Vipenem

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIPENEM (VIPENEM)

Composition:

Active substances: imipenem and cilastatin.

One vial contains imipenem monohydrate 530 mg, equivalent to 500 mg of imipenem, and cilastatin sodium 530 mg, equivalent to 500 mg of cilastatin.

Excipient: sodium hydrogencarbonate.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: powder from white to almost white or light yellow in color.

Pharmacotherapeutic group. Antibacterials for systemic use, carbapenems. Imipenem and enzyme inhibitor. ATC code J01DH51.

Pharmacological Properties.

Pharmacodynamics.

Vipenem consists of two components: imipenem, the first representative of a new class of β-lactam antibiotics – thienamycins, and cilastatin sodium, a specific inhibitor of the enzyme responsible for blocking imipenem metabolism in the kidneys, thereby significantly increasing the concentration of unchanged imipenem in the urinary tract. The weight ratio of imipenem to cilastatin sodium in the medicinal product is 1:1.

The class of thienamycin antibiotics, to which imipenem belongs, is characterized by a broader spectrum of potent bactericidal activity than that provided by any of the previously studied antibiotics.

Vipenem is indicated for the treatment of mixed infections caused by microorganisms susceptible to it, including both aerobic and anaerobic bacteria. Vipenem has demonstrated efficacy in treating numerous infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to cephalosporins, including cefazolin, cefoperazone, cephalothin, cefoxitin, cefotaxime, moxalactam, cefamandole, ceftazidime, and ceftriaxone. A large number of infections caused by pathogens resistant to aminoglycosides (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarcillin, piperacillin, azlocillin, mezlocillin) are also effectively treated with this combination.

Vipenem is not indicated for the treatment of meningitis.

Vipenem is a potent inhibitor of bacterial cell wall synthesis and exerts bactericidal activity against a broad spectrum of gram-positive and gram-negative, aerobic and anaerobic pathogenic microorganisms.

Together with the latest cephalosporins and penicillins, Vipenem has a wide spectrum of activity against gram-negative species; however, its distinguishing feature is high activity against gram-positive species, previously observed only with narrow-spectrum β-lactam antibiotics. The antimicrobial spectrum of Vipenem includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, and Bacteroides fragilis — a diverse and clinically challenging group of pathogens typically resistant to other antibiotics.

Vipenem is effective against a large number of microorganisms such as Pseudomonas aeruginosa, Serratia species, and Enterobacter species, which are inherently resistant to most β-lactam antibiotics.

The antibacterial spectrum of imipenem/cilastatin is broader than that of any other known antibiotic and encompasses all clinically significant pathogenic microorganisms. Microorganisms generally susceptible to Vipenem in vitro include:

Gram-negative aerobic bacteria.

Achromobacter species
Acinetobacter species (previously Mima-Herellea)
Aeromonas hydrophila
Alcaligenes species
Bordetella bronchicanis
Bordetella bronchiseptica
Bordetella pertussis
Brucella melitensis
Burkholderia pseudomallei (previously Pseudomonas pseudomallei)
Burkholderia stutzeri (previously Pseudomonas stutzeri)
Campylobacter species
Capnocytophaga species
Citrobacter species
Citrobacter koseri (previously Citrobacter diversus)
Citrobacter freundii
Eikenella corrodens
Enterobacter species
Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae
Escherichia coli
Gardnerella vaginalis
Haemophilus ducreyi
Haemophilus influenzae (including β-lactamase-producing strains)
Haemophilus parainfluenzae
Hafnia alvei
Klebsiella species
Klebsiella oxytoca
Klebsiella ozaenae
Klebsiella pneumoniae
Moraxella species
Morganella morganii (previously Proteus morganii)
Neisseria gonorrhoeae (including penicillinase-producing strains)
Neisseria meningitidis
Pasteurella species
Pasteurella multocida
Plesiomonas shigelloides
Proteus species
Proteus mirabilis
Proteus vulgaris
Providencia species
Providencia alcalifaciens
Providencia rettgeri (previously Proteus rettgeri)
Providencia stuartii
Pseudomonas species*
Pseudomonas fluorescens
Pseudomonas putida
Pseudomonas aeruginosa
Salmonella species
Salmonella typhi
Serratia species
Serratia proteamaculans (previously Serratia liquefaciens)
Serratia marcescens
Shigella species
Yersinia species (previously Pasteurella)
Yersinia enterocolitica
Yersinia pseudotuberculosis

