Potentox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POTEENTOX (POTENTOX)

Composition:

Active substances: cefepime hydrochloride, amikacin sulfate;

1 vial contains cefepime hydrochloride 1000 mg, amikacin sulfate 250 mg.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white, pale yellow/creamy crystalline powder.

Pharmacotherapeutic group. Cefepime in combination with amikacin. ATC code J01D E01.

Pharmacological Properties.

Pharmacodynamics.

Cefepime

Cefepime hydrochloride is a fourth-generation β-lactam cephalosporin antibiotic with broad-spectrum activity for parenteral administration. It exhibits bactericidal action. It is active against both Gram-positive and Gram-negative bacteria, including most strains resistant to aminoglycosides or third-generation cephalosporins such as ceftazidime. Cefepime is highly stable against the effects of most β-lactamases and rapidly penetrates Gram-negative bacteria. The binding affinity of cefepime to penicillin-binding protein PBP 3 significantly exceeds that of other parenteral cephalosporins. Moderate affinity of cefepime for PBP 1a and 1b also contributes to its level of bactericidal activity. The MBC (minimum bactericidal concentration)/MIC (minimum inhibitory concentration) ratio of cefepime is less than 2 for more than 80% of isolates of all susceptible Gram-positive and Gram-negative bacteria.

Cefepime inhibits bacterial cell wall enzyme synthesis. The drug has low affinity for chromosomally encoded β-lactamases.

Cefepime is active against the following microorganisms:

Gram-positive aerobes: Staphylococcus aureus (including β-lactamase-producing strains) and Staphylococcus epidermidis (including β-lactamase-producing strains); other staphylococcal strains (including S. hominis, S. saprophyticus), Streptococcus pyogenes (Group A); Streptococcus agalactiae (Group B); Streptococcus pneumoniae (including strains with intermediate penicillin resistance — MIC from 0.1 to 1 mcg/mL); other β-hemolytic streptococci (Groups C, G, F); S. bovis (Group D); Viridans group streptococci (most enterococcal strains, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci, which are resistant to most cephalosporin antibiotics, including cefepime);

Gram-negative aerobes: Pseudomonas spp. (including P. aeruginosa, P. putida, P. stutzeri), Escherichia coli, Klebsiella spp. (including K. pneumoniae, K. oxytoca, K. ozaenae), Enterobacter spp. (including E. cloacae, E. aerogenes, E. sakazakii), Proteus spp. (including P. mirabilis, P. vulgaris), Acinetobacter calcoaceticus (including subspecies anitratus, Iwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp. (including C. diversus, C. freundii); Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including β-lactamase-producing strains); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including β-lactamase-producing strains); Neisseria gonorrhoeae (including β-lactamase-producing strains); N. meningitidis; Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica.

Cefepime is inactive against many strains of Xanthomonas (Pseudomonas) maltophilia;

Anaerobes: Bacteroides spp., including B. melaninogenicus and other oral cavity microorganisms belonging to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp.

Cefepime is inactive against Bacteroides fragilis and Clostridium difficile.

Amikacin

Amikacin sulfate is a semi-synthetic third-generation aminoglycoside antibiotic with broad-spectrum activity. It exhibits bactericidal action. After actively penetrating the bacterial membrane, it binds irreversibly to the 30S ribosomal subunit, thereby inhibiting pathogen protein synthesis and leading to its death.

Highly active against aerobic Gram-negative bacteria: Pseudomonas aeruginosa, Escherichia coli, Shigella spp., Salmonella spp., Klebsiella spp., Enterobacter spp., Serratia spp., Providencia stuartii.

Also active against some Gram-positive bacteria: Staphylococcus spp. (including strains resistant to penicillin, methicillin, and certain cephalosporins), and some strains of Streptococcus spp.

Inactive against anaerobic bacteria.

Pharmacokinetics.

Both antibiotics are well absorbed after intramuscular administration. Peak plasma concentrations in healthy volunteers are reached within 1 hour after intramuscular injection of 1.25 g of the drug, amounting to 65 mg/mL for cefepime and 23 mg/mL for amikacin. After 12 hours, plasma levels of cefepime decrease to 1 mg/mL and amikacin to 2 mg/mL. Cefepime and amikacin act synergistically, thereby providing a broad range of activity in the human body against both Gram-positive and Gram-negative bacteria. Elimination occurs primarily via the kidneys, with a mean elimination half-life of 2 hours (± 0.3) and total clearance of 94–120 (± 10) mL/min in healthy patients.

