Meropenem
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERONEM (MERONEM®)
Composition:
Active substance: meropenem;
1 vial contains: meropenem trihydrate 570 mg (equivalent to 500 mg anhydrous meropenem) or meropenem trihydrate 1140 mg (equivalent to 1000 mg anhydrous meropenem);
Excipient: sodium carbonate anhydrous.
Pharmaceutical form. Powder for solution for injection or infusion.
Main physicochemical characteristics: powder from white to light yellow color.
Pharmacotherapeutic group. Antimicrobial agents for systemic use. Carbapenems. ATC code J01DH02.
Pharmacological Properties
Pharmacodynamics
Meropenem exerts a bactericidal effect by inhibiting the synthesis of bacterial cell walls in both Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
As with other beta-lactam antibacterial agents, the time during which meropenem concentrations exceed the minimum inhibitory concentrations (MICs) (T> MIC) correlates strongly with efficacy. Preclinical models have demonstrated meropenem activity at plasma concentrations exceeding the MIC for infecting microorganisms for approximately 40% of the dosing interval. This target value has not been clinically established.
Bacterial resistance to meropenem may arise due to: (1) reduced permeability of the outer membrane in Gram-negative bacteria (due to decreased porin production), (2) reduced affinity for target PBPs, (3) increased expression of efflux pump components, and (4) production of beta-lactamases capable of hydrolyzing carbapenems.
In the European Union, outbreaks of infection caused by carbapenem-resistant bacteria have been reported.
There is no cross-resistance between meropenem and medicinal products belonging to the quinolone, aminoglycoside, macrolide, or tetracycline classes with respect to the target microorganisms. However, bacteria may exhibit resistance to more than one class of antibacterial agents when the mechanism involved includes reduced membrane permeability and/or the presence of efflux pump(s).
The MIC breakpoints established during clinical studies by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are available at the following link:
https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx
The prevalence of acquired resistance may vary geographically and over time for individual species; therefore, it is advisable to refer to local information on microbial resistance, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, expert consultation should be sought.
The following lists pathogenic microorganisms based on clinical experience and therapeutic treatment guidelines.
Typically susceptible species
Gram-positive aerobes
Enterococcus faecalis7
Staphylococcus aureus (methicillin-sensitive)8
Staphylococcus species (methicillin-sensitive), including Staphylococcus epidermidis
Streptococcus agalactiae (Group B)
Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius)
Streptococcus pneumoniae
Streptococcus pyogenes (Group A)
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
Gram-positive anaerobes
Clostridium perfringens
Peptoniphilus asaccharolyticus
Peptostreptococcus species (including P. micros, P. anaerobius, P. magnus)
Gram-negative anaerobes
Bacteroides caccae
Bacteroides fragilis group
Prevotella bivia
Prevotella disiens
Species for which acquired resistance may be a problem
Gram-positive aerobes
Enterococcus faecium7,9
Gram-negative aerobes
Acinetobacter species
Burkholderia cepacia
Pseudomonas aeruginosa
Inherently resistant microorganisms
Gram-negative aerobes
Stenotrophomonas maltophilia
Legionella species
Other microorganisms
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetii
Mycoplasma pneumoniae
7 Species showing intrinsic intermediate susceptibility.
8 All methicillin-resistant staphylococci are resistant to meropenem.
9 Resistance rate > 50% in one or more EU countries.
Glanders and melioidosis: The use of meropenem in humans is based on in vitro susceptibility data for B. mallei and B. pseudomallei and limited human data. Physicians should refer to national and/or international consensus documents regarding the treatment of glanders and melioidosis.
Pharmacokinetics
In healthy individuals, the mean plasma half-life is approximately 1 hour; the mean volume of distribution is about 0.25 L/kg (11–27 L); and the mean clearance is 287 mL/min following administration of a 250 mg dose, decreasing to 205 mL/min with a 2 g dose. After administration of 500, 1000, and 2000 mg doses as 30-minute infusions, mean Cmax values are approximately 23, 49, and 115 µg/mL, respectively; corresponding AUC values are 39.3, 62.3, and 153 µg×h/mL. Following 5-minute infusions, Cmax values are 52 and 112 µg/mL after 500 and 1000 mg doses, respectively. With multiple dosing every 8 hours in patients with normal renal function, accumulation of meropenem is not observed.
In a study involving 12 patients who received meropenem 1000 mg every 8 hours after surgery for intra-abdominal infections, Cmax and half-life values were consistent with those in healthy individuals, but a larger volume of distribution (27 L) was observed.