*Stenotrophomonas maltophilia (previously Xanthomonas maltophilia, previously Pseudomonas maltophilia) and Burkholderia cepacia (previously Pseudomonas cepacia) strains are generally not susceptible to Vipenem.

Gram-positive aerobic bacteria

Bacillus species
Enterococcus faecalis
Erysipelothrix rhusiopathiae
Listeria monocytogenes
Nocardia species
Pediococcus species
Staphylococcus aureus (including penicillinase-producing strains)
Staphylococcus epidermidis (including penicillinase-producing strains)
Staphylococcus saprophyticus
Streptococcus agalactiae
Streptococcus group C
Streptococcus group G
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans Streptococci (including α and γ-hemolytic strains)

Enterococcus faecium and certain methicillin-resistant staphylococci are not susceptible to Vipenem.

Gram-negative anaerobic bacteria.

Bacteroides species
Bacteroides distasonis
Bacteroides fragilis
Bacteroides ovalus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Bilophila wadsworthia
Fusobacterium species
Fusobacterium necrophorum
Fusobacterium nucleatum
Porphyromonas asaccharolytica (previously Bacteroides asaccharolyticus)
Prevotella bivia (previously Bacteroides bivius)
Prevotella disiens (previously Bacteroides disiens)
Prevotella intermedia (previously Bacteroides intermedius)
Prevotella melaninogenica (previously Bacteroides melaninogenicus)
Veillonella spp.

Gram-positive anaerobic bacteria.

Actinomyces species
Bifidobacterium species
Clostridium species
Clostridium perfringens
Eubacterium species
Lactobacillus species
Mobiluncus species
Microaerophilic streptococcus
Peptococcus species
Peptostreptococcus species
Propionibacterium species (including P. acnes)

Others
Mycobacterium fortuitum
Mycobacterium smegmatis

In vitro studies indicate that imipenem acts synergistically with aminoglycosides against certain isolates of Pseudomonas aeruginosa.

Pharmacokinetics.

Imipenem. In healthy volunteers, a 20-minute intravenous infusion of 500 mg resulted in peak plasma concentrations of imipenem ranging from 21 to 58 µg/mL. The protein binding of imipenem to human serum proteins is approximately 20%.

When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Renal recovery in urine ranged from 5 to 40%, averaging 15–20% in several studies.

Cilastatin – a specific inhibitor of dehydropeptidase-I – effectively inhibits the metabolism of imipenem. Therefore, the combined administration of imipenem and cilastatin allows achieving therapeutic antibacterial concentrations of imipenem in both urine and plasma.

The plasma half-life of imipenem is approximately 1 hour. About 70% of the administered antibiotic was recovered unchanged in urine within 10 hours, with no further drug excretion observed. With dosing every 6 hours, no accumulation of imipenem in plasma or urine was observed in patients with normal renal function. Concomitant administration of the drug with probenecid resulted in minimal increases in plasma concentration and half-life of imipenem.

Cilastatin. Peak plasma concentrations of cilastatin after a 20-minute intravenous infusion of 500 mg of the drug ranged from 21 to 55 µg/mL. Protein binding of cilastatin to human serum proteins is approximately 40%. The plasma half-life of cilastatin is approximately 1 hour. About 70–80% of the administered dose of cilastatin is excreted unchanged in urine within 10 hours after administration, after which cilastatin was no longer detectable in urine. Approximately 10% is excreted as the N-acetyl metabolite, which exhibits inhibitory activity against dehydropeptidase comparable to that of the parent drug. Concomitant administration of the drug with probenecid doubled the plasma concentration and half-life of cilastatin but did not affect its urinary recovery.

