Desulpim (Powder) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J01DE51 (Cefepime and beta-lactamase inhibitor)

Active Substances

Sulbactam (Rec.INN registered by WHO)

Cefepime (Rec.INN registered by WHO)

Dosage Form

Desulpim

Powder for solution for intravenous and intramuscular administration 1000 mg+1000 mg

Dosage Form, Packaging, and Composition

Powder for preparation of solution for intravenous and intramuscular administration

2000 mg – vials – cardboard packs – By prescription
2000 mg – vials (10 pcs.) – cardboard boxes – for hospitals
2000 mg – vials (10 pcs.) – cardboard boxes – By prescription
2000 mg – vials (100 pcs.) – cardboard boxes – for hospitals
2000 mg – vials (100 pcs.) – cardboard boxes – By prescription
2000 mg – vials (25 pcs.) – cardboard boxes – for hospitals
2000 mg – vials (25 pcs.) – cardboard boxes – By prescription
2000 mg – vials (5 pcs.) – cardboard boxes – for hospitals
2000 mg – vials (5 pcs.) – cardboard boxes – By prescription
2000 mg – vials (50 pcs.) – cardboard boxes – for hospitals
2000 mg – vials (50 pcs.) – cardboard boxes – By prescription

Clinical-Pharmacological Group

Fourth generation cephalosporin

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; fourth-generation cephalosporins

Pharmacological Action

Combined broad-spectrum antibiotic.

Cefepime is an antibiotic from the group of fourth generation cephalosporins. It acts bactericidally by disrupting the synthesis of the microbial cell wall. The targets of cefepime’s action are penicillin-binding proteins (PBPs); the antibiotic exhibits the greatest affinity for PBP3, somewhat less for PBP2, and moderate affinity for PBP1a and PBP1b of gram-negative bacteria. It has a broad spectrum of activity against gram-positive and gram-negative microorganisms, with no cross-resistance with antibiotics of other groups.

Sulbactam is an irreversible inhibitor of a number of widespread beta-lactamases; it does not possess clinically significant antibacterial activity (with the exception of Neisseria spp. and Acinetobacter spp.). The ability of sulbactam to prevent the destruction of penicillins and cephalosporins by resistant microorganisms has been confirmed in studies using resistant microbial strains, against which Sulbactam exhibited pronounced synergy with penicillins and cephalosporins. Furthermore, Sulbactam interacts with some penicillin-binding proteins, therefore the combination of Cefepime+Sulbactam often exerts a more pronounced effect on susceptible microbial strains than the use of cefepime alone. The combination of sulbactam and cefepime is active against all microorganisms susceptible to cefepime, as well as a number of microorganisms resistant to it.

Cefepime+Sulbactam is active against gram-positive aerobic microorganisms: Staphylococcus aureus (including beta-lactamase producing strains); Staphylococcus epidermidis (including beta-lactamase producing strains); other strains of Staphylococcus spp., including Staphylococcus hominis, Staphylococcus saprophyticus; Streptococcus pyogenes (group A streptococci); Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae (including strains with intermediate resistance to penicillin – minimum inhibitory concentration from 0.1 to 1 mcg/ml); other beta-hemolytic Streptococcus spp. (groups C, G, F), Streptococcus hovis (group D), Streptococcus spp. of the Viridans group; gram-negative aerobic microorganisms: Acinetobacter calcoaceticus (substrains anitratus, lwofii)/Acinetobacter baumannii, Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including Citrobacter diversus, Citrobacter freundii, Campylobacter jejuni; Enterobacter spp. (including Enterobacter cloacae, Enterobacter aerogenes, Enterobacter sakazakii), Escherichia coli; Gardnerella vaginalis, Haemophilus ducreyi; Haemophilus influenzae (including beta-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella ozaenae), Legionella spp., Morganella morganii, Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase producing strains), Neisseria gonorrhoeae (including beta-lactamase producing strains), Neisseria meningitidis, Pantoea agglomerans (formerly known as Enterobacter agglomerans), Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Providencia spp., including Providencia rettgeri, Providencia Stuartii; Pseudomonas spp. (including Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri), Salmonella spp.; Serratia spp., including Serratia marcescens, Serratia liquefaciens; Shigella spp., Yersinia enterocolitica; anaerobic microorganisms: Bacteroides spp., Clostridium perfringens, Fusobacterium spp., Mobiluncus spp., Peptostreptococcus spp., Prevotella melaninogenica (known as Bacteroides melaninogenicus), Veillonella spp.

