Avycaz

Name: Avycaz

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Avycaz Overview

Avycaz is a prescription medication used to treat complicated intra-abdominal infections and complicated urinary tract infections, including kidney infections.

It is a single product containing 2 medications: ceftazidime and avibactam. Ceftazidime belongs to a group of antibiotics called cephalosporins. These work by stopping the growth of bacteria. Avibactam belongs to a group of drugs called non-beta-lactam beta-lactamase inhibitors. These work by inhibiting the enzymes in bacteria that provide resistance to antibiotics. In this combination, avibactam allows the ceftazidime to work more effectively.

This medication is available as an injection and is given into the vein (intravenous (IV)) by a healthcare professional.

Common side effects of Avycaz include vomiting, nausea, constipation and anxiety. Avycaz may cause dizziness. Do not drive or operate heavy machinery until you now how Avycaz affects you.

What happens if I miss a dose?

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

What other drugs will affect avibactam and ceftazidime?

Other drugs may interact with avibactam and ceftazidime, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Before Using Avycaz

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of Avycaz® in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Avycaz® in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving this medicine.

Pregnancy

Pregnancy Category Explanation
All Trimesters B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

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.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Cholera Vaccine, Live
  • Probenecid
  • Warfarin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Chloramphenicol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Allergy to penicillin, history of—May increase risk of an allergic reaction to occur again.
  • Brain disease (eg, encephalopathy) or
  • Diarrhea, severe, history of or
  • Myoclonus (muscle twitching or jerking) or
  • Seizures—Use with caution. May make these conditions worse.
  • Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

What do I need to tell my doctor BEFORE I take Avycaz?

  • If you have an allergy to Avycaz (ceftazidime and avibactam) or any part of this medicine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you are taking probenecid.

This is not a list of all drugs or health problems that interact with Avycaz.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If OVERDOSE is suspected

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.

Use in specific populations

Pregnancy

Risk Summary

There are no adequate and well-controlled studies of Avycaz, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam.

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Data

Animal Data

Ceftazidime

Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime.

Avibactam

Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults.

Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed.

Lactation

Risk Summary

Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats. No information is available on the effects of ceftazidime and avibactam on the breast-fed child or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Avycaz and any potential adverse effects on the breastfed child from Avycaz or from the underlying maternal conditions.

Data

In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams. Exposure to avibactam was observed in both pups and milk on PND 7.

Pediatric Use

Safety and effectiveness in patients less than 18 years of age have not been established.

Geriatric Use

Of the 1373 patients treated with Avycaz in the Phase 2 and Phase 3 clinical trials 385 (28%) were 65 years of age and older, including 173 (15.3 %) patients 75 years of age and older.

In the pooled Phase 2 and Phase 3 cIAI Avycaz clinical trials, 20% (126/630) of patients treated with Avycaz were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the Avycaz plus metronidazole arm and 78.6% (77/98) in the meropenem arm.

In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with Avycaz were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with Avycaz had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the Avycaz arm and 58.8% (80/136) in the doripenem arm.

Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Renal Impairment

Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of Avycaz adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, Avycaz should be administered after hemodialysis on hemodialysis days [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ceftazidime and avibactam were each evaluated for mutagenic potential in several in vitro and in vivo assays. Ceftazidime was negative for mutagenicity in a mouse micronucleus test and an Ames test. Avibactam was negative for genotoxicity in the Ames assay, unscheduled DNA synthesis, chromosomal aberration assay, and a rat micronucleus study.

Avibactam had no adverse effects on fertility of male and female rats given up to 1 g/kg/day (approximately 20 fold higher than the recommended clinical dose on a body surface area basis). There was a dose-related increase in the percentage of pre- and post-implantation loss relative to controls, resulting in a lower mean litter size at doses 0.5 g/kg and greater with intravenous administration to female rats beginning 2 weeks prior to mating.

How Supplied/Storage and Handling

Avycaz 2.5 grams (ceftazidime and avibactam) for injection is supplied in single-dose, clear glass vial containing: ceftazidime 2 grams (equivalent to 2.635 grams of ceftazidime pentahydrate/sodium carbonate) and avibactam 0.5 grams (equivalent to 0.551 grams of avibactam sodium). Vials are supplied as individual vial (NDC# 0456-2700-01) and in cartons containing 10 vials (NDC# 0456-2700-10)

Avycaz vials should be stored at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from light. Store in carton until time of use.

Introduction

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

Interactions for Avycaz

Ceftazidime does not induce CYP1A1, 1A2, 2B6, or 3A4/5 in vitro.1

Avibactam does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2, 2B6, 2C9, or 3A4 in vitro;1 shows some potential to induce CYP2E1 at concentrations exceeding clinically relevant exposures.1

Avibactam is a substrate of organic anion transporter (OAT) 1 and OAT3 kidney transporters.1 Ceftazidime and avibactam do not inhibit OAT1 or OAT3 in vitro;1 ceftazidime does not inhibit avibactam transport mediated by OAT1 and OAT3.1

Ceftazidime and avibactam do not inhibit multidrug resistance transporter (MDR) 1, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 4, organic cation transporter (OCT) 1, or OCT2 in vitro at clinically relevant concentrations.1 Avibactam not a substrate for MDR1, BCRP, MRP4, or OCT2.1

The following drug interactions are based on studies using ceftazidime and avibactam, ceftazidime alone, or avibactam alone.1 When ceftazidime and avibactam used, consider interactions associated with both drugs in the fixed combination.1

Drugs Affecting or Affected by Organic Anion Transporter

OAT1 and/or OAT3 inhibitors: Possible decreased elimination of avibactam.1

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Metronidazole

Metronidazole has no effect on ceftazidime or avibactam peak concentrations or AUC;1 ceftazidime and avibactam has no effect on metronidazole peak concentrations or AUC1

No in vitro evidence of antagonistic antibacterial effects1

Other anti-infectives (colistin [commercially available in US as colistimethate sodium], levofloxacin, linezolid, tigecycline, tobramycin, vancomycin)

No in vitro evidence of antagonistic antibacterial effects1 7

Probenecid

Potential decreased elimination of avibactam; probenecid inhibits renal uptake of avibactam in vitro1

Concomitant use not recommended1

Tests for glucose

Possible false-positive reaction for urine glucose with certain testing methods1

Use urine glucose tests based on enzymatic glucose oxidase reactions1

(web3)