Archifar

Meropenem trihydrate.

Each vial contains meropenem trihydrate equivalent to anhydrous meropenem 500 mg.
It also contains sodium carbonate 104 mg which equates to approximately 2 mEq of sodium (approximately 45 mg).

Pharmacology: Pharmacodynamics: Meropenem is a carbapenem antibiotic for parenteral use, that is relatively stable to human dehydropeptidase-1 (DHP-1) and therefore, does not require the addition of an inhibitor of DHP-1.
Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cell walls, its high level of stability to all serine β-lactamases and its marked affinity for the penicillin binding proteins (PBPs) explain the potent bactericidal action of meropenem against a broad spectrum of aerobic and anaerobic bacteria. Minimum bactericidal concentrations (MBC) are commonly the same as the minimum inhibitory concentrations (MIC). For 76% of the bacteria tested, the MBC: MIC ratios were ≤2.
Meropenem is stable in susceptibility tests and these tests can be performed using normal routine methods. In vitro tests show that meropenem acts synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that meropenem has a post-antibiotic effect.
A single set of meropenem susceptibility criteria are recommended based on pharmacokinetics and correlation of clinical and microbiological outcomes with zone diameter and MIC of the infecting organisms. (See Table 1.)

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Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship: Similar to other β-lactam antibacterial agents, the time that meropenem concentration exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40% of the dosing interval. This target has not been established clinically.
Pharmacokinetics: In healthy subjects the mean plasma half-life (t_½) is approximately 1 hr; the mean volume of distribution is approximately 0.25 L/kg (11-27 L) and the mean clearance is 287 mL/min at 250 mg falling to 205 mL/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 min give mean peak plasma concentration (C_max) values of approximately 23, 49 and 115 mcg/mL respectively, corresponding AUC values were 39.3, 62.3 and 153 mcg·hr/mL. After infusion over 5 min C_max values are 52 and 112 mcg/mL after 500 and 1000 mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.
A study of 12 patients administered meropenem 1000 mg 8 hourly post-surgically for intra-abdominal infections showed a comparable C_max and t_½ to normal subjects but a greater volume of distribution 27 L.
Distribution: The average plasma protein-binding of meropenem was approximately 2% and was independent of concentration. After rapid administration (≤5 min) the pharmacokinetics are biexponential but this is much less evident after 30 min infusion. Meropenem has been shown to penetrate well into several body fluids and tissues including: Lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle and peritoneal exudates.
Metabolism: Meropenem is metabolised by hydrolysis of the β-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human DHP-I compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor.
Elimination: Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50-75%) of the dose is excreted unchanged within 12 hrs. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.
Adults: Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance (CrCl) and age.
Children: The pharmacokinetics in infants and children with infection at doses of 10, 20 and 40 mg/kg showed C_max values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and t_½ similar to those observed in adults in all but the youngest subjects (<6 months t_½ 1.6 hrs). The mean meropenem clearance values were 5.8 mL/min/kg (6-12 years), 6.2 mL/min/kg (2-5 years), 5.3 mL/min/kg (6-23 months) and 4.3 mL/min/kg (2-5 months). Approximately 60% of the dose is excreted in urine over 12 hrs as meropenem with a further 12% as metabolite. Meropenem concentrations in the cerebrospinal fluid of children with meningitis are approximately 20% of concurrent plasma levels although there is significant inter-individual variability.
The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average t_½ of 2.9 hrs. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hrly achieved 60% T>MIC for P. aeruginosa in 95% of pre-term and 91% of full term neonates.
Elderly: Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in CrCl, and a smaller reduction in nonrenal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment (see Dosage & Administration).
Renal Insufficiency: Renal impairment results in higher plasma area under the concentration-time curve (AUC) and longer t_½ for meropenem. There were AUC increases of 2.4-fold in patients with moderate impairment (CrCl 33-74 mL/min), 5-fold in severe impairment (CrCl 4-23 mL/min) and 10-fold in haemodialysis patients (CrCl <2 mL/min) when compared to healthy subjects (CrCl >80 mL/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment (see Dosage & Administration).
Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher than in anuric patients.
Hepatic Insufficiency: A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses.
Toxicology: Preclinical Safety Data: Animal studies indicate that meropenem is well tolerated by the kidney. In animal studies meropenem has shown nephrotoxic effects, only at high dose levels (500 mg/kg).
Effects on the CNS; convulsions in rats and vomiting in dogs, were seen only at high doses (>2000 mg/kg).
For an IV dose the LD₅₀ in rodents is >2000 mg/kg. In repeat dose studies (up to 6 months) only minor effects were seen including a small decrease in red cell parameters and an increase in liver weight in dogs treated with doses of 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive and teratogenic toxicity in studies at the highest possible doses in rats and monkeys; the no effect dose level of a (small) reduction in F₁ body weight in rat was 120 mg/kg. There was an increased incidence of abortions at 500 mg/kg in a preliminary study in monkeys.
There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.
The sole metabolite of meropenem had a similar profile of toxicity in animal studies.
Microbiology: Mechanism of Resistance: Bacterial resistance to meropenem may result from: Decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins); reduced affinity of the target PBPs; increased expression of efflux pump components, and production of β-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to >1 class of antibacterials agents when the mechanism involved includes impermeability and/or an efflux pump(s).
Breakpoints: European committee on antimicrobial susceptibility testing (EUCAST) clinical breakpoints for MIC testing are presented in Table 2 (See Table 2).