Cefepime is not active against Bacteroides fragilis and Clostridium difficile; against many strains of Stenotrophomonas maltophilia, formerly known as Xanthomonas maltophilia and Pseudomonas maltophilia.

Enterococcus spp. and methicillin-resistant staphylococci are resistant to the action of most cephalosporin antibiotics, including Cefepime.

Pharmacokinetics

Cefepime

The bioavailability of cefepime is 100%. The time to reach C_max of cefepime after IV and IM administration is by the end of the infusion and 1-2 hours, respectively. C_max after IM administration in doses of 500 mg, 1 g, and 2 g is 13.9, 29.6, and 57.5 mcg/ml, respectively; after IV administration in doses of 500 mg, 1 g, and 2 g is 39.1, 81.7, and 163.9 mcg/ml, respectively. Therapeutic concentrations of cefepime are found in the following fluids and tissues: urine, bile, peritoneal fluid, bullous fluid, bronchial mucosa, sputum, prostate, appendix, and gallbladder. The binding of cefepime to plasma proteins averages 16.4% and does not depend on the concentration of cefepime in plasma. Cefepime is metabolized to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide. Cefepime is excreted primarily by the kidneys, via glomerular filtration (renal clearance averages 110 ml/min). Approximately 85% of the administered dose of unchanged cefepime is found in the urine, less than 1% as N-methylpyrrolidine, about 6.8% as N-methylpyrrolidine oxide, and about 2.5% as the cefepime epimer. After administration of doses from 250 mg to 2 g, the T_1/2 of cefepime from the body averages about 2 hours. Total clearance averages 120 ml/min. No accumulation was observed when cefepime was administered IV to healthy volunteers at a dose of 2 g every 8 hours for 9 days. The T_1/2 of cefepime increases in renal failure, with a linear relationship observed between total clearance and creatinine clearance. In severe renal impairment requiring dialysis sessions, T_1/2 averages 13 hours with hemodialysis and 19 hours with continuous peritoneal dialysis. After a single IV administration of 1 g of cefepime to healthy volunteers over 65 years of age, an increase in AUC and a decrease in renal clearance were noted compared to young volunteers.

Sulbactam

C_max of sulbactam after IV administration of 1 g was 236.8 mcg/ml; after IM administration of 500 mg – 19 mcg/ml. Sulbactam is well distributed in various tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus. Approximately 84% of the sulbactam dose is excreted by the kidneys. The T_1/2 of sulbactam averages about 1 hour. In case of impaired renal function, a high correlation was found between the total clearance of sulbactam from the body and the estimated creatinine clearance. In patients with end-stage renal disease, a significant prolongation of the T_1/2 of sulbactam (up to 9.7 hours) was detected. Hemodialysis caused significant changes in the T_1/2, total clearance, and V_d of sulbactam. Compared to healthy volunteers, elderly people showed a prolongation of T_1/2, a decrease in clearance, and an increase in the V_d of sulbactam.

Indications

Infectious and inflammatory diseases in adults caused by microorganisms sensitive to the combination of Cefepime + Sulbactam: lower respiratory tract infections, including pneumonia and bronchitis; urinary tract infections, both complicated, including pyelonephritis, and uncomplicated; skin and soft tissue infections; intra-abdominal infections, including peritonitis and biliary tract infections; inflammatory diseases of the pelvic organs; septicemia; febrile neutropenia.

Prophylaxis of surgical site infections during abdominal surgical operations.