Distribution
The mean extent of meropenem binding to plasma proteins is approximately 2% and independent of drug concentration. After rapid administration (5 minutes or less), pharmacokinetics are biexponential, but this is much less evident after a 30-minute infusion. Meropenem has been shown to penetrate well into certain body fluids and tissues, including lungs, bronchial secretions, bile, cerebrospinal fluid, female genital tissues, skin, fascia, muscle, and peritoneal exudates.
Metabolism
Meropenem is metabolized via hydrolysis of the beta-lactam ring, forming a microbiologically inactive metabolite. In vitro, meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem, and there is no need for concomitant administration of a DHP-I inhibitor.
Excretion
Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (50–75%) of the administered dose is excreted unchanged within 12 hours. An additional 28% is excreted as the microbiologically inactive metabolite. Fecal excretion accounts for only about 2% of the dose. Measured renal clearance and the effect of probenecid indicate that meropenem undergoes both glomerular filtration and tubular secretion.
Renal impairment
Impaired renal function results in higher plasma AUC values and a prolonged elimination half-life for meropenem. AUC increased by 2.4-fold in patients with moderate renal impairment (creatinine clearance (CrCl) 33–74 mL/min), 5-fold in patients with severe renal impairment (CrCl 4–23 mL/min), and 10-fold in patients on hemodialysis (CrCl <2 mL/min), compared to healthy individuals (CrCl >80 mL/min). AUC values for the microbiologically inactive open-ring metabolite were also significantly increased in patients with impaired renal function. Dose adjustment is recommended for patients with moderate and severe renal impairment (see section "Dosage and administration").
Meropenem is removed by hemodialysis, with a clearance during hemodialysis approximately 4 times higher than in anuric patients.
Hepatic impairment
A study in patients with alcoholic cirrhosis showed no effect of liver disease on meropenem pharmacokinetics after repeated dosing.
Adult patients
Pharmacokinetic studies in patients have not revealed significant pharmacokinetic differences compared to healthy individuals with similar renal function. A population model developed from data in 79 patients with intra-abdominal infection or pneumonia showed dependence of key parameters on body weight, creatinine clearance, and age.
Children
Pharmacokinetic studies in infants and children with infection receiving doses of 10, 20, and 40 mg/kg showed Cmax values approaching those observed in adults after 500, 1000, and 2000 mg doses, respectively. Comparative analyses revealed pharmacokinetic characteristics between doses and half-lives similar to those in adults, except in the youngest patients (<6 months, t1/2 1.6 hours). 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 within 12 hours as meropenem, and an additional 12% as metabolite. Meropenem concentrations in cerebrospinal fluid in children with meningitis are approximately 20% of simultaneously measured plasma levels, although considerable inter-individual variability exists.
Pharmacokinetics of meropenem in newborns receiving antibacterial treatment demonstrated higher clearance in newborns with greater chronological or gestational age, with an overall mean half-life of 2.9 hours. Monte Carlo simulations based on a population pharmacokinetic model showed that with a dosing regimen of 20 mg/kg every 8 hours, T>MIC of 60% against P. aeruginosa was achieved in 95% of preterm newborns and 91% of term newborns.
Elderly patients
Pharmacokinetic studies in healthy elderly individuals (65–80 years) showed reduced plasma clearance, correlating with age-related reduction in creatinine clearance, and a slight reduction in non-renal clearance. Dose adjustment is not required in elderly patients unless moderate or severe renal impairment is present.
Clinical characteristics.
Indications.
Meronem is indicated for the treatment of the following infections in adults and children aged 3 months and older:
- pneumonia, including community-acquired and hospital-acquired pneumonia;
- bronchopulmonary infections in cystic fibrosis;
- complicated urinary tract infections;
- complicated intra-abdominal infections;
- infections during childbirth and postpartum infections;
- complicated skin and soft tissue infections;
- acute bacterial meningitis.
Meronem may be used for the treatment of patients with neutropenia and fever suspected to be caused by a bacterial infection.
Treatment of patients with bacteremia associated or potentially associated with any of the above-mentioned infections.
Official recommendations regarding appropriate use of antibacterial agents should be taken into account.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Hypersensitivity to any other antibacterial agent of the carbapenem class.
Severe hypersensitivity (e.g., anaphylactic reactions, severe skin reactions) to any other type of beta-lactam antibacterial agent (e.g., penicillins or cephalosporins).
Interaction with other medicinal products and other forms of interaction.
Studies on interaction of the drug with other medicinal products, except probenecid, have not been conducted.
Probenecid competes with meropenem for active tubular secretion and thus inhibits renal excretion of meropenem, resulting in an increased elimination half-life and higher meropenem plasma concentrations. Caution should be exercised when probenecid is administered concomitantly with meropenem.