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The susceptibility to meropenem of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
The antibacterial spectrum of meropenem includes the following species, based on clinical experience and therapeutic guidelines.
Gram-Positive Aerobes: Enterococcus faecalis (note that E. faecalis can naturally display intermediate susceptibility), Staphylococcus aureus [methicillin-susceptible strains only: Methicillin-resistant staphylococci including methicillin-resistant staphylococcus aureus (MRSA) are resistant to meropenem], Staphylococcus species including Staphylococcus epidermidis [methicillin-susceptible strains only: Methicillin-resistant staphylococci including methicillin-resistant staphylococcus epidermidis (MRSE) are resistant to meropenem], Streptococcus agalactiae (Group B streptococcus), Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (Group A streptococcus).
Gram-Negative Aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.
Anaerobic Bacteria: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus spp (including P. micros, P anaerobius, P. magnus).
Bacteroides caccae, Bacteroides fragilis group, Prevotella bivia, Prevotella disiens.
Species for Which Acquired Resistance may be a Problem: Gram-Positive Aerobes: Enterococcus faecium (E. faecium can naturally display intermediate susceptibility even without acquired resistance mechanisms; note that in some European countries the frequency of resistance among E. faecium is >50% of isolates).
Species for Which Acquired Resistance may be a Problem: Gram-Negative Aerobes: Acinetobacter species, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently Resistant Organisms: Gram-negative aerobes.
Stenotrophomonas maltophilia, Legionella species.
Other Inherently Resistant Organisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumonia.
The published medical microbiology literature describes in vitro meropenem-susceptibilities of many other bacterial species. However the clinical significance of such in vitro findings is uncertain. Advice on the clinical significance of in vitro findings should be obtained from local infectious diseases and clinical microbiology experts and local professional guidelines. Meropenem and imipenem have a similar profile of clinical utility and activity against multiresistant bacteria. However, meropenem is intrinsically more potent against Pseudomonas aeruginosa and may be active in vitro against imipenem-resistant strains.
Meropenem is active in vitro against many strains resistant to other β-lactam antibiotics. This is explained in part by enhanced stability to β-lactamases. Activity in vitro against strains resistant to unrelated classes of antibiotics eg, aminoglycosides or quinolones is common.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Treatment in adults and children, of the following infections caused by single or multiple bacteria sensitive to meropenem: Pneumonias and nosocomial pneumonias; urinary tract infections; intra-abdominal infections; gynaecological infections, eg, 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 antiviral or antifungal agents.
Meropenem has proved efficacious alone or in combination with other antimicrobial agents in the treatment of polymicrobial infections.
There is no experience in paediatric patients with neutropenia or primary or secondary immunodeficiency.