Renal impairment.

After a single intravenous dose of imipenem/cilastatin 250 mg/250 mg, the area under the concentration-time curve (AUC) for imipenem increased by 1.1, 1.9, and 2.7 times, respectively, in patients with mild (creatinine clearance (CrCL) 50–80 mL/min/1.73 m²), moderate (CrCL 30–<50 mL/min/1.73 m²), and severe (CrCL <30 mL/min/1.73 m²) renal impairment, compared to patients with normal renal function (CrCL >80 mL/min/1.73 m²). The AUC for cilastatin increased by 1.6, 2, and 6.2 times, respectively, in patients with mild, moderate, and severe renal impairment compared to those with normal renal function. After a single intravenous dose of imipenem/cilastatin 250 mg/250 mg administered 24 hours after hemodialysis, the AUC for imipenem and cilastatin was 3.7 and 16.4 times higher, respectively, compared to patients with normal renal function. Urinary excretion, renal clearance, and plasma clearance of both imipenem and cilastatin decrease with declining renal function following intravenous administration of Vipenem. Dose adjustment is required for patients with impaired renal function.

Hepatic impairment.

The pharmacokinetics of imipenem in patients with hepatic impairment has not been established. Due to the limited hepatic metabolism of imipenem, hepatic impairment is not expected to significantly affect its pharmacokinetics. Therefore, dose adjustment is not recommended for patients with hepatic impairment.

Children.

The mean clearance and volume of distribution of imipenem were approximately 45% higher in children (aged 3 months to 14 years) compared to adults. The AUC for imipenem after administration of a 15/15 mg/kg dose of imipenem/cilastatin in children was approximately 30% higher than exposure in adults receiving a 500 mg/500 mg dose. At a higher dose, exposure after administration of 25/25 mg/kg imipenem/cilastatin in children was 9% higher compared to exposure in adults receiving a 1000 mg/1000 mg dose.

Elderly patients.

In healthy elderly volunteers (aged 65 to 75 years with normal renal function for their age), the pharmacokinetics of a single 20-minute intravenous dose of imipenem/cilastatin 500 mg/500 mg were consistent with those expected in patients with mild renal impairment, for whom no dose adjustments are considered necessary. Mean plasma half-lives of imipenem and cilastatin were 91±7 minutes and 69±15 minutes, respectively. Repeated dosing did not affect the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed.

Clinical characteristics.

Indications.

Treatment of infections in adults and children aged 1 year and older, caused by microorganisms susceptible to the medicinal product:

• intra-abdominal infections;
• lower respiratory tract infections (severe pneumonia, including hospital-acquired and ventilator-associated pneumonia);
• intrapartum and postpartum infections;
• complicated urinary tract infections;
• complicated skin and soft tissue infections;
• bone and joint infections;
• septicemia;
• endocarditis.

The medicinal product can be used in the treatment of patients with neutropenia accompanied by fever, where a bacterial infection is the likely cause.

Treatment of patients with bacteremia associated or likely associated with any of the above-mentioned infections.

Contraindications.

Hypersensitivity to any component of the medicinal product, other carbapenems, or acute hypersensitivity reactions (e.g., anaphylactic reactions, severe skin reactions) to other β-lactam antibiotics (e.g., penicillins or cephalosporins).

Interaction with other medicinal products and other forms of interaction.

Generalized seizures have been observed in patients who received ganciclovir concomitantly with intravenous imipenem/cilastatin. These drugs should be used together only if the expected benefit outweighs the potential risk.

Valproic acid.

Decreased plasma levels of valproic acid have been reported when administered concomitantly with carbapenems, and sudden seizures have been reported in some cases. Therefore, concomitant administration of imipenem and valproic acid/sodium valproate is not recommended. Consideration should also be given to using alternative antibacterial or anticonvulsant therapy (see section "Special precautions for use").

Oral anticoagulants.