Infectious and inflammatory diseases in children over 2 months of age caused by microorganisms sensitive to the combination of Cefepime + Sulbactam: pneumonia; urinary tract infections, both complicated, including pyelonephritis, and uncomplicated; skin and soft tissue infections; septicemia; febrile neutropenia; bacterial meningitis.

ICD codes

Dosage Regimen

Administer intravenously or intramuscularly.

Determine the dose and route based on infection severity, pathogen susceptibility, renal function, and patient condition.

For adults, the usual total daily dose is 1g cefepime + 1g sulbactam to 4g cefepime + 4g sulbactam.

Divide the total daily dose into two or three administrations, typically every 12 hours or every 8 hours.

For severe or life-threatening infections, including septicemia and febrile neutropenia, use a 2g cefepime + 2g sulbactam dose every 8 hours.

For surgical prophylaxis, administer a single 2g cefepime + 2g sulbactam dose 30-90 minutes before the procedure.

For pediatric patients over 2 months, the recommended dose is 50 mg/kg cefepime + 50 mg/kg sulbactam per administration, given every 12 hours.

For bacterial meningitis in children, administer 50 mg/kg cefepime + 50 mg/kg sulbactam every 8 hours.

Adjust the dosage for patients with renal impairment based on creatinine clearance (CrCl).

For CrCl 30-60 mL/min, administer the standard dose every 24 hours.

For CrCl 10-30 mL/min, administer one-half the standard dose every 24 hours.

For CrCl less than 10 mL/min, administer one-quarter the standard dose every 24 hours.

Administer a loading dose of 2g cefepime + 2g sulbactam to patients with renal impairment before initiating the maintenance regimen.

For patients on hemodialysis, administer the dose after the dialysis session; supplemental dosing may be required.

Reconstitute the powder for intravenous infusion with a compatible diluent such as Sterile Water for Injection, 0.9% Sodium Chloride, or 5% Dextrose.

For intravenous bolus injection, administer the reconstituted solution over 3 to 5 minutes.

For intermittent intravenous infusion, infuse the solution over 30 minutes.

For intramuscular injection, reconstitute with Lidocaine Hydrochloride solution to reduce discomfort.

Do not mix with solutions containing Lactated Ringer’s or other sodium bicarbonate solutions.

Complete the administration of the reconstituted solution within 24 hours if stored refrigerated, or use immediately if stored at room temperature.

Adverse Reactions

Infections oral mucosal candidiasis, vaginal infections, candidiasis.

Allergic reactions skin rash, erythema, urticaria, pruritus, anaphylactic reactions, anaphylactic shock, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, angioedema.

Nervous system disorders headache, seizures, paresthesia, dysgeusia, dizziness; post-registration experience: encephalopathy (impaired consciousness, including confusion, hallucinations, stupor and coma), myoclonus, seizures and non-convulsive status epilepticus. Although most cases were noted in patients with renal failure who received Cefepime at doses higher than recommended, in some cases neurotoxicity was noted in patients whose dose was adjusted depending on the degree of renal failure.

Vascular disorders: vasodilation, bleeding.

Respiratory system disorders dyspnea.

Digestive system disorders diarrhea, nausea, vomiting, colitis (including pseudomembranous colitis), abdominal pain, constipation, dyspepsia, increased ALT, AST, ALP, total bilirubin.

Urinary system disorders : renal failure, toxic nephropathy, increased serum creatinine, increased blood urea nitrogen.

Hematopoietic system disorders anemia, eosinophilia, thrombocytopenia, leukopenia and neutropenia, aplastic anemia, hemolytic anemia, agranulocytosis.

Blood coagulation system disorders increased prothrombin time or aPTT.

General disorders and administration site conditions phlebitis at the injection site, pain at the injection site, fever and inflammation at the injection site, chills.

Other genital itching, taste alteration, vaginitis, erythema, false-positive Coombs test without hemolysis.

Contraindications

Hypersensitivity to cefepime, as well as to other cephalosporins, penicillins, other beta-lactam antibiotics, arginine, sulbactam; children under 2 months of age.

