Avycaz

Unless your doctor tells you otherwise, continue your normal diet.

Avibactam and ceftazidime is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

This medicine must be given slowly, and the infusion can take at least 2 hours to complete. You may need to use this medicine for up to 14 days. Follow your doctor's dosing instructions very carefully.

Avibactam and ceftazidime is a powder medicine that must be mixed with a liquid (diluent) in an IV bag before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

After mixing the powder with the diluent, store the IV bag in a refrigerator for up to 24 hours. Do not freeze. After you take the IV bag out of the refrigerator, you must use it within 12 hours.

Do not use avibactam and ceftazidime if it has changed colors or has particles in it. Call your pharmacist for new medication. The mixture should appear clear to light yellow.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Avibactam and ceftazidime will not treat a viral infection such as the flu or a common cold.

This medicine can cause unusual results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using avibactam and ceftazidime.

Store the dry unmixed powder medicine at room temperature away from moisture, heat, and light.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Call your doctor for instructions if you miss a dose of avibactam and ceftazidime.

Before taking Avycaz, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Avycaz or to any of its ingedients
• are allergic to other antibiotics, especially penicillins and cephalosporins
• have kidney disease
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Use Avycaz exactly as prescribed.

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

If you miss a dose,the missed dose should be administered as soon as possible. If it is almost time for the next dose, skip the missed dose and administer the next dose at the regular time. Do not take 2 doses of Avycaz at the same time.

• Keep this and all medications out of the reacgh of children.

Avibactam and ceftazidime are antibiotics that work by fighting bacteria in your body.

Avibactam and ceftazidime is a combination medicine used in adults to treat complicated infections of the bladder, kidney, or stomach and intestines.

Avibactam and ceftazidime may also be used for purposes not listed in this medication guide.

Your doctor will check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it and to check for unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Tell your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loose skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are using this medicine.

This medicine may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop using this medicine. Do not take any medicine to treat diarrhea without first checking with your doctor. If you have any questions or if mild diarrhea continues or gets worse, check with your doctor.

Check with your doctor right away if you have any of the following symptoms while receiving this medicine: confusion, loss of consciousness, jerking or twitching of the muscles, seizures, seeing, hearing, or feeling things that are not there, or severe sleepiness.

Before you have any medical tests, tell the medical doctor in charge that you are receiving this medicine. The results of some tests may be affected by this medicine.

Complicated Intra-abdominal Infections (cIAI)

Avycaz (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

Avycaz (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa in patients 18 years or older.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Avycaz and other antibacterial drugs, Avycaz should be used to treat only indicated 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.

Decreased Clinical Response in cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min

In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 4). The reduction in clinical cure rates was more marked in patients treated with Avycaz plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with Avycaz received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.

The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials.

Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of Avycaz accordingly [see Dosage and Administration (2.2), and Adverse Reactions (6.1)].

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with Avycaz is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to Avycaz occurs.

Clostridium difficile-associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including Avycaz, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs 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. Hypertoxin producing strains of C. 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 antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Central Nervous System Reactions

Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [see Dosage and Administration (2.2)].

Development of Drug-Resistant Bacteria

Prescribing Avycaz in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

Probenecid

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of Avycaz or avibactam alone with probenecid has not been conducted, co-administration of Avycaz with probenecid is not recommended [see Clinical Pharmacology (12.3)].

Drug/Laboratory Test Interactions

The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Applies to avibactam / ceftazidime: intravenous powder for solution

Along with its needed effects, avibactam / ceftazidime 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 avibactam / ceftazidime:

• Agitation
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• bluish color changes in skin color
• chest pain
• chills
• coma
• confusion
• convulsions
• cough
• decreased urine
• dizziness
• fever
• headache
• hostility
• increased thirst
• irregular heartbeat
• lethargy
• loss of appetite
• muscle pain or cramps
• muscle twitching
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• pinpoint red spots on the skin
• rapid weight gain
• seizures
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• stupor
• swelling of the face, ankles, hands, foot, or leg
• swollen glands
• tenderness
• unusual bleeding or bruising
• unusual tiredness or weakness

• Difficulty swallowing
• fast heartbeat
• hives, itching, or skin rash
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest

Some side effects of avibactam / ceftazidime 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:

• Abdominal or stomach pain
• diarrhea
• difficulty having a bowel movement (stool)

• Change in taste
• loss of taste
• redness of the skin
• white patches in the mouth or throat or on the tongue
• white patches with diaper rash

Storage

Parenteral

25°C (may be exposed to 15–30°C).1 Protect from light.1

Reconstituted solution may be stored for up to 30 minutes prior to transfer and dilution.1

