Zerbaxa

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe stomach pain; or
• diarrhea that is watery or bloody.

Side effects may be more likely in older adults.

Common side effects may include:

• nausea, diarrhea;
• headache; or
• fever.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Zerbaxa is a prescription medication used to treat complicated infections of the stomach and urinary tract, including kidney infection.

It is a single product containing 2 medications: ceftolozane and tazobactam.

Ceftolozane belongs to a group of drugs called cephalosporins. Tazobactam belongs to a group of drugs called beta-lactamase inhibitors. These help to eliminate bacteria that cause many kinds of infections.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of Zerbaxa include nausea, diarrhea, headache and fever.

• Cubist Pharmaceuticals, Inc.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Zerbaxa crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with the use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Zerbaxa.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to Zerbaxa.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Zerbaxa or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Zerbaxa (ceftolozane and tazobactam). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to ≤50 mL/min

In a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min compared to those with CrCl >50 mL/min (Table 4). The reduction in clinical cure rates was more marked in the Zerbaxa plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of Zerbaxa accordingly [see Dosage and Administration (2.2)].

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs.

Before initiating therapy with Zerbaxa, make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to Zerbaxa occurs, discontinue the drug and institute appropriate therapy.

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Zerbaxa, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is confirmed, discontinue antibacterials not directed against C. difficile, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing Zerbaxa in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

In the event of overdose, discontinue Zerbaxa and provide general supportive treatment. Zerbaxa can be removed by hemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the tazobactam metabolite M1 were removed by dialysis. No information is available on the use of hemodialysis to treat overdosage.

Applies to ceftolozane / tazobactam: intravenous powder for solution, powder iv (infusion)

Along with its needed effects, ceftolozane / tazobactam may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking ceftolozane / tazobactam:

• Fever

• Blurred vision
• confusion
• convulsions
• decreased urine
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• increased thirst
• irregular heartbeat
• loss of appetite
• muscle pain or cramps
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• pale skin
• rash
• sweating
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Abdominal or stomach cramps or pain
• arm, back, or jaw pain
• bloating
• bloody urine
• chest pain or discomfort
• chest tightness or heaviness
• constipation
• creamy white, curd-like patches in the mouth or throat
• decreased frequency or amount of urine
• diarrhea
• dry, red, hot, or irritated skin
• fast or irregular heartbeat
• hives or welts, itching skin
• increased thirst
• lower back or side pain
• pain when eating or swallowing
• severe constipation
• severe vomiting
• swelling of the face, fingers, or lower legs
• weight gain

• Abdominal or stomach tenderness
• cough
• difficulty with swallowing
• dizziness
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• severe abdominal or stomach cramps and pain
• watery and severe diarrhea, which may also be bloody

Some side effects of ceftolozane / tazobactam may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Headache

• Acid or sour stomach
• belching
• burning feeling in the chest or stomach
• fear or nervousness
• heartburn
• indigestion
• stomach discomfort or upset
• trouble sleeping

• Flushed, dry skin
• fruit-like breath odor
• increased hunger
• increased urination
• unexplained weight loss

Contraindications

• Known serious hypersensitivity to ceftolozane and/or tazobactam, the fixed combination of piperacillin and tazobactam, or other β-lactams.1

Warnings/Precautions

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions reported in patients receiving β-lactam antibacterials.1 Before initiating therapy, carefully inquire about patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or other β-lactams.1

Use with caution in patients allergic to cephalosporins, penicillins, or other β-lactams;1 cross-sensitivity among β-lactams established.1

If anaphylactic reaction occurs, discontinue ceftolozane and tazobactam and initiate appropriate therapy.1

Reduced Efficacy in Patients with Moderate Renal Impairment

In a subgroup analysis of patients with complicated intra-abdominal infections in a phase 3 clinical trial, clinical cure rate in patients with moderate renal impairment (baseline Clcr of 30–50 mL/minute) receiving ceftolozane and tazobactam in conjunction with metronidazole was 47.8% compared with a clinical cure rate of 85.2% in those with normal renal function or only mild renal impairment (Clcr ≥50 mL/minute).1 A similar trend also observed in a clinical trial evaluating ceftolozane and tazobactam for complicated urinary tract infections.1

Monitor Clcr at least once daily in patients with changing renal function;1 adjust dosage accordingly.1 (See Renal Impairment under Cautions.)

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi.1 Monitor carefully, institute appropriate therapy if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.1 12 14 15 C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including ceftolozane and tazobactam, and may range in severity from mild diarrhea to fatal colitis.1 12 14 15 C. difficile produces toxins A and B which contribute to development of CDAD;1 12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 12 14 15 Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible.1 12 Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1 12 14 15

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of ceftolozane and tazobactam and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.1

When prescribing, preparing, and dispensing ceftolozane and tazobactam, consider that dosage of the fixed combination is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftolozane plus dosage of tazobactam).1 (See Dispensing and Dosage and Administration Precautions under Dosage and Administration.)

