ADVERSE REACTIONS
Adults
Clinical studies enrolled 1954 patients treated with ertapenem; in some of the clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.) Most adverse experiences reported in these clinical studies were described as mild to moderate in severity. Ertapenem was discontinued due to adverse experiences in 4.7% of patients. Table 6 shows the incidence of adverse experiences reported in ≥1.0% of patients in these studies. The most common drug-related adverse experiences in patients treated with INVANZ, 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%), vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%), and vomiting (1.1%).
Table 6: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Adult Patients Treated With INVANZ in Clinical Studies | INVANZ
1 g daily | Piperacillin/ Tazobactam
3.375 g q6h | INVANZ
1 g daily | Ceftriaxone
1 or 2 g daily |
| Adverse Events | (N=802) | (N=774) | (N=1152) | (N=942) |
| Local: | | | | |
| Extravasation | 1.9 | 1.7 | 0.7 | 1.1 |
| Infused vein complication | 7.1 | 7.9 | 5.4 | 6.7 |
| Phlebitis/thrombophlebitis | 1.9 | 2.7 | 1.6 | 2.0 |
| Systemic: | | | | |
| Asthenia/fatigue | 1.2 | 0.9 | 1.2 | 1.1 |
| 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 |
| Chest pain | 1.5 | 1.4 | 1.0 | 2.5 |
| Hypertension | 1.6 | 1.4 | 0.7 | 1.0 |
| Hypotension | 2.0 | 1.4 | 1.0 | 1.2 |
| Tachycardia | 1.6 | 1.3 | 1.3 | 0.7 |
| Acid regurgitation | 1.6 | 0.9 | 1.1 | 0.6 |
| Oral candidiasis | 0.1 | 1.3 | 1.4 | 1.9 |
| Constipation | 4.0 | 5.4 | 3.3 | 3.1 |
| Diarrhea | 10.3 | 12.1 | 9.2 | 9.8 |
| Dyspepsia | 1.1 | 0.6 | 1.0 | 1.6 |
| Nausea | 8.5 | 8.7 | 6.4 | 7.4 |
| Vomiting | 3.7 | 5.3 | 4.0 | 4.0 |
| Leg pain | 1.1 | 0.5 | 0.4 | 0.3 |
| Anxiety | 1.4 | 1.3 | 0.8 | 1.2 |
| 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 |
| Cough | 1.6 | 1.7 | 1.3 | 0.5 |
| Dyspnea | 2.6 | 1.8 | 1.0 | 2.4 |
| Pharyngitis | 0.7 | 1.4 | 1.1 | 0.6 |
| Rales/rhonchi | 1.1 | 1.0 | 0.5 | 1.0 |
| Respiratory distress | 1.0 | 0.4 | 0.2 | 0.2 |
| Erythema | 1.6 | 1.7 | 1.2 | 1.2 |
| 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 |
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 studies, 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 PRECAUTIONS.)
Additional adverse experiences that were reported with INVANZ 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, necrosis, candidiasis, weight loss, facial edema, injection site induration, injection site pain, flank pain, and syncope;
Cardiovascular System: heart failure, hematoma, cardiac arrest, bradycardia, arrhythmia, atrial fibrillation, heart murmur, ventricular tachycardia, asystole, and subdural hemorrhage;
Digestive System: gastrointestinal hemorrhage, anorexia, flatulence, C. difficile associated diarrhea, stomatitis, dysphagia, hemorrhoids, ileus, cholelithiasis, duodenitis, esophagitis, gastritis, jaundice, mouth ulcer, pancreatitis, and pyloric stenosis;
Nervous System & Psychiatric: nervousness, seizure (see WARNINGS and PRECAUTIONS), tremor, depression, hypesthesia, spasm, paresthesia, aggressive behavior, and vertigo;
Respiratory System: pleural effusion, hypoxemia, bronchoconstriction, pharyngeal discomfort, epistaxis, pleuritic pain, asthma, hemoptysis, hiccups, and voice disturbance;
Skin & Skin Appendage: sweating, dermatitis, desquamation, flushing, and urticaria;
Special Senses: taste perversion;
Urogenital System: renal insufficiency, oliguria/anuria, vaginal pruritus, hematuria, urinary retention, bladder dysfunction, vaginal candidiasis, and 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.
In a clinical study in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of ertapenem 1 hour prior to surgery and were then followed for safety 14 days post surgery, the overall adverse experience profile was generally comparable to that observed for ertapenem in previous clinical trials. Table 7 shows the incidence of adverse experiences other than those previously described above for ertapenem, regardless of causality, reported in ≥1.0% of patients in this study.
