Vaborem

Uses

Meropenem IV is used for treatment in adults and children for the following infections caused by single or multiple bacteria sensitive to meropenem.

• Pneumonia and Nosocomial Pneumonia
• Urinary Tract Infections
• Intra-abdominal Infections
• Gynaecological Infections, such as endometritis and pelvic inflammatory disease
• Skin and Skin Structure Infections
• Meningitis
• Septicaemia

Empiric treatment, for presumed infections in adult patients with febrile neutropenia, used as monotherapy or in combination with anti-viral or anti-fungal agents.

Vaborbactam is a beta lactamase inhibitor used to treat complicated urinary tract infections.

Indicated in combination with meropenem for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.

Vaborem is also used to associated treatment for these conditions: Bacterial Infections, Complicated Intra-Abdominal Infections, Meningitis, Bacterial, Complicated Bacterial Urinary Tract Infections, Complicated skin infection bacterialComplicated Urinary Tract Infection caused by Enterobacter cloacae, Complicated Urinary Tract Infection caused by Escherichia Coli, Complicated Urinary tract infection caused by klebsiella pneumoniae

How Vaborem works

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding- protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus.

Vaborbactam is a cyclic boronic acid pharmacophore β-lactamase inhibitor that elicits potent inhibition of Klebsiella pneumoniae carbapenemase (KPC) enzymes and other Ambler class A and C enzymes such as serine β-lactamases that confer resistance to commonly-used antibiotics such as Carbapenems. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam interacts with β-lactamases of Ambler classes A and C via precovalent and covalent binding. It exerts no inhibitory actions on class D or class B carbapenemases. The production of contemporary β-lactamase by bacterial isolates potentiate the degradation of β-lactam antibiotic agents, rendering them clinically ineffective and posing challenges for patients receiving the standard antibiotic therapy. In combination with meropenem, varborbactam acts as a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation mediated by serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC).

Dosage

Vaborem dosage

As with other antibiotics, caution may be required in using Meropenem as monotherapy in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infection. Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection. Meropenem should be given as an intravenous bolus injection over approximately 3-5 minutes or by intravenous infusion over approximately 15 to 30 minutes using the specific available presentations.

Adults:

The dosage and duration of therapy should be established depending on type and severity of infection and the condition of the patient. The recommended daily dosage of adult is as follows:

• Pneumonias, Urinary tract infections, gynaecological infections such as endometritis and pelvic inflammatory disease; skin and skin structure infections: Meropenem 500 mg IV every 8 hours
• Nosocomial pneumonias, peritonitis, presumed infections in neutropenic patients and septicaemia: Meropenem 1 g IV every 8 hours
• Meningitis: Meropenem 2 g IV every 8 hours
• Cystic fibrosis: Meropenem IV up to 2 g every 8 hours

Children:

• Children 0 to 3 months: Efficacy and tolerability in children under 3 months old have not been established; therefore Meropenem is not recommended.
• For children over 3 months to 12 years of age: The recommended dose of Meropenem IV is 10 to 20 mg/kg every 8 hours depending on type and severity of infection, susceptibility of the pathogen and the condition of the patient.
• For children aged 4 to 18 years with cystic fibrosis: The doses ranging of Meropenem IV is 25 to 40 mg/kg every 8 hours.
• In children 50 kg weight: Adult dosage should be used.
• In meningitis: The recommended dose of Meropenem IV is 40 mg/kg every 8 hours.
• There is no experience in children with hepatic or renal impairment.

Elderly:

• No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 ml/min.

The content of one vial is to be dissolved in 10 ml water for injection for Meropenem 500 mg IV injection and 20 ml water for injection for Meropenem 1 gm IV injection.

Preparation for injection:

Bolus: Meropenem 500 mg IV injection vials should be constituted with 10 ml sterile water for injections /Meropenem 1g IV injection vials should be constituted with 20 ml sterile water for injections (5 ml per 250 mg meropenem). This provides an approximate concentration of 50 mg/ml. Injection for bolus administration, may be stored for up to 2 hours at controlled room temperature 25°C or for up to 12 hours at 4°C.

Infusion: Meropenem (500 mg and 1 gm) IV injection vials may be directly constituted with a compatible infusion fluid (50 to 200 ml). Alternatively, an injection vial may be constituted, then the resulting solution added to an IV container and further diluted with an appropriate infusion fluid, as needed.