Concomitant use of antibiotics with warfarin may enhance its anticoagulant effects. Numerous reports have documented increased anticoagulant effects of oral anticoagulants, including warfarin, in patients receiving antibiotics concomitantly. The risk may vary depending on the type of infection, age, and overall condition of the patient, making it difficult to assess the exact role of the antibiotic in increasing the international normalized ratio (INR). Frequent monitoring of INR is recommended during and after concomitant use of antibiotics with oral anticoagulants.

Concomitant administration of imipenem/cilastatin and probenecid resulted in minimal increases in imipenem plasma concentrations and plasma half-life of imipenem. Renal excretion of active (unmetabolized) imipenem decreased to approximately 60% of the dose when the drug was administered with probenecid. Concomitant administration of the drug and probenecid doubled the plasma levels and plasma half-life of cilastatin, but had no effect on the renal excretion of cilastatin.

Special precautions for use.

General recommendations.

When selecting imipenem/cilastatin as a medicinal product for treatment in each individual case, consideration should be given to the appropriateness of using carbapenems based on the severity of infection, prevalence of resistance to other suitable antibacterial agents, and the potential presence of carbapenem-resistant bacteria.

Hypersensitivity.

There are some clinical and laboratory data indicating partial cross-allergenicity between the medicinal product Vipenem and other β-lactam antibiotics, penicillins, and cephalosporins. Severe reactions (including anaphylaxis) have been observed with most β-lactam antibiotics. These reactions are most likely to occur in individuals with a history of sensitivity to multiple allergens. The patient's history should be carefully reviewed prior to initiating therapy with this medicinal product to identify any previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other β-lactam antibiotics, or other allergens (see section "Contraindications"). If an allergic reaction occurs during treatment, the drug should be discontinued and appropriate measures should be taken. Serious anaphylactic reactions require immediate treatment.

Liver function.

Liver function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatotoxicity (elevated transaminase levels, liver failure, and fulminant hepatitis).

Patients with pre-existing liver disease require monitoring of liver function during treatment with imipenem/cilastatin. Dose adjustment is not necessary.

Hematology.

A positive direct or indirect Coombs' test may occur during treatment with imipenem/cilastatin.

Antibacterial spectrum.

The antibacterial spectrum of imipenem/cilastatin should be considered before any empirical therapy, especially in conditions that are life-threatening for the patient. In addition, caution should be exercised due to limited susceptibility of certain pathogens (e.g., those associated with skin and soft tissue infections) to imipenem/cilastatin. The use of imipenem/cilastatin is appropriate for treating these types of infections only if the specific pathogen has been documented and is known to be susceptible, or when there are strong clinical grounds to believe that the most likely pathogen(s) are susceptible to this treatment. Concomitant use of this agent against methicillin-resistant Staphylococcus aureus (MRSA) may be indicated when MRSA infection is suspected or confirmed under approved indications. Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infection is suspected or confirmed under approved indications.

Valproic acid.

Concomitant administration of imipenem/cilastatin and valproic acid/sodium valproate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Clostridium difficile.

Pseudomembranous colitis has been reported as a complication of nearly all antibiotics; its severity may range from mild to life-threatening. Therefore, antibiotics should be used cautiously in patients with a history of gastrointestinal disorders, particularly colitis. It is important to consider the possibility of pseudomembranous colitis in patients who develop diarrhea during or after antibiotic therapy. Discontinuation of imipenem/cilastatin therapy and initiation of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be prescribed.

Meningitis.

The medicinal product is not recommended for the treatment of meningitis.

Renal impairment.

Imipenem/cilastatin accumulates in patients with impaired renal function. If the dose is not reduced according to renal function, adverse reactions involving the central nervous system may occur (see "Method of administration and dosage" and below).

Central nervous system (CNS).

As with other β-lactam antibiotics, adverse effects involving the CNS such as myoclonus, confusion, or seizures have been reported during treatment with this medicinal product, particularly when recommended doses are exceeded based on renal function and body weight. Such disorders have usually been observed in patients with CNS disorders (e.g., head trauma or history of seizures) and/or in patients with impaired renal function, in whom drug accumulation may occur. Therefore, strict adherence to recommended dosages and treatment regimens is essential, especially in such patients. Anticonvulsant therapy should be continued in patients with a history of seizures.

