INVANZ is a penem antibacterial indicated in adult patients and pediatric patients (3 months of age and older) for the treatment of the following moderate to severe infections caused by susceptible bacteria: Complicated intra-abdominal infections. ( 1.1 ) Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis. ( 1.2 ) Community-acquired pneumonia. ( 1.3 ) Complicated urinary tract infections including pyelonephritis.
( 1.4 ) Acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecologic infections. ( 1.5 ) INVANZ is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. ( 1.6 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of INVANZ and other antibacterial drugs, INVANZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
( 1.7 )
1.1Complicated Intra-Abdominal Infections
INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated intra-abdominal infections due to Escherichia coli , Clostridium clostridioforme , Eubacterium lentum , Peptostreptococcus species, Bacteroides fragilis , Bacteroides distasonis , Bacteroides ovatus , Bacteroides thetaiotaomicron , or Bacteroides uniformis .
1.2Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis
INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae , Streptococcus pyogenes , Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Bacteroides fragilis , Peptostreptococcus species, Porphyromonas asaccharolytica , or Prevotella bivia .
INVANZ has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies (14) ].
1.3Community Acquired Pneumonia
INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with community acquired pneumonia due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis .
1.4Complicated Urinary Tract Infections Including Pyelonephritis
INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated urinary tract infections including pyelonephritis due to Escherichia coli , including cases with concurrent bacteremia, or Klebsiella pneumoniae .
1.5Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post-Surgical Gynecologic Infections
INVANZ is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with acute pelvic infections including postpartum endomyometritis, septic abortion and post-surgical gynecological infections due to Streptococcus agalactiae, Escherichia coli , Bacteroides fragilis, Porphyromonas asaccharolytica, Peptostreptococcus species, or Prevotella bivia .
1.6Prophylaxis of Surgical Site Infection Following Elective Colorectal Surgery
INVANZ is indicated in adults for the prevention of surgical site infection following elective colorectal surgery.
1.7Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of INVANZ and other antibacterial drugs, INVANZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Contraindications
INVANZ is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. Due to the use of lidocaine HCl as a diluent, INVANZ administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. Known hypersensitivity to product components or anaphylactic reactions to β-lactams.
( 4 ) Due to the use of lidocaine HCl as a diluent, INVANZ administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. ( 4 )
Warnings and precautions
Serious hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. ( 5.1 ) Seizures and other central nervous system adverse experiences have been reported during treatment. ( 5.2 ) Co-administration of INVANZ with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.3 ) Clostridioides difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs.
( 5.4 ) Caution should be taken when administering INVANZ intramuscularly to avoid inadvertent injection into a blood vessel. ( 5.5 )
5.1Hypersensitivity Reactions Serious
and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam.
Before initiating therapy with INVANZ, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams and other allergens. If an allergic reaction to INVANZ occurs, discontinue the drug immediately. Serious anaphylactic reactions require immediate emergency treatment as clinically indicated.
5.2Seizure Potential Seizures
and other central nervous system (CNS) adverse experiences have been reported during treatment with INVANZ [see Adverse Reactions (6.1) ] . During clinical investigations in adult patients treated with INVANZ (1 g once a day), seizures, irrespective of drug relationship, occurred in 0.5% of patients during study therapy plus 14-day follow-up period [see Adverse Reactions (6.1) ] . These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function.
Close adherence to the recommended dosage regimen is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of INVANZ re-examined to determine whether it should be decreased or discontinued.
5.3Interaction with Valproic Acid
Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction.
The concomitant use of ertapenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of INVANZ is necessary, supplemental anti-convulsant therapy should be considered [see Drug Interactions (7.2) ].
5.4 Clostridioides difficile- Associated Diarrhea (CDAD) CDAD has been reported with use of nearly all antibacterial agents, including ertapenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridioides difficile . Clostridioides difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of Clostridioides difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against Clostridioides difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridioides difficile , and surgical evaluation should be instituted as clinically indicated.
5.5Caution with Intramuscular Administration
Caution should be taken when administering INVANZ intramuscularly to avoid inadvertent injection into a blood vessel [see Dosage and Administration (2.7) ] .
5.6 Development of Drug-Resistant Bacteria As with other antibiotics, prolonged use of INVANZ may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken. Prescribing INVANZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
5.7Laboratory Tests While
INVANZ possesses toxicity similar to the beta-lactam group of antibiotics, periodic assessment of organ system function, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.