The potential effect of Meronem on protein binding of other drugs or metabolism has not been studied. However, since protein binding is so low, interactions with other compounds via this mechanism are not expected.
Decreased levels of valproic acid in blood have been reported when co-administered with carbapenems, resulting in approximately 60–100% reduction in valproic acid levels within about 2 days. Due to the rapid onset and extent of reduction, concomitant administration of valproic acid/sodium valproate/valpromide and carbapenems is considered non-adjustable; therefore, such interaction should be avoided (see section "Special precautions for use").
Oral anticoagulants
Concomitant use of antibiotics with warfarin may enhance its anticoagulant effect. Numerous reports have documented increased anticoagulant effect of oral anticoagulants, including warfarin, in patients receiving antibacterial agents concomitantly. The risk may vary depending on the type of underlying infection, age, and general condition of the patient, thus making it difficult to assess the contribution of antibacterial agents to increased INR (International Normalized Ratio). Frequent monitoring of INR levels is recommended during and immediately after concomitant use of antibiotics with oral anticoagulants.
Children
All drug interaction studies have been conducted in adults only.
Special precautions for use
When selecting meropenem as a treatment option, consideration should be given to the appropriateness of using a carbapenem-class antibacterial agent, taking into account factors such as the severity of infection, prevalence of resistance to other suitable antibacterial agents, and the risk of selecting for carbapenem-resistant bacteria.
Resistance of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter
In the European Union, resistance to penems among Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter varies. When prescribing the drug, local resistance patterns of these bacteria to penems should be taken into account.
Hypersensitivity reactions
As with other beta-lactam antibiotics, serious, and sometimes fatal, hypersensitivity reactions have been reported (see sections «Contraindications» and «Adverse reactions»).
Patients with a history of hypersensitivity to carbapenems, penicillins, or other beta-lactam antibiotics may also be at increased risk of hypersensitivity to meropenem. A thorough patient history regarding prior hypersensitivity reactions to beta-lactam antibiotics should be obtained before initiating meropenem therapy.
If a severe allergic reaction occurs, administration of the drug must be discontinued immediately and appropriate measures initiated.
Severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, and acute generalized exanthematous pustulosis have been reported in patients receiving meropenem treatment (see section «Adverse reactions»). If signs or symptoms suggestive of these reactions occur, meropenem should be discontinued immediately and alternative therapy considered.
Hypersensitivity reactions with other beta-lactam antibiotics have been reported to progress to Kounis syndrome (acute allergic coronary artery spasm, which may lead to myocardial infarction; see section «Adverse reactions»).
Antibiotic-associated colitis
Cases of antibiotic-associated colitis, including pseudomembranous colitis, have been reported with the use of nearly all antibacterial agents, including meropenem, with severity ranging from mild to life-threatening. Therefore, this diagnosis should be considered in patients who develop diarrhea during or after meropenem therapy (see section «Adverse reactions»). Discontinuation of meropenem and initiation of specific therapy directed against Clostridium difficile should be considered. Medicinal products that inhibit intestinal peristalsis should not be administered.
Seizures
Seizures have been rarely reported during treatment with carbapenems, including meropenem (see section «Adverse reactions»).
Liver function monitoring
Due to the risk of hepatotoxicity (liver function abnormalities with cholestasis and cytolysis) during meropenem therapy, liver function should be closely monitored (see section «Adverse reactions»).
Use in patients with liver disease: liver function should be closely monitored in patients with pre-existing liver disease during meropenem therapy. Dose adjustment is not required (see section «Dosage and administration»).
Seroconversion in the direct antiglobulin test (Coombs test)
Treatment with meropenem may result in a positive direct or indirect Coombs test.
Concomitant use of meropenem and valproic acid/sodium valproate/valpromide is not recommended (see section «Interaction with other medicinal products and other forms of interaction»).
Meronem 500 mg: this medicinal product contains 45 mg of sodium per 500 mg vial, equivalent to 2.25% of the maximum daily sodium intake for an adult (2 g) recommended by the WHO.
Meronem 1000 mg: this medicinal product contains 90 mg of sodium per 1000 mg vial, equivalent to 4.5% of the maximum daily sodium intake for an adult (2 g) recommended by the WHO.
Use during pregnancy or breastfeeding
Pregnancy
Data on the use of meropenem in pregnant women are lacking or limited in quantity.
Animal studies have not shown direct or indirect effects of reproductive toxicity. As a precautionary measure, it is advisable to avoid the use of meropenem during pregnancy.
Breastfeeding
It has been reported that small amounts of meropenem pass into human breast milk. Meropenem may be used during lactation only if the expected benefit to the mother outweighs the potential risk to the infant.
