Tivibact Infusion

Ceftazidime 2 gm / Avibactam 0.5 gm Powder for Concentrate for Solution for Infusion

Each vial contains :

Ceftazidime (As Ceftazidime

Pentahydrate) IP 2.0 gm

Avibactam Sodium

equivalent to Avibactam 0.5 gm

Excipients q.s.

Powder for concentrate for solution for infusion, Ceftazidime 2 gm / Avibactam 0.5 gm

4.1 Therapeutic Indication

• Complicated intra-abdominal infection (cIAI).
• Complicated urinary tract infection (cUTI), including pyelonephritis.
• Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) with susceptible gram negative microorganisms.

Treatment of patients with bacteremia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

4.2 Posology & Method of Administration

It is recommended that Tivibact should be used to treat infections due to aerobic Gram-negative organisms in adults and paediatric patients aged 3 months and older with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases.

Posology

Dosage in adults with creatinine clearance (CrCL) > 50 mL/min Table 1 shows the recommended intravenous dose for adults with estimated creatinine clearance (CrCL) > 50 mL/min.

T 1 able : 1 Recommended dose for adults with estimated CrCL > 50 mL/min

1 CrCL estimated using the Cockcroft-Gault formula. 2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process. 3 To be used in combination with an antibacterial agent active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process. 4 The total duration shown may include intravenous Tivibact followed by appropriate oral therapy. 5 There is very limited experience with the use of Tivibact for more than 14 days. Dosage in paediatric patients with creatinine clearance (CrCL) >50 mL/min/1.73 m2 Table 2 shows the recommended intravenous doses for paediatric patients with estimated creatinine clearance 2 (CrCL) > 50 mL/min/1.73 m . T 1 2 able 2 : Recommended dose for paediatric patients with estimated CrCL > 50 mL/min/1.73 m

1 CrCL estimated using the Schwartz bedside formula. 2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process. 3 To be used in combination with an antibacterial agent active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process. 4 The total treatment duration shown may include intravenous Tivibact followed by appropriate oral therapy. 5 There is very limited experience with the use of Tivibact for more than 14 days. 6 There is limited experience with the use of Tivibact in paediatric patients 3 months to < 6 months. 7 Ceftazidime/avibactam is a combination product in a xed 4:1 ratio and dosage recommendations are based on the ceftazidime component only.

Special populations

Elderly

No dosage adjustment is required in elderly patients.

Renal impairment

No dosage adjustment is required in patients with mild renal impairment (estimated CrCL > 50 - ≤ 80 mL/min).

Table 3 shows the recommended dose adjustments for adults with estimated CrCL ≤ 50 mL/min.

Dosage in adults with CrCL ≤ 50 mL/min

Table 3: Recommended dose for adults with estimated CrCL ≤ 50 mL/min

1 CrCL estimated using the Cockcroft-Gault formula. 2 Dose recommendations are based on pharmacokinetic modelling. 3 Ceftazidime and avibactam are removed by haemodialysis. Dosing of Tivibact on haemodialysis days should occur after completion of haemodialysis.

4 Ceftazidime/avibactam is a combination product in a xed 4:1 ratio and dosage recommendations are based on the ceftazidime component only. Table 4 and Table 5 show the recommended dose adjustments for paediatric patients with 2 estimated CrCL ≤ 50 mL/min/1.73 m according to different age groups. Dosage in paediatric patients ≥ 2 years of age with CrCl ≤ 50 mL/min/1.73 m2 T 1 2 able 4: Recommended dose for paediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m

1 CrCL estimated using the Schwartz bedside formula. 2 Dose recommendations are based on pharmacokinetic modelling. 3 Ceftazidime and avibactam are removed by haemodialysis. Dosing of Tivibact on haemodialysis days should occur after completion of haemodialysis. 4 Ceftazidime/avibactam is a combination product in a xed 4:1 ratio and dosage recommendations are based on the ceftazidime component only. Dosage in paediatric patients <2 years of age with CrCl ≤ 50 mL/min/1.73 m2 T 1 2 able 5: Recommended dose for paediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m

There is insufcient information to recommend a dosage regimen for paediatric patients < 2 2 years of age that have a CrCL < 16 mL/min/1.73 m .

Hepatic impairment

No dosage adjustment is required in patients with hepatic impairment

Paediatric population

The safety and efficacy of Tivibact in paediatric patients < 3 months old have not been established. No data are available.