Table 7: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Adult Patients Treated With INVANZ for Prophylaxis of Surgical Site Infections Following Elective Colorectal Surgery
Adverse Events | INVANZ
1 g
(N= 476) |
Cefotetan
2 g
(N= 476) |
| Anemia | 5.7 | 6.9 |
| Small intestinal obstruction | 2.1 | 1.9 |
| Cellulitis | 1.5 | 1.5 |
| C. difficile infection or colitis | 1.7 | 0.6 |
| Pneumonia | 2.1 | 4.0 |
| Postoperative infection | 2.3 | 4.0 |
| Urinary tract infection | 3.8 | 5.5 |
| Wound infection | 6.5 | 12.4 |
| Anastomotic leak | 1.5 | 1.3 |
| Seroma | 1.3 | 1.9 |
| Wound complication | 2.9 | 2.3 |
| Wound dehiscence | 1.3 | 1.5 |
| Wound secretion | 1.9 | 2.1 |
| Dysuria | 1.1 | 1.3 |
| Atelectasis | 3.4 | 1.9 |
Additional adverse experiences that were reported in this prophylaxis study with INVANZ, regardless of causality, with an incidence <1.0% and >0.5% within each body system are listed below:
Gastrointestinal Disorders: dry mouth, hematochezia;
General Disorders and Administration Site Condition: crepitations;
Infections and Infestations: abdominal abscess, fungal rash, pelvic abscess;
Injury, Poisoning and Procedural Complications: incision site complication, incision site hemorrhage, intestinal stoma complication;
Musculoskeletal and Connective Tissue Disorders: muscle spasms;
Nervous System Disorders: cerebrovascular accident;
Renal and Urinary Disorders: pollakiuria;
Respiratory, Thoracic and Mediastinal Disorders: crackles lung, lung infiltration, pulmonary congestion, pulmonary embolism, wheezing.
Pediatric Patients
Clinical studies enrolled 384 patients treated with ertapenem; in some of the clinical studies, parenteral therapy was followed by a switch to an appropriate oral antimicrobial. (See CLINICAL STUDIES.) The overall adverse experience profile in pediatric patients is comparable to that in adult patients. Table 8 shows the incidence of adverse experiences reported in ≥1.0% of pediatric patients in clinical studies. The most common drug-related adverse experiences in pediatric patients treated with INVANZ, 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 8: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies | INVANZ
| Ceftriaxone | Ticarcillin/ Clavulanate |
| Adverse Events | (N=384) | (N=100) | (N=24) |
| Local: |
| Infusion Site Erythema | 3.9 | 3.0 | 8.3 |
| Infusion Site Induration | 1.0 | 1.0 | 0.0 |
| Infusion Site Pain | 7.0 | 4.0 | 20.8 |
| Infusion Site Phlebitis | 1.8 | 3.0 | 0.0 |
| Infusion Site Swelling | 1.8 | 1.0 | 4.2 |
| Infusion Site Warmth | 1.3 | 1.0 | 4.2 |
| Systemic: |
| Abdominal Pain | 4.7 | 3.0 | 4.2 |
| Upper Abdominal Pain | 1.0 | 2.0 | 0.0 |
| Constipation | 2.3 | 0.0 | 0.0 |
| Diarrhea | 11.7 | 17.0 | 4.2 |
| Loose Stools | 2.1 | 0.0 | 0.0 |
| Nausea | 1.6 | 0.0 | 0.0 |
| Vomiting | 10.2 | 11.0 | 8.3 |
| Pyrexia | 4.9 | 6.0 | 8.3 |
| Abdominal Abscess | 1.0 | 0.0 | 4.2 |
| Herpes Simplex | 1.0 | 1.0 | 4.2 |
| Nasopharyngitis | 1.6 | 6.0 | 0.0 |
| Upper Respiratory Tract Infection | 2.3 | 3.0 | 0.0 |
| Viral Pharyngitis | 1.0 | 0.0 | 0.0 |
| Hypothermia | 1.6 | 1.0 | 0.0 |
| Dizziness | 1.6 | 0.0 | 0.0 |
| Headache | 4.4 | 4.0 | 0.0 |
| Cough | 4.4 | 3.0 | 0.0 |
| Wheezing | 1.0 | 0.0 | 0.0 |
| Dermatitis | 1.0 | 1.0 | 0.0 |
| Pruritus | 1.6 | 0.0 | 0.0 |
| Diaper Dermatitis | 4.7 | 4.0 | 0.0 |
| Rash | 2.9 | 2.0 | 8.3 |
Additional adverse experiences that were reported with INVANZ with an incidence <1.0% and >0.5% within each body system are listed below:
General Disorders and Administration Site Condition: chest pain, infusion site pruritus;
Infections and Infestations: candidiasis, ear infection, oral candidiasis;
Metabolism and Nutrition Disorders: decreased appetite;
Musculoskeletal and Connective Tissue Disorders: arthralgia;
Nervous System Disorders: somnolence;
Psychiatric Disorders: insomnia;
Reproductive System and Breast Disorders: genital rash;
Respiratory, Thoracic and Mediastinal Disorders: pleural effusion, rhinitis, rhinorrhea;
Skin and Subcutaneous Tissue Disorders: dermatitis atopic, rash erythematous, skin lesion;
Vascular Disorders: phlebitis.