Effect on ability to drive and use machines
Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.
When driving vehicles or operating machinery, special caution is recommended due to the possibility of developing headache, paresthesia, or seizures, which have been reported during meropenem use.
Method of Administration and Dosage.
Dosage
The tables below provide general recommendations for dosing of the medicinal product.
The dose of meropenem and duration of treatment depend on the causative pathogen, severity of the infection, and the patient's response to therapy.
Meronem administered at doses up to 2 g three times daily in adults and children with body weight over 50 kg, and up to 40 mg/kg three times daily in children, may be particularly appropriate for the treatment of certain infections caused by less susceptible bacterial species (e.g. Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species) or in cases of severe infections.
Additional dosage recommendations must be followed when treating patients with renal impairment (see below).
Table 1
Recommended doses for adults and children with body weight over 50 kg
| Infection |
Single dose administered every 8 hours |
| Pneumonia, including community-acquired and hospital-acquired pneumonia |
500 mg or 1 g |
| Bronechopulmonary infections in cystic fibrosis |
2 g |
| Complicated urinary tract infections |
500 mg or 1 g |
| Complicated intra-abdominal infections |
500 mg or 1 g |
| Infections during childbirth and postpartum infections |
500 mg or 1 g |
| Complicated skin and soft tissue infections |
500 mg or 1 g |
| Acute bacterial meningitis |
2 g |
| Treatment of patients with febrile neutropenia |
1 g |
Meropenem should usually be administered as an intravenous infusion over 15 to 30 minutes.
Additionally, doses of up to 1 g may be given as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of the 2 g dose as an intravenous bolus injection in adults are limited.
Renal impairment
Table 2
Recommended doses of the drug for adults and children with body weight over 50 kg when the patient's creatinine clearance is less than 51 ml/min
| Creatinine clearance (mL/min) |
Single dose (see Table 1) |
Frequency |
| 26–50 |
full single dose |
every 12 hours |
| 10–25 |
half the single dose |
every 12 hours |
| <10 |
half the single dose |
every 24 hours |
Data supporting the use of the doses of the drug indicated in Table 2, adjusted per 2 g dose unit, are limited.
Meropenem is eliminated by hemodialysis and hemofiltration; therefore, the required dose of the drug should be administered after completion of the hemodialysis procedure.
There are no recommendations regarding established dosing for patients undergoing peritoneal dialysis.
Hepatic impairment
Dose adjustment of the drug is not required for patients with hepatic impairment (see section «Special warnings and precautions for use»).
Dosing in elderly patients
Dose adjustment is not required for elderly patients with normal renal function or with creatinine clearance values above 50 mL/min.
Children under 3 months of age
There are no data on the safety and efficacy of meropenem in children under 3 months of age, and the optimal dosing regimen has not been established. Limited pharmacokinetic data support the use of a meropenem dose of 20 mg/kg every 8 hours (see section «Pharmacokinetics»).
Table 3
Recommended doses of the drug for children aged from 3 months to 11 years and with body weight up to 50 kg
| Infection |
Single dose administered every 8 hours |
| Pneumonia, including community-acquired and hospital-acquired pneumonia |
10 or 20 mg/kg body weight |
| Respiratory tract infections in cystic fibrosis |
40 mg/kg body weight |
| Complicated urinary tract infections |
10 or 20 mg/kg body weight |
| Complicated intra-abdominal infections |
10 or 20 mg/kg body weight |
| Complicated skin and soft tissue infections |
10 or 20 mg/kg body weight |
| Acute bacterial meningitis |
40 mg/kg body weight |
| Treatment of patients with febrile neutropenia |
20 mg/kg body weight |
Children with body weight more than 50 kg
The dose for adults should be used.
There is no experience with the use of the drug in children with impaired renal function.
Method of administration
Meronem is usually administered as an intravenous infusion over 15 to 30 minutes. Additionally, doses of meropenem up to 20 mg/kg may be administered as an intravenous bolus injection over approximately 5 minutes. Safety data supporting administration of the drug as an intravenous bolus injection at a dose of 40 mg/kg in children are limited.
Preparation for intravenous bolus injection
The solution for bolus injection should be prepared by dissolving the Meronem medicinal product in water for injections to obtain a concentration of 50 mg/mL.
Chemical and physical stability of the prepared bolus injection solution has been demonstrated for 3 hours at temperatures up to 25 °C or for 12 hours under refrigeration (2–8 °C).
From a microbiological standpoint, if the method of opening/reconstitution/dilution does not exclude the risk of microbial contamination, the medicinal product should be used immediately.