Following reconstitution and dilution, may be stored for up to 12 hours at room temperature.1 Alternatively, may be stored for up to 24 hours at 2–8°C and then used within 12 hours after removal from refrigeration to room temperature.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Ceftazidime and avibactam is a fixed combination of ceftazidime (a third generation cephalosporin antibiotic) and avibactam (a non-β-lactam β-lactamase inhibitor).1 2

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

• Avibactam is a non-β-lactam β-lactamase inhibitor;1 5 6 25 26 27 differs structurally and pharmacologically from β-lactam β-lactamase inhibitors (e.g., sulbactam, clavulanic acid, tazobactam).5 6 25 26 27 Avibactam inactivates many β-lactamases in Ambler class A (e.g., some extended-spectrum β-lactamases [ESBLs], carbapenemases such as K. pneumoniae carbapenemases [KPCs]), class C (e.g., cephalosporinases such as AmpC), and class D (e.g., some oxacillinases [OXAs]).1 5 6 10 25 26 27 28 Cannot inactivate Ambler class B metallo-β-lactamases (MBLs)5 26 28 or certain OXA-type carbapenemases.5 9 26

• Because avibactam inactivates certain β-lactamases, concomitant use with ceftazidime can protect ceftazidime from degradation by these β-lactamases and expand its spectrum of activity to include many β-lactamase-producing bacteria resistant to ceftazidime alone.1 5 6 10 11 13 16 17 18 19 Avibactam does not decrease antibacterial activity of ceftazidime against ceftazidime-susceptible bacteria.1

• Ceftazidime and avibactam is bactericidal in action.1 13

• Active in vitro against many Enterobacteriaceae, including C. freundii,1 8 11 16 18 C. koseri,1 16 19 E. coli,1 8 9 11 13 16 18 E. aerogenes,1 E. cloacae,1 8 11 16 18 19 K. pneumoniae,1 8 9 11 16 18 K. oxytoca,1 18 19 Morganella morganii,1 11 18 Proteus1 11 (including P. mirabilis1 8 11 16 19 and P. vulgaris19 ), P. rettgeri,1 11 P. stuartii,1 and Serratia marcescens.1 8 18 19

• Active in vitro against many strains of Ps. aeruginosa,1 8 9 10 13 16 18 20 21 including some multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains.10 21

• Active in vitro against some Enterobacteriaceae that produce certain TEM, SHV, CTX-M, KPC, AmpC, or OXA β-lactamases and active in vitro against some Ps. aeruginosa that produce certain AmpC β-lactamases.1 5 6 8 9 10 11 13 16 18 20 21

• Has only limited activity in vitro against most anaerobic bacteria.5 31

• Resistance or reduced susceptibility to ceftazidime and avibactam can occur.1 5 13 16 17 19 26 29 Mechanism of resistance may be multifactorial.20

• Bacteria that produce metallo-β-lactamases are resistant to ceftazidime and avibactam;5 13 26 bacterial strains producing certain OXA β-lactamases (e.g., Acinetobacter, Ps. aeruginosa) also resistant to ceftazidime and avibactam.5 9 13 26

• Bacteria resistant to ceftazidime because of altered PBPs may also be resistant to ceftazidime and avibactam.5 Some strains of gram-negative bacteria (e.g., Ps aeruginosa, S. marcescens) that over-express efflux pumps or have porin mutations that result in resistance to ceftazidime may also have reduced susceptibility or resistance to ceftazidime and avibactam.1 5 8 16 20

• Cross-resistance between ceftazidime and avibactam and other classes of anti-infectives not reported.1 Some bacteria resistant to carbapenems, other cephalosporins (including ceftazidime alone), or fluoroquinolones may be susceptible to ceftazidime and avibactam.1 8

• Advise patients that antibacterials (including ceftazidime and avibactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1

• Importance of completing full course of therapy, even if feeling better after a few days.1

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ceftazidime and avibactam or other antibacterials in the future.1

• Advise patients that allergic reactions, including serious allergic reactions, requiring immediate treatment could occur.1 Importance of informing clinicians about any previous hypersensitivity reactions to ceftazidime and avibactam, other β-lactams (including cephalosporins), or other allergens.1

• Advise patients that adverse neurologic reactions can occur while receiving ceftazidime and avibactam.1 Importance of immediately informing a clinician if any neurologic signs and symptoms, including encephalopathy (disturbance of consciousness such as confusion, hallucinations, stupor, coma), myoclonus, and seizures, occur;1 immediate treatment, dosage adjustment, or discontinuance of ceftazidime and avibactam may be necessary.1

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)