With caution

History of gastrointestinal diseases (especially colitis), renal failure.

Use in Pregnancy and Lactation

Adequate and controlled clinical studies in pregnant women have not been conducted. During pregnancy, use is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

Cefepime and Sulbactam are excreted in breast milk. If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be considered.

Special Precautions

In the presence of factors that can cause impaired renal function, dose adjustment of cefepime and sulbactam is required to compensate for the reduced rate of drug excretion by the kidneys. The dosage regimen depends on the degree of renal failure, the severity of the infection, and the sensitivity of the microorganisms. For mild or moderate renal impairment, the initial dose of the drug is the same as for normal renal function. The risk of developing toxic reactions is especially increased in elderly patients with impaired renal function.

As with the use of other representatives of cephalosporins, cases of encephalopathy (usually reversible) (confusion, hallucinations, stupor, coma), myoclonus, seizures (including non-convulsive status epilepticus) and/or renal failure have been observed in patients during the practice of using cefepime. Most cases were noted in patients with renal failure who were prescribed doses higher than recommended. Usually, the symptoms of neurotoxicity disappeared after discontinuation of treatment and/or after hemodialysis, but sometimes they ended fatally. In patients with impaired renal function or in the presence of other factors that may lead to delayed excretion of cefepime, its dose should be adjusted.

Before starting treatment, the patient’s history of allergic reactions to Cefepime, Sulbactam, other cephalosporin antibiotics, penicillins and other beta-lactam antibiotics, as well as other forms of allergy should be established. Cases of severe hypersensitivity reactions, sometimes fatal, have been observed with the use of all types of beta-lactam antibiotics. If an allergic reaction occurs, treatment with the drug should be discontinued and appropriate measures taken. If a severe allergic reaction (e.g., anaphylactic reaction) occurs directly during administration, the use of epinephrine and other supportive therapy may be required.

Cephalosporin group antibiotics may cause a false-positive reaction for glucose in the urine in tests based on the reduction of copper ions (with Benedict’s or Fehling’s solutions or with Clinitest tablets), but not in enzymatic tests (with glucose oxidase). In this regard, it is recommended to use enzymatic tests with glucose oxidase to determine glucose in urine.

When prescribing empirical therapy, data on the acquired resistance of causative microorganisms should be taken into account. The level of microorganism resistance may change over time and vary in different geographical regions. To identify the causative microorganism and determine its susceptibility to cefepime+sulbactam, appropriate tests should be performed. The drug can be used as monotherapy even before the identification of the causative microorganism, as it has a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms. When there is a risk of mixed aerobic/anaerobic infection (especially when microorganisms not susceptible to cefepime+sulbactam may be present), treatment with the drug in combination with another drug active against anaerobes can be initiated before pathogen identification.

After identification of the pathogen and determination of antibiotic susceptibility, treatment should be carried out in accordance with the test results.

As with the use of other antibacterial drugs, treatment with cefepime+sulbactam may lead to the colonization of non-susceptible flora. If superinfections occur during treatment, appropriate measures must be taken.

With the use of almost all broad-spectrum antibacterial drugs, the occurrence of Clostridium difficile-associated diarrhea (CDAD) is possible, which can range from mild to severe, even fatal. If diarrhea occurs during treatment with a drug containing this combination, the diagnosis of CDAD must be confirmed. Patients should be carefully monitored for the development of CDAD, as cases of its occurrence more than two months after the cessation of antibacterial drug use have been reported. If CDAD is suspected or confirmed, the use of antibacterial drugs not directed against Clostridium difficile should be discontinued. The use of drugs that inhibit intestinal peristalsis is contraindicated in this situation.

Effect on the Ability to Drive Vehicles and Operate Machinery

During the treatment period, it is necessary to refrain from engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, taking into account the possibility of developing side effects from the central nervous system.

Drug Interactions

Concomitant use with bacteriostatic antibacterial drugs may reduce the effect of the beta-lactam antibiotic.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.