Method of administration

Intravenous use.

Tivibact is administered by intravenous infusion over 120 minutes in an appropriate infusion

volume.

Reconstitution data

The powder must be reconstituted with water for injections and the resulting concentrate must then be immediately diluted prior to use. Tivibact (ceftazidime/avibactam) is a combination product; each vial contains 2 g of ceftazidime and 0.5 g of avibactam in a xed 4:1 ratio. Dosage recommendations are based on the ceftazidime component only.

Standard aseptic techniques should be used for solution preparation and administration. Doses may be prepared in an appropriately sized infusion bag or infusion syringe. Parenteral medicinal products should be inspected visually for particulate matter prior to administration.

Each vial is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

The total time interval between starting reconstitution and completing preparation of the intravenous infusion should not exceed 30 minutes

Instructions for preparing adult and paediatric doses in INFUSION BAG or in INFUSION SYRINGE:

NOTE: The following procedure describes the steps to prepare an infusion solution with a nal concentration of 8-40 mg/mL of ceftazidime. All calculations should be completed prior to initiating these steps. For paediatric patients aged 3 to 12 months, detailed steps to prepare a 20 mg/mL concentration (sufcient for most scenarios) are also provided. 1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime): a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water for injections. b) Withdraw the needle and shake the vial to give a clear solution. c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve the internal pressure (this is important to preserve product sterility). 2. Prepare the nal solution for infusion (nal concentration must be 8-40 mg/mL of ceftazidime): a) Infusion bag: Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution to an infusion bag containing any of the following: sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer's solution. b) Infusion syringe: Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution combined with a sufficient volume of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection) to an infusion syringe. Refer to Table 7 below. Table 7: Preparation of Tivibact for adult and paediatric doses in INFUSION BAG or in INFUSION

1 Based on ceftazidime component only. 2 Dilute to final ceftazidime concentration of 8 mg/mL for in-use stability up to 12 hours at 2 - 8°C, followed by up to 4 hours at not more than 25°C (i.e. dilute 2 g dose of ceftazidime in 250 mL, 1 g dose of ceftazidime in 125 mL, 0.75 g dose of ceftazidime in 93 mL, etc.). All other ceftazidime concentrations (> 8 mg/mL to 40 mg/mL) have in-use stability up to 4 hours at not more than 25°C.

Preparation of Tivibact for use in paediatric patients aged 3 to 12 months of age in INFUSION SYRINGE:

NOTE: The following procedure describes the steps to prepare an infusion solution with a nal concentration of 20 mg/mL of ceftazidime (sufficient for most scenarios). Alternative concentrations may be prepared, but must have a nal concentration range of 8-40 mg/mL of ceftazidime.

1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime): a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water for injections. b) Withdraw the needle and shake the vial to give a clear solution. c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve the internal pressure (this is important to preserve product sterility). 2. Prepare the nal solution for infusion to a nal concentration of 20 mg/mL of ceftazidime: a) Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution combined with a sufcient volume of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection) to an infusion syringe. b) Refer to Table 8, 9, or 10 below to conrm the calculations. Values shown are approximate as it may be necessary to round to the nearest graduation mark of an appropriately sized syringe. Note that the tables are NOT inclusive of all possible calculated doses but may be utilized to estimate the approximate volume to verify the calculation. Table 8: Preparation of Tivibact (final concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 2 to 12 months of age with creatinine clearance (CrCL) > 50 mL/min/1.73 m

1 Based on ceftazidime component only. Table 9: Preparation of Tivibact (nal concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 2 to 12 months of age with CrCL 31 to 50 mL/min/1.73 m

1 Based on ceftazidime component only. Table 10: Preparation of Tivibact (nal concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 2 to 12 months of age with CrCL 16 to 30 mL/min/1.73 m

1 Based on ceftazidime component only.

4.3 Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in the formulation. • Hypersensitivity to any cephalosporin antibacterial agent. • Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

4.4 Warning & Precautions

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions are possible. In case of hypersensitivity reactions, treatment with Tivibact must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems

Clostridioides difficile- associated diarrhoea

Clostridioides diffcile-associated diarrhoea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Tivibact. Discontinuation of therapy with Tivibact and the administration of specic treatment for Clostridioides difcile should be considered. Medicinal products that inhibit peristalsis should not be given.