Interactions
Co-administration with probenecid inhibits the renal excretion of ertapenem and is therefore not recommended. ( 7.1 ) The concomitant use of ertapenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. ( 5.2 , 7.2 )
7.1Probenecid
Probenecid interferes with the active tubular secretion of ertapenem, resulting in increased plasma concentrations of ertapenem [see Clinical Pharmacology (12.3) ] . Co-administration of probenecid with ertapenem is not recommended.
7.2Valproic Acid
Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid [see Warnings and Precautions (5.3) ].
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Available data from a small number of post-marketing cases with INVANZ use in pregnancy are insufficient to inform any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies after intravenous administration of ertapenem during the period of organogenesis, there was no evidence of developmental malformations in rats at systemic exposures (AUC) up to approximately 1.2 times the human exposure at the maximum recommended human dose (MRHD) and in mice at doses up to approximately 3 times the MRHD based on body surface area comparison.
In pregnant rats administered ertapenem during organogenesis through lactation, fetal toxicity, developmental delays, and impaired reproduction did not occur in first generation offspring at systemic exposures (AUC) approximately 1.2 times the human exposure at the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, intravenous administration of ertapenem dosages of up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during the period of organogenesis (gestation days [GD] 6-20) revealed no maternal or embryofetal effects.
Pregnant mice intravenously administered ertapenem dosages of up to 700 mg/kg/day (approximately 3 times the MRHD based on body surface area comparison) during the period of organogenesis (GD 6-15) showed slight decreases in average fetal weight and an associated decrease in the average number of ossified sacrocaudal vertebrae. There were no maternal effects at any dosage. In a pre-postnatal study in rats, ertapenem administered to pregnant rats at dosages up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during organogenesis through lactation, (GD 6 until Lactation Day (LD) 20) did not result in fetal toxicity, developmental delays, or impaired reproduction in first generation offspring, and fetal deaths and malformations were not increased in second generation offspring.
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) ] Adults: The most common adverse reactions (≥5%) in patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, were diarrhea, nausea, headache and infused vein complication.
( 6.1 ) In the prophylaxis indication the overall adverse experience profile was generally comparable to that observed for ertapenem in other clinical trials. ( 6.1 ) Pediatrics: Adverse reactions in this population were comparable to adults. The most common adverse reactions (≥5%) in pediatric patients treated with INVANZ, including those who were switched to therapy with an oral antimicrobial, were diarrhea, vomiting and infusion site pain.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 INVANZ as a Treatment Regimen Clinical trials enrolled 1954 patients treated with INVANZ; 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. INVANZ 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 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%), 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 INVANZ in Clinical Trials INVANZ Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials 1 g daily Piperacillin/ Tazobactam 3.375 g q6h INVANZ Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 1 g daily Ceftriaxone 1 or 2 g daily Adverse Events (N=802) (N=774) (N=1152) (N=942) 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 Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor 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 In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving INVANZ 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 INVANZ, 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 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, 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 INVANZ, the adverse experience profile was generally similar to that seen in previous clinical trials. Prophylaxis of Surgical Site Infection following Elective Colorectal Surgery In a clinical trial in adults for the prophylaxis of surgical site infection following elective colorectal surgery in which 476 patients received a 1 g dose of INVANZ 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 INVANZ in previous clinical trials.
Table 4 shows the incidence of adverse experiences other than those previously described above for INVANZ that were reported regardless of causality in ≥2.0% of patients in this trial. Table 4 Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2.0% 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 Pneumonia 2.1
4.0 Postoperative infection 2.3
4.0 Urinary tract infection 3.8
5.5 Wound infection 6.5
12.4 Wound complication 2.9
2.3 Atelectasis 3.4
1.9 Additional adverse experiences that were reported in this prophylaxis trial with INVANZ, regardless of causality, with an incidence >0.5% within each body system are listed below: Gastrointestinal Disorders: C. difficile infection or colitis, dry mouth, hematochezia General Disorders and Administration Site Condition: crepitations Infections and Infestations: cellulitis, abdominal abscess, fungal rash, pelvic abscess Injury, Poisoning and Procedural Complications: incision site complication, incision site hemorrhage, intestinal stoma complication, anastomotic leak, seroma, wound dehiscence, wound secretion Musculoskeletal and Connective Tissue Disorders: muscle spasms Nervous
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Composition
Active ingredients
ERTAPENEM SODIUM EQ 1GM BASE/VIAL
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA021337.
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