Adults: The dosage and duration of therapy shall be established depending on type and severity of infection and the condition of the patient. The recommended daily dosage is as follows: 500 mg IV every 8 hrs in the treatment of pneumonia, UTI, gynaecological infections eg, endometritis, skin and skin structure infections.
Nosocomial Pneumonias, Peritonitis, Presumed Infections in Neutropenic Patients, Septicaemia: 1 g IV every 8 hrs.
Meningitis: Recommended Dose: 2 g every 8 hrs.
Infections Known or Suspected to be Caused by Pseudomonas aeruginosa: 1 g 3 times daily (or every 8 hrs) or higher is recommended.
There is limited safety data available to support a dose of >2 g 3 times daily (or every 8 hrs).
Children: Infections Known or Suspected to be Caused by Pseudomonas aeruginosa: Recommended Dose: Dose of up to 40 mg/kg 3 times daily (or every 8 hrs).
Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infection.
Children >3 months and up to 12 years: Recommended Dose: 10-20 mg/kg every 8 hrs depending on type and severity of infection, susceptibility of the pathogen and the condition of the patient.
Children >50 kg: Adult dosage should be used.
Meningitis: Recommended Dose: 40 mg/kg every 8 hrs.
There is no experience in children with renal impairment.
Elderly: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values >50 mL/min.
Impaired Renal Function: Dosage should be reduced in patients with creatinine clearance (CrCl) <51 mL/min, as scheduled as follows: CrCl 26-50 mL/min: 1-unit dose every 12 hrs, CrCl 10-25 mL/min: ½-unit dose every 12 hrs and CrCl <10 mL/min: ½-unit dose every 24 hrs (based on unit doses of 500 mg).
Meropenem is cleared by haemodialysis and hemofiltration; if continued treatment with Archifar 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 Insufficiency: No dosage adjustment is necessary in patients with hepatic insufficiency (see Precautions).
Administration: Archifar can be given as an IV bolus injection over approximately 5 min or by IV infusion over approximately 15-30 min using the specific available presentations.
There is limited safety data available to support the administration of a 40 mg/kg bolus dose.
There is limited safety data available to support the administration of a 2 g bolus dose.
Archifar to be used for bolus IV injection should be constituted with sterile water for injection (5 mL/250 mg meropenem). This provides an approximate concentration of 50 mg/mL.
Archifar for IV infusion may be constituted with compatible infusion fluids (see Interactions and Cautions for Usage).

Accidental overdosage could occur during therapy, particularly in patients with renal impairment. Limited post-marketing experience indicates that adverse events following overdosage are consistent with the adverse event profile described in adverse reactions. 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.

Hypersensitivity to meropenem trihydrate.

The selection of meropenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors eg, severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria.
As with all β-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported (see Contraindications and Adverse Reactions).
Patients who have a history of hypersensitivity to carbapenems, penicillins or other β-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to β-lactam antibiotics.
If a severe allergic reaction occurs, Archifar should be discontinued and appropriate measures taken.
Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents, including meropenem, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of meropenem (see Adverse Reactions). Discontinuation of therapy with meropenem and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see Adverse Reactions).
Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see Adverse Reactions).
A positive direct or indirect Coombs test may develop during treatment with meropenem.
The concomitant use of valproic acid/sodium valproate and Archifar is not recommended (see Interactions).
Archifar may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients.
Archifar contains sodium. Archifar contains approximately 2 mEq of sodium per 500 mg dose, which should be taken into consideration by patients on a controlled sodium diet.
Effects on the Ability to Drive or Operate Machinery: No studies on the ability to drive and use machines have been performed. However when driving or operating machines, it should be taken into account that headache, paraesthesia and convulsions have been reported for meropenem.
Hepatic Impairment: Patients with preexisting liver disorders should have liver function monitored during treatment with meropenem. There is no dose adjustment necessary (see Dosage & Administration).
Use in pregnancy: The safety of meropenem in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing foetus. The only adverse effect observed in animal reproductive studies was an increased incidence of abortions in monkeys at 13 times the expected exposure in man.
Archifar should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. In every case, it should be used under the direct supervision of the physician.
Use in lactation: Meropenem is detectable at very low concentrations in animal breast milk. Archifar should not be used in breastfeeding women unless the potential benefit justifies the potential risk to the baby.
Use in children: Efficacy and tolerability in infants <3 months have not been established; therefore, Archifar is not recommended for use below this age. There is no experience in children with altered hepatic or renal function.
Keep all medicines away from children.