Renal impairment

Ceftazidime and avibactam are eliminated via the kidneys, therefore, the dose should be reduced according to the degree of renal impairment. Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment. In patients with renal impairment, close monitoring of estimated creatinine clearance is advised. In some patients, the creatinine clearance estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection.

Nephrotoxicity

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolytic anaemia Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia. While DAGT seroconversion in patients receiving Tivibact was very common in clinical studies (the estimated range of seroconversion across Phase 3 studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least one follow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with Tivibact treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Tivibact should be investigated for this possibility.

Complicated intra-abdominal infections in adults

In two studies in patients with cIAI, the most common diagnosis (approximately 42%) was appendiceal perforation or peri-appendiceal abscess. Approximately 87% of patients had

APACHE II scores of ≤ 10 and 4% had bacteraemia at baseline. Death occurred in 2.1% (18/857) of patients who received Tivibact and metronidazole and in 1.4% (12/863) of patients who received meropenem. Among a subgroup with baseline CrCL 30 to 50 mL/min death occurred in 16.7% (9/54) of patients who received Tivibact and metronidazole and 6.8% (4/59) of patients who received meropenem. Patients with CrCL 30 to 50 mL/min received a lower dose of Tivibact than is currently recommended for patients in this sub-group.

Complicated urinary tract infections in adults

In two studies in patients with cUTI, 381/1091 (34.9%) patients were enrolled with cUTI without pyelonephritis while 710 (65.1%) were enrolled with acute pyelonephritis (mMITT population). A total of 81 cUTI patients (7.4%) had bacteraemia at baseline. Hospital-acquired pneumonia (including ventilator-associated pneumonia) in adults. In a single study in patients with nosocomial pneumonia 280/808 (34.7%) had VAP and 40/808 (5%) were bacteraemic at baseline.

Patients with limited treatment options

The use of ceftazidime/avibactam to treat patients with infections due to Gram-negative aerobic pathogens who have limited treatment options is based on experience with ceftazidime alone and on analyses of the pharmacokinetic-pharmacodynamic relationship for ceftazidime/avibactam. Spectrum of activity of ceftazidime/avibactam Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes. Additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process. The inhibitory spectrum of avibactam includes many of the enzymes that inactivate ceftazidime, including Ambler class A β-lactamases and class C β-lactamases. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes.

Non-susceptible organisms

Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. enterococci, fungi), which may require interruption of treatment or other appropriate measures.

Interference with laboratory tests

Ceftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) for detection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria.

Controlled sodium die

The maximum daily dose of this product is equivalent to 22% of the WHO recommended maximum daily intake for sodium. Tivibact is considered high in sodium. This should be considered when administering Tivibact to patients who are on a controlled sodium diet. Tivibact may be diluted with sodium-containing solutions and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

Paediatric population

There is a potential risk of overdosing, particularly for paediatric patients aged from 3 to less than 12 months of age. Care should be taken when calculating the volume of administration of the dose.

4.5 Drug Interactions

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake of avibactam from the blood compartment and, therefore, affect its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and, therefore, has the potential to alter the elimination of avibactam. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-administration of avibactam with probenecid is n9ot recommended. Avibactam showed no signicant inhibition of cytochrome P450 enzymes in vitro. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction at clinically relevant concentrations. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low. Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam, and between ceftazidime/avibactam and metronidazole.

Other types of interaction

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this nding is unknown, but due to the possibility of antagonism in vivo this drug combination should be avoided.

4.6 Special populations

Pregnancy

Animal studies with ceftazidime do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects. Ceftazidime/avibactam should only be used during pregnancy if the potential benet outweighs the possible risk.

Breast-feeding

Ceftazidime is excreted in human milk in small quantities. It is unknown whether avibactam is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast feeding or to discontinue/abstain from ceftazidime/avibactam therapy taking into account the benet of breast feeding for the child and the benet of therapy for the woman.

Fertility

The effects of ceftazidime/avibactam on fertility in humans have not been studied. No data are available on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmful effects with respect to fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects may occur (e.g. dizziness), which may inuence the ability to drive and use machines following administration of Tivibact.

