Infection                 2.3                    3.0                   0.0 Headache                                          4.4                    4.0                   0.0 Cough                                             4.4                    3.0                   0.0 Diaper Dermatitis                                 4.7                    4.0                   0.0 Rash                                              2.9                    2.0                   8.3 *     Includes Phase IIb Complicated skin and skin structure infections, Community acquired pneumonia and Complicated urinary tract infections trials in which patients 3 months to 12 years of age received Ertapenem 15 mg/kg IV twice daily up to a maximum of 1 g or ceftriaxone 50 mg/kg/day IV in two divided doses up to a maximum of 2 g, and patients 13 to 17 years of age received Ertapenem 1 g IV daily or ceftriaxone 50 mg/kg/day IV in a single daily dose.
†     Includes Phase IIb Acute pelvic infections and Complicated intra-abdominal infections trials in which patients 3 months to 12 years of age received Ertapenem 15 mg/kg IV twice daily up to a maximum of 1 g and patients 13 to 17 years of age received Ertapenem 1 g IV daily or ticarcillin/clavulanate 50 mg/kg for patients   60 kg or ticarcillin/clavulanate 3.0 g for patients 60 kg, 4 or 6 times a day.


Additional adverse experiences that were reported with Ertapenem with an incidence 0.5% within each body system are listed below:
Gastrointestinal Disorders: nausea
General Disorders and Administration Site Condition: hypothermia, chest pain, upper abdominal pain; infusion site pruritus, induration, phlebitis, swelling, and warmth
Infections and Infestations: candidiasis, oral candidiasis, viral pharyngitis, herpes simplex, ear infection, abdominal abscess
Metabolism and Nutrition Disorders: decreased appetite Musculoskeletal and Connective Tissue
Disorders: arthralgia Nervous System
Disorders: dizziness, somnolence Psychiatric
Disorders: insomnia

Reproductive System and Breast Disorders: genital rash
Respiratory, Thoracic and Mediastinal Disorders: wheezing,
nasopharyngitis, pleural effusion, rhinitis, rhinorrhea
Skin and Subcutaneous Tissue Disorders: dermatitis, pruritus, rash erythematous, skin lesion
Vascular Disorders: phlebitis.
6.2 Post-Marketing Experience
The following additional adverse reactions have been identified during the post-approval use of Ertapenem. 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 drug exposure.
Gastrointestinal Disorders: teeth staining
Immune System Disorders: anaphylaxis including anaphylactoid reactions Musculoskeletal and Connective Tissue Disorders: muscular weakness
Nervous System Disorders: coordination abnormal, depressed level of consciousness,    dyskinesia,  gait  disturbance,      myoclonus,    tremor, encephalopathy (recovery was prolonged in patients with renal impairment) Psychiatric Disorders: altered mental status (including aggression, delirium), hallucinations
Skin    and    Subcutaneous      Tissue   Disorders:       Acute   Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS syndrome), hypersensitivity vasculitis
6.3 Adverse Laboratory Changes in Clinical Trials
Adults Receiving Ertapenem as Treatment Regimen
Laboratory adverse experiences that were reported during therapy in 2.0% of adult patients treated with Ertapenem in clinical trials are presented in Table 6. Drug-related laboratory adverse experiences that were reported during therapy in 2.0% of adult patients treated with Ertapenem, including those who were switched to therapy with an oral antimicrobial, in clinical trials were ALT increased (6.0%), AST increased
(5.2%), serum alkaline phosphatase increased (3.4%), and platelet count increased (2.8%). Ertapenem was discontinued due to laboratory adverse experiences in 0.3% of patients.

Table 6
Incidence* (%) of Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in   2.0% of Adult Patients Treated With Ertapenem in Clinical Trials 
Ertapenem ‡            Piperacillin/        Ertapenem   §
Ceftriaxone§
1 g daily              Tazobactam‡          1 g daily        1 or 2 g daily Adverse laboratory experiences                        (n†=766)               3.375 g q6h         (n†=1122)           (n†=920) (n†=755)
ALT increased                                              8.8                     7.3                 8.3              6.9 AST increased                                              8.4                     8.3                 7.1              6.5 Serum alkaline phosphatase increased                       6.6                     7.2                 4.3              2.8 Eosinophils increased                                      1.1                     1.1                 2.1              1.8 Hematocrit decreased                                       3.0                     2.9                 3.4              2.4 Hemoglobin decreased                                       4.9                     4.7                 4.5              3.5 Platelet count increased                                   6.5                     6.3                 4.3              3.5 Urine RBCs increased                                       2.5                     2.9                 1.1              1.0 Urine WBCs increased                                       2.5                     3.2                 1.6              1.1 * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test † Number of patients with one or more laboratory tests
‡ Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute  pelvic infections trials
§
Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 

Additional              laboratory          adverse            experiences             that          were   reported         during therapy in 0.1% of patients treated with Ertapenem in clinical trials include: increases in serum creatinine, serum glucose, BUN, total, direct and indirect serum bilirubin, serum sodium and potassium, PT and PTT; decreases in serum potassium, serum albumin, WBC, platelet count, and segmented neutrophils.
In a clinical trial for the treatment of diabetic foot infections in which 289 adult diabetic patients were treated with Ertapenem, the laboratory adverse experience profile was generally similar to that seen in previous clinical trials.


Pediatric Patients Receiving Ertapenem as a Treatment Regimen
Laboratory adverse experiences that were reported during therapy in 2.0% of pediatric patients treated with Ertapenem in clinical trials are presented in Table 7. Drug-related laboratory adverse experiences that were reported during therapy in 2.0% of pediatric patients treated with Ertapenem , including those who were switched to therapy with an oral antimicrobial, in clinical trials were neutrophil count decreased (3.0%), ALT increased (2.2%), and AST increased (2.1%).

Table 7
Incidence* (%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in        2.0% of Pediatric Patients Treated With Ertapenem      in Clinical Trials


Ertapen               Ceftriaxone           Ticarcillin/
Adverse laboratory                        em                      (n†=97)             Clavulanate experiences                               (n†=379)                                      (n†=24) ALT Increased                                3.8                      1.1                 4.3 AST Increased                                3.8                      1.1                 4.3 Neutrophil Count Decreased                   5.8                      3.1                 0.0 * Number of patients with laboratory adverse experiences/Number of patients with the laboratory test; where at least 300 patients had the test
† Number of patients with one or more laboratory tests
Additional   laboratory   adverse      experiences   that   were   reported   during therapy in 0.5% of patients treated with Ertapenem in clinical trials include: alkaline phosphatase increased, eosinophil count increased, platelet count increased, white blood cell count decreased and urine protein present.

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