Use in pregnancy: The safety of meropenem in human pregnancy has not been evaluated. Animal studies have not shown any adverse effect on the developing foetus. The only adverse effect observed in animal reproductive studies was an increased incidence of abortions in monkeys at 13 times the expected exposure in man.
Archifar should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus. In every case, it should be used under the direct supervision of the physician.
Use in lactation: Meropenem is detectable at very low concentrations in animal breast milk. Archifar should not be used in breastfeeding women unless the potential benefit justifies the potential risk to the baby.

The following adverse reactions have been identified following clinical studies with meropenem. Their frequency is presented in Frequency of Adverse Reactions (data derived from clinical trial data sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level.
Frequencies of occurrence of undesirable effects are defined as: Very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%).
Frequency of Adverse Reactions (Data Derived from Clinical Trial Data Sources): Infections and Infestations: Uncommon: Oral and vaginal candidiasis.
Blood and Lymphatic System Disorders: Common: Thrombocythaemia. Uncommon: Eosinophilia, thrombocytopenia, leucopenia, neutropenia.
Nervous System Disorders: Common: Headache. Uncommon: Paraesthesiae. Rare: Convulsions.
Gastrointestinal Disorders: Common: Diarrhoea, vomiting, nausea, abdominal pain.
Hepatobiliary Disorders: Increased common alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood lactate dehydrogenase and γ-glutamyltransferase. Uncommon: Increased blood bilirubin.
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritis. Uncommon: Urticaria.
General Disorders and Administration Site Conditions: Common: Inflammation, pain. Uncommon: Thrombophlebitis. Not Known: Pain at the injection site.
The following adverse reactions have been identified from post-marketing clinical trials and spontaneous reports. Their frequency is presented in Reporting Rate of Adverse Reactions (data derived from a combination of post-marketing clinical trial and spontaneous sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level.
Frequencies of occurrence of undesirable effects are defined as: Very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%).
Reporting Rate of Adverse Reactions (Data Derived from a Combination of Post-Marketing Clinical Trial and Spontaneous Sources): Blood and Lymphatic System Disorders: Rare: Agranulocytosis. Very Rare: Haemolytic anaemia.
Immune System Disorders: Very Rare: Angioedema, manifestations of anaphylaxis.
Gastrointestinal Disorders: Very Rare: Pseudomembranous colitis.
Skin and Subcutaneous Tissue Disorders: Very Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

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. As the potency and duration of action of Archifar dosed without probenecid are adequate, the co-administration of probenecid with Archifar is not recommended.
The potential effect of Archifar on the protein-binding of other drugs or metabolism has not been studied. The protein binding of Archifar is low (approximately 2%) and, therefore, no interactions with other compounds based on displacement from plasma proteins would be expected.
Archifar may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients.
Archifar has been administered concomitantly with other medications without adverse pharmacological interactions. However, no specific data regarding potential drug interactions is available (apart from probenecid as previous;y mentioned).
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100% decrease in valproic acid levels in about 2 days. Due to the rapid onset and the extent of the decrease, co-administration of Archifar in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see Precautions).
Oral Anticoagulants: Simultaneous administration of antibiotics with warfarin may augment its anticoagulant effects. There have been many reports of increases in the anticoagulant effects of orally administered anticoagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in international normalised ratio (INR) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anticoagulant agent.
Incompatibilities: Archifar must not be mixed with other medicinal products except those mentioned in Cautions for Usage.

Instructions for Disposal and Handling: It is recommended to use freshly prepared solutions.
Injection: Meropenem to be used for bolus IV injection should be constituted with sterile water for injection.
Infusion: For IV infusion, meropenem may be directly constituted with 0.9% sodium chloride or 5% glucose solution for infusion.
Each vial is for single use only.
Standard aseptic techniques should be used for solution preparation and administration.
The solution should be shaken before use.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.

Other Beta-Lactams

J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

POM