4.8 Undesirable Effects

The most common adverse reactions were Coombs direct test positive, nausea, and diarrhoea. Nausea and diarrhoea were usually mild or moderate in intensity. Table 6: Frequency of adverse reactions by system organ class

Paediatric population

The safety assessment in paediatric patients is based on the safety data from two trials in which 61 patients (aged from 3 years to less than 18 years) with cIAI and 67 patients with cUTI (aged from 3 months to less than 18 years) received Tivibact. Overall, the safety prole in these 128 paediatric patients was similar to that observed in the adult population with cIAI and cUTI.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benet/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : http://www.zuventus.co.in/safety.aspx By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy, convulsions and coma, due to the ceftazidime component. Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis. During a 4-hour haemodialysis period, 55% of the avibactam dose was removed.

5.1 Mechanism of Action

Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (PBPs), which leads to bacterial cell lysis and death. Avibactam is a non β-lactam, β-lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. It inhibits both Ambler class A and class C β-lactamases and some class D enzymes, including extended-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes (metalloβ-lactamases) and is not able to inhibit many class D enzymes.

5.2 Pharmacodynamic Properties

Efficacy has been demonstrated in clinical studies against the following pathogens that were susceptible to ceftazidime/avibactam in vitro.

Complicated intra-abdominal infections

Gram-negative micro-organisms

• Citrobacter freundii

• Enterobacter cloacae

• Escherichia coli

• Klebsiella oxytoca

• Klebsiella pneumoniae

• Pseudomonas aeruginosa

Complicated urinary-tract infections

Gram-negative micro-organisms

• Escherichia coli

• Klebsiella pneumoniae

• Proteus mirabilis

• Enterobacter cloacae

• Pseudomonas aeruginosa

Hospital-acquired pneumonia including ventilator-associated pneumonia

Gram-negative micro-organisms

• Enterobacter cloacae

• Escherichia coli

• Klebsiella pneumoniae

• Proteus mirabilis

• Serratia marcescens

• Pseudomonas aeruginosa

Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to ceftazidime/avibactam in the absence of acquired mechanisms of resistance. Gram-negative micro-organisms

• Citrobacter koseri

• Enterobacter aerogenes

• Morganella morganii

• Proteus vulgaris

• Providencia rettgeri

In-vitro data indicate that the following species are not susceptible to ceftazidime/avibactam

• Staphylococcus aureus (methicillin-susceptible and methicillin-resistant)

• Anaerobes

• Enterococcus spp.

• Stenotrophomonas maltophilia

• Acinetobacter spp.

5.3 Pharmacokinetic properties

Distribution

The human protein binding of both ceftazidime and avibactam is approximately 10% and 8%, respectively. The steady-state volumes of distribution of ceftazidime and avibactam were about 17 L and 22 L, respectively in healthy adults following multiple doses of 2 g/0.5 g ceftazidime/avibactam infused over 2 hours every 8 hours. Both ceftazidime and avibactam penetrate into human bronchial epithelial lining uid (ELF) to the same extent with concentrations around 30% of those in plasma. The concentration time proles are similar for ELF and plasma. Penetration of ceftazidime into the intact blood-brain barrier is poor. Ceftazidime concentrations of 4 to 20 mg/L or more are achieved in the CSF when the meninges are inamed. Avibactam penetration of the blood brain barrier has not been studied clinically; however, in rabbits with inflamed meninges, CSF exposures of ceftazidime and avibactam were 43% and 38% of plasma AUC, respectively. Ceftazidime crosses the placenta readily, and is excreted in the breast milk.

Biotransformation

Ceftazidime is not metabolised. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component 14 in human plasma and urine following dosing with [ C]-avibactam.

Elimination

The terminal half-life (t½) of both ceftazidime and avibactam is about 2 h after intravenous administration. Ceftazidime is excreted unchanged into the urine by glomerular ltration; approximately 80-90% of the dose is recovered in the urine within 24 h. Avibactam is excreted unchanged into the urine with a renal clearance of approximately 158 mL/min, suggesting active tubular secretion in addition to glomerular ltration. Approximately 97% of the avibactam dose is recovered in the urine, 95% within 12 h. Less than 1% of ceftazidime is excreted via the bile and less than 0.25% of avibactam is excreted into faeces

6.1 Animal Toxicology or Pharmacology

Ceftazidime

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproduction toxicity or genotoxicity. Carcinogenicity studies have not been conducted with ceftazidime.

Avibactam

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted with avibactam.