The combination of cefepime and amikacin shows no chemical or physicochemical incompatibility.

The pharmacokinetics of Potentox administered at doses of 650 mg–1.5 g is linear. There is no evidence of accumulation in the body of healthy individuals receiving clinically significant doses over 5 days.

Cefepime.

After intramuscular administration, it is rapidly and completely absorbed. Therapeutic concentrations of cefepime are achieved in urine, bile, peritoneal fluid, bronchial secretions, sputum, prostate, appendix, and gallbladder. The mean elimination half-life of cefepime is approximately 2 hours. In healthy individuals receiving doses up to 2 g intravenously every 8 hours for 9 days, no drug accumulation was observed. Mean total clearance is 120 mL/min. Cefepime is excreted almost exclusively via renal mechanisms, primarily by glomerular filtration (mean renal clearance is 110 mL/min). Approximately 85% of the administered dose is recovered unchanged in urine. Plasma protein binding of cefepime is less than 19% and does not depend on drug concentration in blood serum.

Amikacin.

After intramuscular administration, it is rapidly and completely absorbed. It distributes into extracellular fluid, including blood serum, lymph, pericardial, synovial, peritoneal fluids, pleural effusion, ascitic fluid, and abscess fluid. High concentrations are found in urine. Low concentrations are found in bile, breast milk, bronchial secretions, sputum, and cerebrospinal fluid (CSF). Penetration into CSF increases during meningitis. It penetrates all body tissues and accumulates intracellularly. High concentrations are found in the liver, lungs, and kidneys (in the kidney, amikacin accumulates in the cortical substance). Elimination half-life in adults is 2–4 hours, in neonates 5–8 hours, and in older children 2.5–4 hours. Approximately 75–95% is excreted unchanged by the kidneys via glomerular filtration.

Children. Pharmacokinetic evaluation of Potentox was conducted in children aged 2 months to 11 years after single and multiple doses. Absolute bioavailability of cefepime after intramuscular injection at a dose of 50 mg/kg is 82.3 (± 15)%. Elimination half-life is inversely proportional to postnatal age and renal clearance of both antibiotics. Patient age and sex have no significant effect on total body clearance or volume of distribution when corrected for body weight. Cefepime exposure in children after intravenous administration at 50 mg/kg is comparable to exposure after a 2 g intravenous dose in adults. The volume of distribution of the drug is determined by amikacin.

Elderly patients. Dosage adjustment for elderly patients is required based on creatinine clearance. Pharmacokinetics of Potentox were studied in elderly patients with a mean creatinine clearance of 64 (± 15) mL/min. An increase in the elimination half-life of Potentox was observed, dependent on creatinine clearance values. It is advisable to calculate maximum and minimum serum concentrations immediately after completing a treatment course. Peak plasma concentration occurs 30–90 minutes after injection.

Studies conducted in patients with varying degrees of renal impairment demonstrated prolonged elimination half-life of the drug. In patients with reduced renal function (creatinine clearance ≤ 60 mL/min), the dose should be individually adjusted. Mean elimination half-life in patients with severe renal impairment undergoing dialysis is 13 hours for hemodialysis and 19 hours for peritoneal dialysis. Pharmacokinetics of the drug in patients with impaired liver function are unchanged. Dose adjustment is not required in such patients.

Clinical characteristics.

Indications.

• Bacterial septicemia;
• Respiratory tract infections (community-acquired and hospital-acquired pneumonia, including complicated cases);
• Skin and soft tissue infections;
• Urinary tract infections and complicated urinary tract infections (acute and chronic pyelonephritis), except for initial treatment of the first episode of urinary tract infections, since the potential benefit is limited by the nephrotoxic effect of amikacin sulfate;
• Bone and joint infections (osteomyelitis, arthritis);
• Intra-abdominal infections (peritonitis, cholecystitis);
• Meningitis;
• Burns.

To identify the causative microorganism(s) and determine susceptibility to Potentox, appropriate tests should be performed. Antibiotic therapy should be adjusted accordingly upon receipt of test results.

Contraindications.

• Hypersensitivity to cefepime, amikacin, cephalosporins, penicillins, or other β-lactam antibiotics, aminoglycoside antibiotics, or their derivatives.
• Severe renal impairment, azotemia (blood urea nitrogen level above 150 mg%), renal failure.
• Auditory nerve neuritis, vestibular dysfunction.
• Myasthenia gravis.
• Prior treatment with ototoxic or nephrotoxic agents.

Interaction with other medicinal products and other forms of interaction.