Post-Marketing Experience:
The following post-marketing adverse experiences have been reported:
Immune System: anaphylaxis including anaphylactoid reactions
Nervous System & Psychiatric: hallucinations
Adverse Laboratory Changes
Adults
Laboratory adverse experiences that were reported during therapy in ≥1.0% of adult patients treated with INVANZ in clinical studies are presented in Table 9. Drug-related laboratory adverse experiences that were reported during therapy in ≥1.0% of adult patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, in clinical studies were ALT increased (6.0%), AST increased (5.2%), serum alkaline phosphatase increased (3.4%), platelet count increased (2.8%), and eosinophils increased (1.1%). Ertapenem was discontinued due to laboratory adverse experiences in 0.3% of patients.
Table 9: Incidence
(%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Adult Patients Treated With INVANZ in Clinical Studies | INVANZ
1 g daily | Piperacillin/
Tazobactam
3.375 g q6h | INVANZ
1 g daily | Ceftriaxone
1 or 2 g daily |
| Adverse laboratory experiences | (n
=766) | (n=755) | (n=1122) | (n=920) |
| ALT increased | 8.8 | 7.3 | 8.3 | 6.9 |
| AST increased | 8.4 | 8.3 | 7.1 | 6.5 |
| Serum albumin decreased | 1.7 | 1.5 | 0.9 | 1.6 |
| Serum alkaline phosphatase increased | 6.6 | 7.2 | 4.3 | 2.8 |
| Serum creatinine increased | 1.1 | 2.7 | 0.9 | 1.2 |
| Serum glucose increased | 1.2 | 2.3 | 1.7 | 2.0 |
| Serum potassium decreased | 1.7 | 2.8 | 1.8 | 2.4 |
| Serum potassium increased | 1.3 | 0.5 | 0.5 | 0.7 |
| Total serum bilirubin increased | 1.7 | 1.4 | 0.6 | 1.1 |
| 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 decreased | 1.1 | 1.2 | 1.1 | 1.0 |
| Platelet count increased | 6.5 | 6.3 | 4.3 | 3.5 |
| Segmented neutrophils decreased | 1.0 | 0.3 | 1.5 | 0.8 |
| Prothrombin time increased | 1.2 | 2.0 | 0.3 | 0.9 |
| WBC decreased | 0.8 | 0.7 | 1.5 | 1.4 |
| Urine RBCs increased | 2.5 | 2.9 | 1.1 | 1.0 |
| Urine WBCs increased | 2.5 | 3.2 | 1.6 | 1.1 |
Additional laboratory adverse experiences that were reported during therapy in >0.1% but <1.0% of patients treated with INVANZ in clinical studies include: increases in BUN, direct and indirect serum bilirubin, serum sodium, monocytes, PTT, urine epithelial cells; decreases in serum bicarbonate.
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.
In a clinical study in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of ertapenem 1 hour prior to surgery and were then followed for safety 14 days post surgery, the overall laboratory adverse experience profile was generally comparable to that observed for ertapenem in previous clinical trials. Additional laboratory adverse experiences that were reported during therapy and the 14 days post surgery period in >1.0% of patients, regardless of causality, include: white blood cell count increased and urine protein present.
Pediatric Patients
Laboratory adverse experiences that were reported during therapy in ≥1.0% of pediatric patients treated with INVANZ in clinical studies are presented in Table 10. Drug-related laboratory adverse experiences that were reported during therapy in ≥2.0% of pediatric patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, in clinical studies were neutrophil count decreased (3.0%), ALT increased (2.2%), and AST increased (2.1%).
Table 10: Incidence
(%) of Specific Laboratory Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥1.0% of Pediatric Patients Treated With INVANZ in Clinical Studies | INVANZ | Ceftriaxone | Ticarcillin/
Clavulanate |
| Adverse laboratory experiences | (n
=379) | (n=97) | (n=24) |
| ALT Increased | 3.8 | 1.1 | 4.3 |
| Alkaline Phosphatase Increased | 1.1 | 0.0 | 0.0 |
| AST Increased | 3.8 | 1.1 | 4.3 |
| Eosinophil Count Increased | 1.1 | 2.1 | 0.0 |
| Neutrophil Count Decreased | 5.8 | 3.1 | 0.0 |
| Platelet Count Increased | 1.3 | 0.0 | 8.7 |
Additional laboratory adverse experiences that were reported during therapy in >0.5% but <1.0% of patients treated with INVANZ in clinical studies include: white blood cell count decreased and urine protein present.
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