INSTRUCTIONS

for medical use of the medicinal product

 

IMIFORS

Composition:

active substance: imipenem and cilastatin;

1 vial contains imipenem monohydrate equivalent to imipenem anhydrous 500 mg, cilastatin sodium equivalent to cilastatin 500 mg;

excipients: sodium bicarbonate.

 

Dosage form. Powder for solution for infusion.

Basic physical and chemical properties: white to light yellow powder.

 

Pharmacotherapeutic group.

Antibacterials for systemic use. Imipenem and cilastatin. ATC code: J01D H51.

 

Pharmacological properties.

Pharmacodynamics.

Imifors consists of two components: imipenem, the first representative of new b-lactam antibiotics class – thienamycins, and cilastatin sodium, a special enzyme inhibitor that blocks the metabolism of imipenem in the kidney and significantly increases the concentration of unchanged imipenem in the urinary tract. Imipenem and cilastatin sodium weight ratio is 1:1.

Thienamycin antibiotics class, including imipenem, has a wider spectrum of potent bactericidal activity than that provided by any of studied antibiotics.

Imifors is intended for the treatment of mixed infections caused by aerobic and anaerobic bacteria strains susceptible to Imifors action. The preparation is effective in the treatment of many infections caused by aerobic and anaerobic gram-positive and gram-negative bacteria resistant to cephalosporins, including cefazolin, cefoperazone, cefalotin, cefoxytine, cefotaxime, moxalactam, cefamandol, ceftazidime and ceftriaxone. A large number of infections caused by aminoglycoside resistant agents (gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin-G, ticarbillin, piperacillin, azlocyline, mesolocillin), are also treatable with the preparation.

Imifors is not intended for the treatment of meningitis.

Imifors is a potent inhibitor of bacterial cell wall synthesis and exerts its bactericidal activity against a wide range of gram-positive and gram-negative, aerobic and anaerobic pathogens.

Imifors, along with the newest cephalosporins and penicillins, has a wide range of actions relative to gram-negative species, but its high profile is the high activity against gram-positive species. Such activity was previously observed in narrow spectrum b-lactam antibiotics only. The activity spectrum of the preparation covers Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis, and a clinically problematic group with a diverse composition of pathogens resistant to other antibiotics.

Imifors is effective against a large number of pathogens such as Pseudomonas aeruginosa, Serratia and Enterobacter species, which are naturally resistant to most b-lactam antibiotics.

Imifors antibacterial spectrum is wider than any other well-known antibiotics, and covers all clinically important pathogens. Imifors is usually effective in vitro for the following pathogens:

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

*Stenotrophomonas maltophilia (formerly Xanthomas maltophilia, formerly Pseudomonas maltophilia) and Burkholderia cepacia strains (formerly Pseudomonas cepacia) are generally resistant to Imifors.

Gram-positive aerobic bacteria: Bacillus, Enterococcus faecalis species, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Nocardia species, Pediococcus species, Staphylococcus aureus (including penicillin-producing strains), Staphylococcus epidermidis (including penicillin-producing strains), Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus of С group, Streptococcus of G group, Streptococcus pneumonia, Streptococcus pyogenes, Viridans Streptococci (including α and γ-hemolytic strains), Enterococcus faecium and some methicillin-resistant staphylococci are resistant to Imifors.

Gram-negative anaerobic bacteria: Bacteroides species, Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovalus, Bacteroides thelaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bilophila wadsworthia, Fusobacterium species, Fusobacterium necrophorum, Fusobacterium nucleatum, Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus), Prevotella bivia (formerly Bacteroides bivius), Prevotella disiens (formerly Bacteroides disiens), Prevotella intermedia (formerly Bacteroides intermedius), Prevotella melaninogenica (formerly Bacteroides melaninogenicus), Veilonella spp.

Gram-positive anaerobic bacteria: Actinomyces species, Bifidobacterium species, Clostridium species, Clostridium perfringens, Eubacterium species, Lactoballus species, Mobiluncus species, Microaerophilic streptococcus, Peptococcus species, Peptostreptococcus species, Propionibacterium species (including P. acnes).

Others: Mycobacterium fortuitum, Mycobacterium smegmatis.

In vitro tests indicate that imipenem synergistically acts with aminoglycosides against some isolates of Pseudomonas aeruginosa.

Pharmacokinetics.

In healthy volunteers, intravenous infusion of 500 mg imipenem over 20 minutes resulted in peak plasma levels of imipenem ranging from 21 to 58 μg/ml.