If the medicinal product is not used immediately, the storage period and conditions of the prepared solution should be strictly controlled.
Preparation for intravenous infusion
The infusion solution should be prepared by dissolving the Meronem medicinal product in 0.9 % sodium chloride solution for infusion or in 5 % glucose (dextrose) solution for infusion to obtain a concentration of 1–20 mg/mL.
Chemical and physical stability of the prepared infusion solution using 0.9 % sodium chloride solution has been demonstrated for 3 hours at 25 °C or for 24 hours under refrigeration (2–8 °C). From a microbiological standpoint, the medicinal product should be used immediately. If the medicinal product is not used immediately, the storage period and conditions of the prepared solution should be strictly controlled.
The Meronem solution prepared with 5 % glucose (dextrose) solution should be used immediately.
Prepared solutions should not be frozen.
Children.
The drug may be administered to children aged 3 months and older.
Overdose.
Relative overdose is possible in patients with impaired renal function if the dose of the drug is not adjusted as described in the section «Method of administration and dosage». Limited post-marketing experience suggests that if adverse reactions occur after overdose, they are consistent with the profile of the adverse reactions listed in the section «Adverse reactions», are generally mild in severity, and resolve after discontinuation of the drug or dose reduction. Symptomatic treatment should be considered as necessary.
In individuals with normal renal function, the drug is rapidly eliminated by the kidneys.
Haemodialysis removes meropenem and its metabolites from the body.
Adverse Reactions
In the review of data from 4872 out of 5026 patients regarding the effects of meropenem treatment, the most commonly reported adverse reactions associated with meropenem use were diarrhea (2.3%), rash (1.4%), nausea/vomiting (1.4%), and injection site inflammation (1.1%). The most frequently reported laboratory abnormalities associated with meropenem use were thrombocytosis (1.6%) and elevated liver enzymes (1.5–4.3%).
The table below lists all adverse reactions by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Infections and infestations – uncommon: oral and vaginal candidiasis.
Blood and lymphatic system disorders – common: thrombocytosis; uncommon: agranulocytosis, hemolytic anemia, thrombocytopenia, neutropenia, leukopenia, eosinophilia.
Immune system disorders – uncommon: anaphylactic reaction (see sections «Contraindications» and «Special warnings and precautions for use»), angioedema.
Psychiatric disorders – rare: delirium.
Nervous system disorders – common: headache; uncommon: paresthesia; rare: seizures (see section «Special warnings and precautions for use»).
Gastrointestinal disorders – common: diarrhea, abdominal pain, vomiting, nausea; uncommon: antibiotic-associated colitis (see section «Special warnings and precautions for use»).
Hepatobiliary disorders – common: increased transaminase levels, increased alkaline phosphatase levels in blood, increased lactate dehydrogenase levels in blood; uncommon: increased blood bilirubin levels.
Skin and subcutaneous tissue disorders – common: rash, pruritus; uncommon: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria; frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (see section «Special warnings and precautions for use»).
Renal and urinary disorders – uncommon: increased blood creatinine levels, increased blood urea levels.
General disorders and administration site conditions – common: inflammation, pain; uncommon: thrombophlebitis, injection site pain.
There are no data suggesting an increased risk of adverse reactions in children based on the limited available data. All reported events corresponded to adverse reactions observed in adult patients.
Description of selected adverse reactions
Kounis syndrome
Cases of acute coronary syndrome associated with allergic reaction (Kounis syndrome) have been reported during treatment with other beta-lactam antibiotics (see section «Special warnings and precautions for use »).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 4 years.
Storage conditions.
Store at a temperature not exceeding 30 °C. Do not freeze. Keep out of reach of children.
Each vial is intended for single use only.
Standard aseptic techniques should be used during reconstitution and administration of the solution.
The solution should be shaken before use.
Any unused product or waste material must be disposed of in accordance with local requirements.
Incompatibilities. Meronem must not be mixed or added to other medicinal products.
Meronem intended for intravenous bolus injection should be reconstituted with sterile water for injection.
Meropenem in vials for intravenous infusion may be directly reconstituted with 0.9% sodium chloride solution or 5% glucose solution for infusion.
Packaging. Glass vials stoppered with rubber closures and sealed with aluminum caps. 10 vials per cardboard box.
Prescription status. Prescription only.
Manufacturer.
AstraZeneca UK Limited.
Manufacturer's location and address of its business operations.
Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.
Or*
Manufacturer.
Zambon Switzerland Ltd.
Manufacturer's location and address of its business operations.
Via Industria 13, 6814 Cadempino, Switzerland.
٭ The instruction leaflet inside the cardboard package will indicate only one manufacturer (the one responsible for the batch in question).