Particular caution is required regarding neurological symptoms or seizures in children with known risk factors for seizures or who are receiving concomitant treatment with anticonvulsant medications.

If focal tremor, myoclonus, or seizures occur during treatment, patients should undergo neurological evaluation and anticonvulsant therapy should be initiated if not already prescribed. If CNS adverse effects persist, the dose of Vipenem should be reduced or the drug discontinued.

Vipenem is not indicated for use in patients with CrCl ≤ 5 mL/min/1.73 m², except when hemodialysis will be performed within 48 hours. For patients undergoing hemodialysis, Vipenem is recommended only when the expected benefits outweigh the potential risk of seizures.

Excipients.

The medicinal product contains 37.6 mg of sodium (1.6 mg-eq.), which should be taken into account when administering it to patients on a controlled sodium (salt-restricted) diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Adequate and well-controlled studies of the use of this medicinal product in pregnant women have not been conducted.

Reproductive toxicity was observed in studies conducted in pregnant monkeys. The potential risk to humans is unknown. Vipenem should be used during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Breastfeeding period.

Imipenem and cilastatin are excreted in small amounts in breast milk. When considering the use of this medicinal product, the benefit of breastfeeding for the infant should be weighed against the potential risk associated with the drug's use.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, certain adverse effects such as hallucinations, somnolence, dizziness, and vertigo associated with the use of this medicinal product may affect the ability of some patients to drive or operate machinery.

Dosage and Administration.

Dosage recommendations for the medicinal product Vipenem refer to the amount of imipenem/cilastatin to be administered.

The daily dose of Vipenem is determined based on the severity of infection, the type of isolated pathogen(s), and should be divided into several equal doses, taking into account renal function and body weight.

Adults and adolescents.

Dosage for patients with normal renal function (creatinine clearance ≥90 mL/min):

• 500 mg/500 mg every 6 hours, or
• 1000 mg/1000 mg every 8 hours or every 6 hours.

For treatment of infections caused by less susceptible bacterial species (such as Pseudomonas aeruginosa) and for severe infections (e.g., febrile neutropenic patients), a dosage regimen of 1000 mg/1000 mg every 6 hours is recommended.

Dosage adjustment is required for patients with creatinine clearance <90 mL/min (see Table 1).

The maximum daily dose should not exceed 4000 mg/4000 mg per day.

Adult patients with impaired renal function

To determine the reduced dosage for adult patients with impaired renal function:

1. Determine the total daily dose (i.e., 2000/2000, 3000/3000, or 4000/4000 mg) normally administered to patients with normal renal function.
2. Select the appropriate reduced dosage regimen (see Table 1) according to the patient’s creatinine clearance and the duration of infusion (see section "Administration").

Table 1

Creatinine clearance (mL/min)	Total daily dose 2000 mg	Total daily dose 3000 mg	Total daily dose 4000 mg
≥90 (normal)	500 every 6 hours	1000 every 8 hours	1000 every 6 hours
reduced dose (mg) for patients with impaired renal function
<90‑≥60	400 every 6 hours	500 every 6 hours	750 every 8 hours
<60‑≥30	300 every 6 hours	500 every 8 hours	500 every 6 hours
<30‑≥15	200 every 6 hours	500 every 12 hours	500 every 12 hours

Patients with creatinine clearance <15 mL/min.

Vipenem for intravenous administration should not be administered to patients who are not scheduled to undergo hemodialysis within the next 48 hours.

Hemodialysis.

For treatment of patients with creatinine clearance <15 mL/min who are on hemodialysis, use the doses recommended for patients with creatinine clearance of 15–29 mL/min (see Table 1).

Both imipenem and cilastatin are removed during hemodialysis. The patient should receive imipenem/cilastatin immediately after a hemodialysis session, and subsequent doses should be administered every 12 hours following dialysis. Patients on hemodialysis, especially those with underlying central nervous system disorders, require close monitoring; imipenem/cilastatin should be prescribed for such patients only if the anticipated benefit outweighs the potential risk of seizures (see section "Special precautions").