The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. The patients with normal renal function treated with the preparation under the scheme (every 6 hours), there was no accumulation of imipenem in plasma or urine. The co-administration of imipenem and probenecid resulted in a minimal increase in plasma levels and plasma half-life of imipenem. When using alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual recovery in urine ranged from 5 to 40%, on average in several studies – 15-20%. The binding of imipenem to human serum proteins is approximately 20%.

Cilastatin is a specific enzyme inhibitor of dehydropeptidase-I, which effectively inhibits the metabolism of imipenem, therefore the concomitant use of imipenem and cilastatin makes it possible to achieve therapeutic antibacterial levels of imipenem in urine and plasma. Peak plasma levels of cilastatin, following a 20 minute intravenous infusion of 500 mg preparation, ranged from 21 to 55 μg/ml. The plasma half-life of cilastatin was one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10 hours of administration of the preparation. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Due to the co-administration of imipenem/cilastatin and probenecid, the plasma levels and plasma half-life of cilastatin were increased by two times. The co-administration of imipenem/cilastatin and probenecid had no effect on the recovery of cilastatin in urine.

The binding of cilastatin to human serum proteins is approximately 40%.

Renal impairment

Following a single 250 mg/250 mg intravenous dose of the preparation, the area under the curve (AUCs) for imipenem increased 1.1-fold, 1.9-fold, and 2.7-fold 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), and AUCs for cilastatin increased 1.6-fold, 2.0-fold, and 6.2-fold in patients with mild, moderate, and severe renal impairment, compared to patients with normal renal function. Following a single 250 mg/250 mg intravenous dose of the preparation given 24 hours after hemodialysis, AUCs for imipenem and cilastatin were 3.7-fold and 16.4-fold higher, compared to patients with normal renal function. Urinary recovery, renal clearance and plasma clearance of imipenem and cilastatin decrease with decreasing renal function following intravenous administration of the preparation. Dose adjustment is necessary for patients with impaired renal function.

Hepatic impairment

The pharmacokinetics of imipenem in patients with hepatic insufficiency has not been established. Due to the limited extent of hepatic metabolism of imipenem, its pharmacokinetics is not expected to be affected by hepatic impairment. Therefore, no dose adjustment is recommended in patients with hepatic impairment.

Children

The average clearance (CL) and volume of distribution (Vdss) for imipenem were approximately 45% higher in paediatric patients (3 months to 14 years) compared to adults. The AUC for imipenem following administration of 15/15 mg/kg per body weight of imipenem/cilastatin to paediatric patients was approximately 30% higher than the exposure in adults receiving a 500 mg/500 mg dose. At the higher dose, the exposure following administration of 25/25 mg/kg imipenem/cilastatin to children was 9% higher as compared to the exposure in adults receiving a 1000 mg/1000 mg dose.

Elderly

In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of the preparation 500 mg/500 mg administered intravenously over 20 minutes were consistent with those expected in patients with mild renal impairment for whom any dose adjustment is considered as unnecessary. The mean plasma half-lives of imipenem and cilastatin were 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing has no effect on the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed.

 

Clinical particulars.

Indications.

Treatment of infections caused by pathogens susceptible to the preparation:

- intra-abdominal infections;

- infections of the lower respiratory tract (severe pneumonia, including nosocomial and ventilator-associated pneumonia);

- intra- and postpartum infections;

- urinary tract infections;

- skin and soft tissue infections;

- bones and joints infections;

- septicemia;

- endocarditis.

 

Imifors may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

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

 

Contraindications.

Hypersensitivity to any of the components of the preparation, other carbapenems or beta-lactam antibiotics (e.g. penicillin or cephalosporins).

 

Interaction with other medicinal products and other forms of interaction.

Generalized seizures have been reported in patients who received ganciclovir and imipenem/cilastatin. These medicinal products may be used concomitantly only if the potential benefit outweighs the risks.

Post-marketing studies have been reported a decrease in valproic acid levels in plasma when imipenem/cilastatin was co-administered with carbapenems; in some cases, sudden seizures have been reported. Therefore, the concomitant use of imipenem and valproic acid/sodium valproate is not recommended.

The co-administration of antibiotics with warfarin may augment its anti-coagulant effects.  The risk may vary with the underlying infection, age and general status of the patient. It is recommended that the INR should be monitored during and after co-administration of antibiotics with an oral anti-coagulant agent.

The co-administration of imipenem/cilastatin and probenecid resulted in minimal increase in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non-metabolized) imipenem decreased to approximately 60% of the dose when the preparation was administered with probenecid. The co-administration of imipenem/cilastatin and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on urine recovery of cilastatin.