Specific Populations

Category B.1

Use during pregnancy only if potential benefits to the woman justify potential risks to fetus.1

No adequate and well-controlled studies in pregnant women.1 In animals, no evidence of fetal toxicity with ceftolozane or tazobactam dosages tested;1 ceftolozane associated with decreased auditory startle response in postnatal day 60 male pups;1 tazobactam associated with decreased maternal food consumption and body weight gain at end of gestation and increased incidence of stillbirths.1

Not known whether ceftolozane or tazobactam distributed into human milk.1

Use with caution in nursing women.1

Safety and efficacy not established in patients <18 years of age.1

Incidence of adverse effects higher in patients ≥65 years of age compared with younger adults.1

Clinical cure rate in geriatric patients treated with ceftolozane and tazobactam in conjunction with metronidazole for complicated intra-abdominal infections was 69% compared with cure rate of 82.4% in comparator group.1 Differences in cure rates between ceftolozane and tazobactam regimen and comparator regimen not observed in geriatric patients with complicated urinary tract infections.1

Ceftolozane and tazobactam substantially eliminated by kidneys;1 risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients are more likely to have reduced renal function, select dosage with caution and consider renal function monitoring.1 Adjust dosage in geriatric patients based on renal function.1

Ceftolozane and tazobactam do not undergo hepatic metabolism;1 hepatic impairment not expected to affect systemic clearance.1

Ceftolozane, tazobactam, and tazobactam metabolite M1 are eliminated by the kidneys.1 18 23

Adjust dosage in adults with moderate or severe renal impairment (Clcr ≤50 mL/minute), including those undergoing hemodialysis.1 Monitor Clcr at least once daily in patients with changing renal function;1 adjust dosage accordingly.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea,1 diarrhea1 ), headache,1 pyrexia.1

• Ceftolozane and tazobactam is a fixed combination of ceftolozane (a third generation cephalosporin) and tazobactam (a β-lactamase inhibitor).1 2

• Like other cephalosporins, antibacterial activity of ceftolozane results from inhibition of mucopeptide synthesis in bacterial cell wall and is mediated by penicillin-binding proteins (PBPs).1 3 10 21 Ceftolozane has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins,2 21 and is distinguished from many other cephalosporins by its activity against Ps. aeruginosa.2 21

• Tazobactam is a penicillanic acid sulfone β-lactamase inhibitor structurally similar to sulbactam.5 21 28 Tazobactam inactivates certain β-lactamases, including some extended-spectrum β-lactamases (ESBLs).1 3 5 21 28 Inactivates many β-lactamases in Ambler class A (e.g., penicillinases, ESBLs) and some in class C (e.g., cephalosporinases such as AmpC).1 3 5 21 28 Cannot inactivate Ambler class A carbapenemases (e.g., K. pneumoniae carbapenemases [KPCs]), Ambler class D β-lactamases, or Ambler class B metallo-β-lactamases (MLBs).1 5 28

• Because tazobactam inactivates certain β-lactamases, concomitant use with ceftolozane can protect ceftolozane from degradation by these β-lactamases and expand its spectrum of activity to include many β-lactamase-producing bacteria resistant to ceftolozane alone.1 3 5 6 11 13 21

• Ceftolozane and tazobactam is bactericidal in action.1 21

• Gram-positive aerobes: Active in vitro against S. anginosus,1 S. constellatus,1 S. salivarius,1 S. agalactiae,1 S. intermedius,1 S. pyogenes,1 and S. pneumoniae.1

• Gram-negative aerobes: Active in vitro against Enterobacteriaceae, including E. aerogenes,1 E. cloacae,1 E. coli,1 6 9 11 K. oxytoca,1 9 K. pneumoniae,1 6 9 11 P. mirabilis,1 6 9 P. vulgaris,1 C. freundii,1 K. koseri,1 Morganella morganii,1 Providencia rettgeri,1 P. stuartii,1 Serratia liquefacians,1 and S. marcescens.1 Active in vitro against Acinetobacter baumannii,1 Burkholderia cepacia,1 Haemophilus influenzae,1 Moraxella catarrhalis,1 and Pantoea agglomerans.1 Also active in vitro against Ps. aeruginosa (including isolates with chromosomal AmpC, loss of outer membrane porin [OprD], or up-regulation of efflux pumps [e.g., MexXY, MexAB]).1 5 6 7 8 9 11 16

• Anaerobic bacteria: Active in vitro against some strains of B. fragilis,1 6 17 Fusobacterium,1 17 Prevotella,1 17 and Propionibacterium.17

• Resistance or reduced susceptibility to ceftolozane and tazobactam can occur.1 21

• Bacteria that produce Ambler class B metallo-β-lactamases or serine carbapenemases (such as KPC) are resistant to ceftolozane and tazobactam.1 Although some isolates of E. coli and K. pneumoniae producing β-lactamases in certain enzyme groups (e.g., CTX-M, OXA, TEM, SHV) are susceptible to ceftolozane and tazobactam in vitro, other isolates of E. coli and K. pneumoniae producing β-lactamases in these enzyme groups are resistant to the drug.1 Ps. aeruginosa with reduced susceptibility or resistance to ceftolozane and tazobactam have been produced in vitro.16

• Cross-resistance between ceftolozane and tazobactam and other cephalosporins may occur;1 16 however, some bacteria resistant to other cephalosporins may be susceptible to the fixed combination.1