Side Effects

Meropenem is generally well tolerated. Side effects like inflammation, thrombophlebitis, pain at the site of injection, skin reactions like rash, pruritus, urticaria, abdominal pain, nausea, vomiting, diarrhoea, headache, parasthesiae may occur.

Toxicity

In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

In case of overdose, general supportive treatments should be initiated and hemodialysis to remove varobactam may be performed. In a pharmacokinetic study, mild lethargy observed in the highest-dose group.

Precaution

Caution in patients with history of hypersensitivity to carbapenems or other β-lactam antibiotics. Before initiating therapy with Meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics. If an allergic reaction to Meropenem occurs, the drug should be discontinued and appropriate measures should be taken. Monitor transaminase and bilirubin levels when used in hepatic disease. Not recommended for methicillin-resistant staphylococci infections. Monitor for overgrowth of non susceptible organisms. In patients who develop diarrhoea, consider diagnosis of pseudomembranous colitis. Caution in individuals with a history of gastro-intestinal complaints, particularly colitis. Caution if to be co-administered with potentially nephrotoxic drugs. Co-administration with probenicid not recommended. Meronem may reduce serum valproic acid levels, sub-therapeutic levels may occur. No specific drug interaction data are available. Caution when used as monotherapy for known or suspected Pseudomonas aeruginosa lower respiratory tract infections, regular sensitivity testing is recommended.

Interaction

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion, with the effect of increasing the elimination half-life and plasma concentration of meropenem. Meropenem may reduce serum valproic acid levels. Sub therapeutic levels may be reached in some patients.

Volume of Distribution

The steady-state volume of distribution of vaborbactam in patients was 18.6 L.

Elimination Route

The peak plasma concentrations (Cmax) and AUC of vaborbactam increase in a dose-proportional manner. In healthy adult subjects, the Cmax following administration of multiple 2 g dose as a 3-hour infusion was 55.6 mg/L and AUC was 588 mg•h/L. In patients with the same dosing regimen, the Cmax was 71.3 mg/L and AUC was 835 mg•h/L at steady state. The exposure of vaborbactam in terms of Cmax and AUC are not expected to change with repeated dosing, and there was no evidence of accumulation of vaborbactam in plasma in a repeated dosing study.

Half Life

Approximately 1 hour in adults and children 2 years of age and older with normal renal function. Approximately 1.5 hours in children 3 months to 2 years of age.

The half life of vaborbactam in healthy subjects following multiple 2 g dose administration as a 3-hour infusion was 1.68 hours. The half life of vaborbactam following administration of 2 g by 3 hour infusion was 2.25 hours.

Clearance

The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route. The clearance of vaborbactam in healthy subjects following administration of multiple doses of 2 g as a 3-hour infusion was 10.9 L/h. The clearance of vaborbactam in patients following administration of 2 g by 3 hour infusion was 7.95 L/h.

Elimination Route

Approximately 70% of the intravenously administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable.

Vaborbactam predominantly undergoes renal excretion, where about 75 to 95% of the dose is excreted unchanged in the urine over a 24 to 48 hour period.

Pregnancy & Breastfeeding use

The safety of Meropenem in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing foetus. Meropenem should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. Meropenem is detectable at very low concentrations in animal breast milk. It should be used in lactating women unless the potential benefit justifies the potential risk to the baby.

Contraindication

Meropenem is contraindicated in patients who have demonstrated hypersensitivity to this product.

Special Warning

Renal Impairment:

• CrCl 10-25: Half the usual dose 12 hrly.
• CrCl 26-50: Usual dose 12 hrly.

Meropenem is cleared by haemodialysis; if continued treatment with Meropenem is necessary, it is recommended that the unit dose (based on the type and severity of infection) is administered at the completion of the haemodialysis procedure to restore therapeutically effective plasma concentrations. There is no experience with the use of Meropenem in patients under peritoneal dialysis.

Hepatic Impairment: No dosage adjustment needed.

Acute Overdose

Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Treatment of overdosage should be symptomatic. In normal individuals, rapid renal elimination will occur; in subjects with renal impairment, haemodialysis will remove meropenem and its metabolite.

Storage Condition

Store in a cool and dry place (below 30° C). It is recommended to use freshly prepared solutions of Meropenem for IV injection and infusion. Reconstituted product should be used immediately and must be stored for no longer than 24 hours under refrigeration, only if necessary.

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