 

Precautions for use.

Some clinical and laboratory data that indicate partial cross-allergenicity of the preparation and other b-lactam antibiotics, penicillins and cephalosporins are reported. Severe reactions (including anaphylaxis) are observed when using most b-lactam antibiotics. Before initiating therapy, careful inquiry should be made concerning previous hypersensitivity reactions to b-lactam antibiotics. If an allergic reaction occurs during the use of the preparation, the therapy should be discontinued and appropriate measures should be taken. Serious anaphylactic reactions require immediate emergency treatment.

Hepatic function should be closely monitored during treatment with imipenem/cilastatin due to the risk of hepatic toxicity (such as increase in transaminases, hepatic failure and fulminant hepatitis).

Patients with pre-existing liver disorders should have liver function monitored during treatment with imipenem/cilastatin. There is no dose adjustment necessary.

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

The antibacterial spectrum of imipenem/cilastatin should be taken into account especially in life-threatening conditions before any empiric treatment. Furthermore, due to the limited susceptibility of specific pathogens associated with e.g. bacterial skin and soft-tissue infections, to imipenem/cilastatin, caution should be exercised. The use of imipenem/cilastatin is not suitable for treatment of these types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment. Concomitant use of an appropriate anti-MRSA agent may be indicated when MRSA infections are suspected or proven to be involved in the approved indications.  Concomitant use of an aminoglycoside may be indicated when Pseudomonas aeruginosa infections are suspected or proven to be involved in the approved indications.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with imipenem/cilastatin and with nearly all other anti-bacterial agents and may range from mild to life-threatening in severity. Therefore, antibiotics should be prescribed with caution to patients with a history of gastrointestinal diseases, particularly colitis. It is important to consider the risk of pseudomembranous colitis in patients who develop diarrhoea during the use of antibiotics. Discontinuation of therapy with imipenem/cilastatin and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be prescribed.

Imifors is not recommended for the therapy of meningitis.

In case of therapy with both imipenem/cilastatin, and other antibiotics of β-lactam group, CNS adverse reactions such as myoclonic activity, confusional states, or seizures have been reported, especially when recommended doses based on renal function and body weight were exceeded. Such incidences have been reported in patients with CNS disorders (e.g. brain lesions or history of seizures) and/or in patients with impaired renal function in whom the accumulation of the administered preparation could occur. Hence close adherence to recommended dose schedule is urged especially in these patients. Anticonvulsant therapy should be continued in patients with a known seizure disorder.

Special awareness should be made to neurological symptoms or convulsions in children with known risk factors for seizures, or on concomitant treatment with medicinal products lowering the seizures threshold.

If focal tremors, myoclonus, or seizures occur, the patients should be evaluated neurologically and anticonvulsant therapy must be initiated. If CNS symptoms persist, the dose of Imifors should be lowered or discontinued.

Patients with creatinine clearances of £ 5 ml/min/1.73 m² should not receive Imifors unless hemodialysis to be initiated in 48 hours. For patients on hemodialysis, Imifors is recommended only when the benefit outweighs the potential risk of seizures

Imifors contains 37.6 mg of sodium (1.6 mEq), which should be considered for patients on a controlled sodium diet.

 

Pregnancy and lactation.

Pregnancy

There are no adequate studies for the use of Imifors in pregnant women; therefore it can be used during pregnancy only if the potential benefit to the mother overweighs the potential risk to the foetus.

Breastfeeding.

Imipenem and cilastatin are excreted into the mother's milk in small quantities. If necessary, breastfeeding should be discontinued.

 

Effects on ability to drive and use machines.

Given the risk of side effects such as myoclonia, hallucinations, confusion and convulsions, driving vehicles and operating other mechanisms should be avoided.

 

Method of administration and dosage.

The dose recommendations for Imifors represent the quantity of imipenem/cilastatin to be administered.

 

The daily dose of Imifors should be based on the type and severity of infection and pathogen(s); the dose should be equally divided into several administrations considering the patient's body weight and renal function

 

Patients with normal renal function

Dosage for patients with normal renal function (creatinine clearance > 70 ml/min/1.73 m²) and body weight not less than 70 kg:

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

 

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 1000 mg/1000 mg administered every 6 hours.

The dose should be lowered for patients with creatinine clearance £ 70 ml/min/1.73 m² and/or body mass less than 70 kg. The dose reduction is particularly important for patients whose body mass is significantly less than 70 kg and/or those with moderate/severe renal impairment.