Currently, there is insufficient data on the use of the medicinal product in patients undergoing peritoneal dialysis; therefore, its use is not recommended for this patient population.

Hepatic impairment.

Dose adjustment is not required for patients with hepatic dysfunction.

Elderly patients.

Dose adjustment is not required for elderly patients with normal renal function.

Children aged 1 year and older.

For children aged >1 year, the recommended dose is 15/15 or 25/25 mg/kg/dose every 6 hours.

For the treatment of infections likely or confirmed to be caused by less susceptible organisms (such as Pseudomonas aeruginosa) and for severe infections (e.g., febrile neutropenic patients), a dose of 25/25 mg/kg every 6 hours is recommended.

Children under 1 year of age and children with renal impairment.

The use of the medicinal product is not recommended in children under 1 year of age and in children with renal impairment (serum creatinine >2 mg/dL) due to insufficient clinical data.

Route of administration.

Each vial is intended for single use only.

Before administration, the vial contents (powder) must be reconstituted and diluted appropriately (see recommendations below). Each dose not exceeding 500 mg/500 mg of Vipenem for intravenous use should be administered over 20–30 minutes. Each dose exceeding 500 mg/500 mg should be administered over 40–60 minutes. If nausea occurs during infusion, the rate of administration should be reduced.

Preparation of solution for intravenous infusion.

Vipenem for intravenous infusion is supplied as a sterile powder in vials containing 500 mg of imipenem equivalent and 500 mg of cilastatin equivalent.

Vipenem contains sodium hydrogencarbonate as a buffer, which ensures a solution pH between 6.5 and 8.5. These pH variations are not clinically significant when the solution is prepared and stored according to the provided instructions. Vipenem contains 37.5 mg of sodium (1.6 mEq).

The sterile powder of Vipenem should be reconstituted as specified in Table 2. The resulting solution should be shaken until a clear solution is obtained. Variations in solution color from colorless to yellow do not affect the drug's activity.

Table 2.

Preparation of Vipenem solution for intravenous administration

Dose of Vipenem (imipenem/cilastatin)	Required volume of diluent (ml)	Approximate average concentration of imipenem/cilastatin (mg/ml)
500/500	100	5/5

The contents of the vial should be suspended and diluted to 100 mL with the appropriate infusion solution.

In the first step, it is recommended to add approximately 10 mL of 0.9% sodium chloride solution to the vial. Under exceptional circumstances, when 0.9% sodium chloride solution cannot be used for clinical reasons, 5% glucose may be used as the solvent.

Shake well and transfer the resulting suspension to a container with the infusion solution.

Warning: the suspension is not a ready-to-use infusion solution.

Repeat the procedure by adding another 10 mL of infusion solution to ensure complete transfer of the vial contents into the infusion solution. The resulting mixture should be shaken until it becomes clear.

The concentration of the reconstituted solution after the above procedure is approximately 5 mg/mL of imipenem and cilastatin.

Diluted solutions should be used immediately. The time interval between the start of reconstitution and the end of intravenous infusion should not exceed 2 hours.

Do not freeze the reconstituted solution.

Unused materials and any remaining product should be disposed of in accordance with current regulations.

Children.

Due to insufficient clinical data, the use of the medicinal product Vipenem is not recommended in children under 1 year of age and in children with impaired renal function (serum creatinine >2 mg/dL) (see section "Dosage and administration").

Overdose.

Symptoms. Symptoms of overdose are consistent with the profile of adverse reactions and may include seizures, confusion, tremor, nausea, vomiting, hypotension, and bradycardia.

Treatment. There is no specific information on the treatment of overdose with this medicinal product. Vipenem is removed by hemodialysis, but the effectiveness of this procedure in overdose has not been established. Treatment is symptomatic.

Adverse reactions

The most common systemic adverse reactions that may have been related to treatment with imipenem/cilastatin were nausea (2%), diarrhea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), arterial hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%).