Interactions related to cefepime

Amikacin

Renal and auditory function should be closely monitored when cefepime is used concomitantly with aminoglycosides due to increased potential for nephrotoxicity and ototoxicity.

Diuretics

Nephrotoxicity has been reported after concomitant use of other cephalosporins with diuretics such as furosemide. Renal function should be closely monitored when cefepime is used concomitantly with diuretics.

Effect on laboratory test results

Cefepime may cause false-positive glucose in urine tests when using Benedict's reagent. Glucose tests based on enzymatic glucose oxidation reactions are recommended.

To avoid possible drug interactions with other agents, cefepime solutions (like most other β-lactam antibiotics) should not be administered simultaneously with metronidazole, vancomycin, gentamicin, tobramycin sulfate, or netilmicin sulfate. If co-administration of Potentox with these agents is necessary, each antibiotic should be administered separately.

Interactions related to amikacin

Pharmaceutically incompatible with penicillins, heparin, cephalosporins, capreomycin, amphotericin B, hydrochlorothiazide, erythromycin, nitrofurantoin, vitamins B and C, and potassium chloride.

Amikacin exhibits synergy when used with carbenicillin, benzylpenicillin, and cephalosporins (in patients with severe chronic renal failure, concomitant use with beta-lactam antibiotics may reduce aminoglycoside efficacy).

Nalidixic acid, polymyxin B, cisplatin, and vancomycin increase the risk of ototoxicity and nephrotoxicity.

Concomitant use with penicillins, cephalosporins, sulfonamides, vancomycins, methoxyflurane, enflurane, nonsteroidal anti-inflammatory drugs (NSAIDs), radiographic contrast agents, cyclosporine, cisplatin, amphotericin B, cephalothin, polymyxin, and diuretics (especially furosemide) increases the risk of nephrotoxicity.

Indomethacin, phenylbutazone, and other NSAIDs that impair renal blood flow may slow the elimination rate of amikacin. If amikacin is used concomitantly with intravenous indomethacin in premature infants, plasma concentrations of amikacin may increase, increasing the risk of toxicity.

Enhances the muscle-relaxant effect of curare-like agents.

Methoxyflurane, parenteral polymyxin, capreomycin, and other agents that block neuromuscular transmission (halogenated hydrocarbons used for inhalational anesthesia, opioid analgesics), and large-volume blood transfusions with citrate anticoagulants increase the risk of respiratory arrest.

Parenteral administration of indomethacin increases the risk of aminoglycoside toxicity (increased half-life and reduced clearance).

Amikacin reduces the efficacy of drugs used in myasthenia gravis.

Concomitant use with ethyl ether and neuromuscular blocking agents increases the risk of respiratory depression.

The risk of ototoxicity increases with concomitant use of amikacin and furosemide or ethacrynic acid.

Interactions related to Potentox.

Concomitant use of Potentox with anticoagulants, heparin, or thrombolytics increases the risk of bleeding.

Potentox, by suppressing intestinal flora, interferes with vitamin K synthesis. Therefore, concomitant use with agents that reduce platelet aggregation (NSAIDs, salicylates) increases the risk of bleeding. Concomitant use with other aminoglycoside antibiotics increases the risk of all listed adverse effects. Two aminoglycosides should not be administered simultaneously, nor should one aminoglycoside be replaced by another if the first has been used within the past 7–10 days. Re-treatment should not be initiated earlier than 4–6 weeks. When administered concomitantly with penicillin-group antibiotics, serum concentrations of the drug may decrease.

Special precautions for use.

Prior to administration of the medicinal product, susceptibility of the isolated pathogens should be determined.

Related to cefepime

It is essential to establish whether the patient has previously experienced immediate-type hypersensitivity reactions to cefepime or other β-lactam antibiotics. Antibiotics should be administered with caution to all patients with any form of allergy, especially to medicinal products. If an allergic reaction occurs, the drug should be discontinued immediately. Severe immediate-type hypersensitivity reactions may require administration of epinephrine and other therapeutic interventions.

Use with caution in patients with gastrointestinal disorders (particularly in medical history), especially colitis.

Cases of pseudomembranous colitis have been reported with the use of practically all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of this condition developing in case of diarrhea occurring during treatment with Potentox. Studies indicate that the toxin produced by Clostridium difficile is the primary cause of antibiotic-associated colitis. After confirmation of the diagnosis of pseudomembranous colitis, appropriate therapeutic measures should be taken. Mild to moderate pseudomembranous colitis may resolve after discontinuation of the drug. In cases of moderate to severe pseudomembranous colitis, consideration should be given to the need for fluid and electrolyte replacement, protein supplementation, and administration of an antibacterial agent effective against Clostridium difficile.