The dose for patients whose body mass is less than 70 kg should be calculated using the formula:

Actual body weight (kg) * standard dose

                              70 (kg)

 

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

 

Patients with renal impairment

To determine the reduced dose for adults with impaired renal function:

1. The total daily dose (i.e. 2000/2000, 3000/ 3000 or 4000/4000 mg) that would usually be applicable to patients with normal renal function should be selected.
2. The appropriate reduced dose regimen (Table 1) is selected according to the patient's creatinine clearance and duration of infusion (see Method of administration).

Table 1

Dosage for patients

with impaired renal function and body mass of 70 kg or more *

Total daily dose for patients with normal renal function (mg / day)	Creatinine clearness (ml/min/1.73 m2)
	41 – 70	21 – 40	6 – 20
	Dosage (mg) Interval (hours)
2000/2000	500/500 (8)	250/250 (6)	250/250 (12)
3000/3000	500/500 (6)	500/500 (8)	500/500 (12) **
4000/4000	750/750 (8)	500/500 (6)	500/500 (12) **

 * For patients with body mass less than 70 kg, the prescribed dose should be lowered proportionally.

** At the dose of 500 mg / 500 mg, patients with creatinine clearance of 6-20 ml/min/1.73 m², the risk of seizures increases significantly.

 

Patients with creatinine clearances of £5 ml/min/1.73 m² should not receive Imifors unless hemodialysis is instituted within 48 hours.

 

Hemodialysis

When treating patients with creatinine clearances of £5 ml/min/1.73 m² who are undergoing dialysis use the dose recommendation for patients with creatinine clearances of 6 to 20 ml/min/1.73 m² (see Table 1).

Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive Imifors after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session. Dialysis patients, especially those with background central nervous system (CNS) disease, should be carefully monitored; for patients on hemodialysis , Imifors is recommended only when the benefit outweighs the potential risk of seizures  (see Precautions for use).

Currently, there are inadequate data to use of Imifors for patients undergoing peritoneal dialysis, so it is not recommended to use it for the treatment of this category of patients.

 

Hepatic impairment

No dose adjustment is required for patients with impaired hepatic function.

Elderly population

No dose adjustment is required for elderly patients with normal renal function.

Children over 1 year of age

For paediatric patients ≥1 year of age, the recommended dose is 15/15 or 25/25 mg/kg/dose administered every 6 hours.

It is recommended that infections suspected or proven to be due to less susceptible bacterial species (such as Pseudomonas aeruginosa) and very severe infections (e.g. in neutropenic patients with a fever) should be treated with 25/25 mg/kg administered every 6 hours.

Clinical data are insufficient to recommend dosing for paediatric patients with renal impairment (serum creatinine >2mg/dl).

Method of administration

Each dose of ≤500 mg/500 mg should be given by intravenous infusion over 20 to 30 minutes. Each dose >500 mg/500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

Reconstitution of solution for intravenous administration.

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

The composition of Imifors includes sodium bicarbonate as a buffer, in order to obtain pH solution between 6.5 and 8.5. There is no significant modification of the pH when the solutions are prepared and used as indicated. Imifors contains 37.5 mg of sodium (1.6 mEq).

Imifors sterile powder must be reconstituted as indicated in Table 2. The reconstituted solution must be shaken until a clear fluid is formed. The variations in colour, from colourless to light yellow do not affect the potency of the product.

 

Table 2

Reconstitution of Imifors solution for intravenous administration

Dosage of Imifors (imipenem/cilastatin)	Volume of diluent to be added  (ml)	Approximate mean concentration of product  (mg/ml)
500/500	100	5/5

 

Reconstitution of Imifors solution in 20 ml vials

The contents of the vial should be suspended and made up to 100 ml with an appropriate solution for infusion.

It is recommended to add about 10 ml of 0.9% sodium chloride solution to the vial. In exceptional circumstances, when 0.9% sodium chloride solution can not be used due to clinical reasons, 5% glucose can be used as a diluent.

The resulting suspension should be shaken well and transferred to the infusion solution container.

Caution: suspension is a not final solution for direct infusion.

Repeat with an additional 10 ml of infusion solution to ensure complete transfer of the vial contents to the infusion solution. The resulting mixture should be agitated until clear.

After the above procedure the concentration of the reconstituted solution is approximately 5 mg/ml imipenem and cilastatin.

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

 

Children.

Clinical data are insufficient, therefore Imifors is not recommended for children under 1 year of age and those with renal impairment (serum creatinine >2mg/dl) (see Method of administration and dosage).