The most common local adverse reactions were phlebitis/thrombophlebitis (3.1%), injection site pain (0.7%), injection site erythema (0.4%), and venous induration (0.2%).

Elevations in serum transaminases and alkaline phosphatase levels have also been observed.

Adverse reactions are presented in Table 3 by system organ classes 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), and frequency not known (cannot be estimated based on available data).

Table 3

System organ class	Frequency	Adverse reactions
Infections and infestations	rare	pseudomembranous colitis, candidiasis
	very rare	gastroenteritis
Blood and lymphatic system disorders	common	eosinophilia
	uncommon	pancytopenia, neutropenia, leukopenia, thrombocytopenia, thrombocytosis
	rare	agranulocytosis
	very rare	hemolytic anemia, bone marrow suppression
Immune system disorders	rare	anaphylactic reactions
Psychiatric disorders	uncommon	psychiatric disturbances including hallucinations and confusion
Nervous system disorders	uncommon	seizures, myoclonic activity, dizziness, somnolence
	rare	encephalopathy, paraesthesia, focal tremor, taste disturbance
	very rare	worsening of severe myasthenia, headache
	unknown	agitation, dyskinesia
Ear and labyrinth disorders	rare	hearing loss
	very rare	vertigo, tinnitus
Cardiac disorders	very rare	cyanosis, tachycardia, palpitations
Vascular disorders	common	thrombophlebitis
	uncommon	arterial hypotension
	very rare	flushing
Respiratory, thoracic and mediastinal disorders	very rare	dyspnea, hyperventilation, pharyngeal pain
Gastrointestinal disorders	common	diarrhea, vomiting, nausea (nausea and/or vomiting associated with the medicinal product occur more frequently in patients with granulocytopenia than in patients without granulocytopenia)
	rare	change in color of teeth and/or tongue
	very rare	haemorrhagic colitis, abdominal pain, epigastric pain, glossitis, hypertrophy of tongue papillae, increased salivation
Hepatobiliary disorders	rare	liver failure, hepatitis
	very rare	fulminant hepatitis
Skin and subcutaneous tissue disorders	common	rash (e.g. exanthematous)
	uncommon	urticaria, pruritus
	rare	toxic epidermal necrolysis, angioedema (Quincke's edema), Stevens-Johnson syndrome, polymorphic erythema, exfoliative dermatitis
	very rare	hyperhidrosis, changes in skin structure
Musculoskeletal and connective tissue disorders	very rare	polyarthralgia, thoracic spine pain
Renal and urinary disorders	rare	acute renal failure, oliguria/anuria, polyuria, change in urine color (harmless, should not be confused with hematuria). The role of the medicinal product in changes in renal function is difficult to assess, as predisposing factors for prerenal azotemia or worsening renal function were usually present
Reproductive system and breast disorders	very rare	genital pruritus
General disorders and administration site conditions	uncommon	fever, local pain and induration at injection site, erythema at injection site
	very rare	chest discomfort, asthenia/weakness
Investigations	common	increased serum transaminases, increased serum alkaline phosphatase
	uncommon	positive direct Coombs test, prolonged prothrombin time, decreased hemoglobin, increased serum bilirubin, increased serum creatinine, increased blood urea nitrogen

Adverse reactions reported in children older than 3 months receiving imipenem/cilastatin were entirely similar to those observed in adult patients.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.

Incompatibilities.

The medicinal product is chemically incompatible with lactates (lactic acid salts) and must not be reconstituted with solvents containing lactates. However, Vipenem may be administered through the same intravenous line used for lactate solution infusions.

The medicinal product must not be mixed with other antibiotics or any other medicinal products, except those specified in the section "Dosage and administration".

Packaging.

500 mg/500 mg powder in a vial; 1 or 10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ACS DOBFAR S.P.A.

Manufacturer's address and location of operations.

NUCLEO INDUSTRIALE S. NICOLÒ A TORDINO, 64100 TERAMO (TE), Italy