Reproduction toxicity

In pregnant rabbits administered avibactam at 300 and 1000 mg/kg/day, there was a dose-related lower mean foetal weight and delayed ossication, potentially related to maternal toxicity. Plasma exposure levels at maternal and foetal NOAEL (100 mg/kg/day) indicate moderate to low margins of safety.

In the rat, no adverse effects were observed on embryofetal development or fertility. Following administration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pup survival, growth or development, however there was an increase in incidence of dilation of the renal pelvis and ureters in less than 10% of the rat pups at maternal exposures greater than or equal to approximately 1.5 times human therapeutic exposures.

Tivibact is an antibacterial combination product consisting of the semisynthetic cephalosporin ceftazidime pentahydrate and the β-lactamases inhibitor avibactam sodium for IV administration.

Ceftazidime

Ceftazidime pentahydrate is is the pentahydrate of (6R,7R,Z)-7-(2-(2aminothiazol-4-yl)-2-(2- carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1azabicyclooct-2-ene-2-carboxylate. Its molecular weight is 636.6. The empirical formula is C₂₂H₃₂N₆O₁₂S₂.

Avibactam

Avibactam sodium chemical name is sodium octan-6-yl] sulphate. Its molecular weight is 287.23. The empirical formula is C₇H₁₀N₃O₆SNa.

8.1 Incompatibilities

The compatibility of Tivibact with other medicines has not been established. Tivibact should not be mixed with or physically added to solutions containing other medicinal products.

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

20 ml USP Type - I glass vial containing 2.5 g Ceftazidim/Avibactam packed in carton along with pack insert.

8.4 Storage and handing instructions Store below 30°C. Protect from light

Keep out of reach of children.

Do not use Tivibact if

• you are allergic to ceftazidime, avibactam or any of the other ingredients of this medicine

• you are allergic to other cephalosporin antibiotics

• you have ever had a severe allergic reaction to other antibiotics belonging to the penicillin or carbapenem groups.

Do not use Tivibact if any of the above apply to you. If you are not sure, talk to your doctor or nurse before using Tivibact

Warnings and precautions

Talk to your doctor or nurse before using Tivibact if:

• you have ever had any allergic reaction (even if only a skin rash) to other antibiotics belonging to the penicillin or carbapenem groups

• you have kidney problems - your doctor may give you a lower dose to make sure you don’t get too much medicine. This could cause symptoms such as fits (see section If you use more Tivibact than you should)

If any of the above apply to you (or you are not sure), talk to your doctor or nurse before using Tivibact.

Talk to your doctor or nurse if you suffer from diarrhoea during your treatment.

Other infections

There is a small possibility that you may get a different infection caused by another bacteria during or after treatment with Tivibact. These include thrush (fungal infections of the mouth or genital area).

Lab tests

Tell your doctor that you are taking Tivibact if you are going to have any tests. This is because you may get an abnormal result with a test called “DAGT” or “Coombs”. This test looks for antibodies that fight against your red blood cells. Tivibact can also affect the results of some urine tests for sugar. Tell the person taking the sample that you have been given Tivibact.

Paediatric patients

Tivibact should not be used in paediatric patients aged under 3 months. This is because it is not known if the medicine is safe to use in this age group.

Other medicines and Tivibact

Tell your doctor or nurse if you are using, have recently used or might use any other medicines. Talk to your doctor before using Tivibact if you are taking any of the following medicines:

• an antibiotic called chloramphenicol

• a type of antibiotic called an aminoglycoside - such as gentamicin, tobramycin

• a water tablet called furosemide

• a medicine for gout called probenecid

Tell your doctor before using Tivibact if any of the above apply to you.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Driving and using machines

Tivibact may make you feel dizzy. This may affect you being able to drive, use tools or machines.

Tivibact contains sodium

This medicine contains approximately 148 mg sodium in each vial. Talk to your doctor or pharmacist if you need 3 or more vials daily for a prolonged period, especially if you have been advised to have a low salt (sodium) diet.

How to use Tivibact

Tivibact will be given to you by a doctor or a nurse

If you use more Tivibact than you should

Tivibact will be given to you by a doctor or a nurse, so it is unlikely you will be given the wrong dose. However, if you have side effects or think you have been given too much Tivibact, tell your doctor or nurse straight away. If you have too much Tivibact it could have an effect on the brain and cause fits or coma.

If you miss a dose of Tivibact

If you think you have missed a dose, tell your doctor or nurse straight away. If you have any further questions on the use of this medicine, ask your doctor or nurse.