 

Overdose.

Symptoms of overdose that may occur are consistent with the adverse reaction profile; they may include seizures, confusion, tremors, nausea, vomiting, hypotension and bradycardia. No specific information is available on treatment of overdose caused by Imifors. Imifors is haemodialyzable. However, usefulness of this procedure in the overdose setting is unknown. The treatment is symptomatic

 

Adverse reactions.

In clinical trials involving 1723 patients treated with imipenem/cilastatin intravenous, the most frequently reported systemic adverse reactions that were possibly related to therapy were as follows: nausea (2.0%), diarrhoea (1.8%), vomiting (1.5%), rash (0.9%), fever (0.5%), hypotension (0.4%), seizures (0.4%), dizziness (0.3%), pruritus (0.3%), urticaria (0.2%), somnolence (0.2%); the most frequently reported local adverse reactions were phlebitis/thrombophlebitis (3.1%), pain at the injection site (0.7%), erythema at the injection site (0.4%) and vein induration (0.2%); increases in serum transaminases and alkaline phosphatase are also commonly reported.

The following adverse reactions have been reported in clinical studies or during post-marketing experience. The adverse reactions have been categorized by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)

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 depression.

Immune system disorders: rare – anaphylactic reactions.

Psychiatric disorders: uncommon – psychic disturbances including hallucinations and confusional state.

Nervous system disorders: uncommon- seizures, myoclonic activity, dizziness, somnolence; rare – encephalopathy, paraesthesia, focal tremor, taste perversion; very rare – aggravation of myasthenia gravis, headache.

Ear and labyrinth disorders: rare – hearing loss; very rare – vertigo, tinnitus.

Cardiac disorders: very rare – cyanosis, tachycardia, palpitation.

Vascular disorders: common – thrombophlebitis; uncommon – hypotension; very rare – flushing.

Respiratory, thoracic and mediastinal disorders: very rare – dyspnoea, hyperventilation, pharyngeal pain.

Gastrointestinal disorders: common – diarrhoea, vomiting, nausea. Medicinal product-related nausea and/or vomiting appear to occur more frequently in granulocytopenic patients than in non-granulocytopenic patients treated with the preparation. Rare – staining of teeth and/or tongue; very rare – haemorrhagic colitis, abdominal pain, heartburn, glossitis, tongue papilla hypertrophy, hypersalivation.

Hepatobiliary disorders: rare – hepatic failure, hepatitis; very rare – fulminant hepatitis.

Skin and subcutaneous tissue disorders: common – rash (e.g. exanthematous); uncommon – urticaria, pruritus; rare – toxic epidermal necrolysis, angioedema, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis; very rare – hyperhidrosis, skin texture changes.

Musculoskeletal and connective tissue disorders: very rare – polyarthralgia, thoracic spine pain.

Renal and urinary disorders: rare – acute renal failure, oligurial/anuria, polyuria, urine discoloration (harmless and should not be confused with haematuria). The role of imipenem/cilastatin in changes in renal function is difficult to assess, since factors predisposing to pre-renal azotemia or to impaired renal function usually have been present.

Reproductive system and breast disorders: very rare – pruritus vulvae.

General disorders and administration site conditions: uncommon – ever, local pain and induration at the injection site, erythema at the injection site; very rare – chest discomfort, asthenia/weakness.

Investigations: common – increases in serum transaminases, increases in serum alkaline phosphatase; uncommon – a positive direct Coombs' test, prolonged prothrombin time, decreased haemoglobin, increases in serum bilirubin, elevations in serum creatinine, elevations in blood urea nitrogen.

In studies of 178 paediatric patients ≥3 months of age, the reported adverse reactions were consistent with those reported for adults.

 

Shelf-life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25˚C in the original manufacturer’s packaging.

Keep out of reach of children.

Do not freeze the reconstituted solutions of the medicinal product.

The shelf life of reconstituted solutions is given in the section "Method of administration and dosage".

 

Incompatibility.

The medicinal product is chemically incompatible with lactate (lactic acid salts) and shall not be reconstituted in diluters containing lactate. However, the drug can be ad administered into an I.V system through which a lactate solution is being infused.

The product shall not be mixed with other antibiotics.

 

Packaging.

Powder in a glass vial closed with a rubber stopper and an aluminum cap with a flip-off component, 1 vial in a box.

 

Terms of dispensing. On prescription.

 

Manufacturer. “Venus Remedies Limited”.

 

Manufacturer’s registered address.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh, 173205, India.

 

Applicant. Ananta Medicare Ltd.

 

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom