A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Invanz Side Effects, and Drug Interactions - Ertapenem
Invanz Side Effects, and Drug Interactions - Ertapenem
SIDE EFFECTS
Clinical studies enrolled 1954 patients treated with ertapenem;
in some of the clinical parenteral therapy was followed by a switch to an appropriate
oral antimicrobial. (See STUDIES.) Most adverse experiences reported in these
clinical studies were described as mild moderate in severity. Ertapenem was
discontinued due to adverse experiences in 4.7% of patients. 3 shows the incidence
of adverse experiences reported in 1.0% of patients in these studies.
The common drug-related adverse experiences in patients treated with INVANZ,
including those who switched to therapy with an oral antimicrobial, were diarrhea
(5.5%), infused vein complication (3. nausea (3.1%), headache (2.2%), vaginitis
in females (2.1%), phlebitis/thrombophlebitis (1.3%), vomiting (1.1%).
|
Table 3 Incidence (%) of Adverse Experiences Reported
During Study Therapy Plus 14-Day Follow-Up in ³1.0%
of Patients Treated With INVANZ in Clinical Studies
|
|
Adverse Events
|
INVANZ* 1 g daily (N=802)
|
Piperacillin/ Tazobactam* 3.375 g q6h (N=774)
|
INVANZ† 1 g daily (N=1152)
|
Ceftriaxone† 1 or 2 g daily (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
|
|
*Includes Phase IIb/III Complicated intra-abdominal infections,
Complicated skin and skin structure infections and Acute pelvic infections
studies
†Includes Phase IIb/III Community acquired
pneumonia and Complicated urinary tract infections, and Phase IIa studies
‡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 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.
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
Laboratory adverse experiences that were reported
during therapy in ³1.0%
of patients treated with INVANZ in clinical studies are presented in Table 4.
Drug-related laboratory adverse experiences that were reported during therapy
in ³1.0% of 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 4 Incidence* (%) of Specific Laboratory Adverse
Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ³1.0%
of Patients Treated With INVANZ in Clinical Studies
|
|
Adverse laboratory experiences
|
INVANZ‡ 1 g daily (n†=766)
|
Piperacillin/ Tazobactam‡ 3.375 g q6h (n†=755)
|
INVANZ§
1 g daily (n†=1122)
|
Ceftriaxone§
1 or 2 g daily (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
|
|
* 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 studies
§ Includes Phase IIb/III Community acquired
pneumonia and Complicated urinary tract infections, and Phase IIa studies
|
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.
DRUG INTERACTIONS
When ertapenem is co-administered with probenecid (500 mg p.o.
every 6 hours), probenecid competes for active tubular secretion and reduces
the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid
increased the AUC by 25% and reduced the plasma and renal clearances by 20%
and 35%, respectively. The half-life increased from 4.0 to 4.8 hours. Because
of the small effect on half-life, the coadministration with probenecid to extend
the half-life of ertapenem is not recommended. In vitro studies indicate that
ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine
and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
In vitro studies in human liver microsomes indicate that ertapenem does not
inhibit metabolism mediated by any of the following six cytochrome p450 (CYP)
isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. Drug interactions caused by inhibition
of P-glycoprotein-mediated drug clearance or CYP-mediated drug clearance with
the listed isoforms are unlikely. (See CLINICAL
PHARMACOLOGY, Distribution and Metabolism.) Other than with probenecid,
no specific clinical drug interaction studies have been conducted.
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