For patients with impaired renal function (creatinine clearance ≤ 60 mL/min), the dose of cefepime must be adjusted to compensate for reduced renal elimination. Because increased serum concentrations of the antibiotic may occur when standard doses of cefepime are administered to patients with renal insufficiency or other conditions that may impair renal function, the maintenance dose of cefepime should be reduced in such patients. When determining the next dose of cefepime, the degree of renal impairment, severity of infection, and microbial susceptibility to the antibiotic should be taken into account.

During post-marketing surveillance of cefepime-containing drugs, severe adverse events that were life-threatening or fatal have been reported: encephalopathy (altered consciousness, including confusion, hallucinations, stupor, and coma), myoclonus, and seizures. Most cases occurred in patients with impaired renal function who received doses of cefepime exceeding the recommended ones. Some cases occurred in patients receiving doses adjusted according to renal function. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.

Prescribing cefepime in the absence of proven or suspected bacterial infection or for prophylactic use is unlikely to be beneficial and increases the risk of emergence of bacteria resistant to this medicinal product. Prolonged use of cefepime (as with other antibiotics) may lead to development of superinfection. Re-evaluation of the patient’s condition should be performed regularly. In case of superinfection development, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with reduced prothrombin activity. Patients at risk include those with impaired hepatic or renal function, malnourished patients, and those receiving prolonged courses of antimicrobial therapy. Prothrombin levels should be monitored in patients at risk, and vitamin K should be administered if necessary.

During cefepime therapy, positive results in the direct Coombs test may be obtained. When performing hematological or transfusion procedures involving blood group determination by cross-matching, where antiglobulin testing or Coombs test is performed, or in neonates whose mothers received cephalosporin antibiotics before delivery, it should be considered that a positive Coombs test may be due to the drug administration.

Related to amikacin

Amikacin should not be administered to patients with hypersensitivity to other aminoglycosides due to the risk of cross-allergy.

Amikacin should be used with caution in patients with Parkinsonism, myasthenia (except M. gravis, where use is contraindicated), botulism (aminoglycosides may impair neuromuscular transmission, leading to further skeletal muscle weakness), dehydration, infants (especially premature), and elderly patients.

During treatment, renal function, auditory nerve function, and vestibular apparatus should be monitored at least once a week.

The risk of nephrotoxic effects is higher in patients with impaired renal function and when the drug is administered in high doses or for prolonged periods (such patients require daily monitoring of renal function).

If audiometric tests show abnormalities, the dose should be reduced or treatment discontinued.

Patients with infectious-inflammatory diseases of the urinary tract are recommended to consume large amounts of fluids.

The main toxic effect of the drug following parenteral administration is its effect on the eighth cranial nerve, initially manifesting as hearing loss in the high-frequency range. The risk of ototoxic complications is significantly higher in patients with impaired renal function. Prior to initiating therapy, correction of the patient’s fluid and electrolyte balance is necessary. In dehydrated patients, the risk of toxicity increases due to elevated serum drug concentrations. During treatment with amikacin sulfate, adequate fluid intake is required, plasma creatinine concentrations should be frequently monitored, and dosage adjustments should be made as necessary. Ototoxicity caused by aminoglycoside antibiotics may develop even after discontinuation of the drug and is usually irreversible. The risk of ototoxicity is increased in patients with impaired renal function, as well as with high-dose or prolonged treatment.

Patients with mitochondrial DNA mutations (particularly nucleotide substitution 1555 A to G in the 12S rRNA gene) may have an increased risk of ototoxicity, even if serum aminoglycoside levels during treatment remain within the recommended range. Alternative treatment options should be considered for such patients.

Patients with mitochondrial DNA mutations in family history or aminoglycoside-induced hearing loss should consider the possibility of alternative treatments or genetic testing prior to drug administration.

Dosage of amikacin should be reduced in elderly patients due to decreased renal function and possible reduction in body mass. Renal function should be regularly assessed. Urinalysis should be performed before and during treatment.

Amikacin administration may alter the following laboratory parameters: serum alanine aminotransferase, aspartate aminotransferase, bilirubin, lactate dehydrogenase, alkaline phosphatase, blood urea nitrogen, creatinine, and calcium, magnesium, potassium, and sodium ions.

For patients with impaired renal function, the daily dose should be reduced and/or the dosing interval extended according to serum creatinine concentration to prevent drug accumulation in the blood and minimize the risk of ototoxicity. If signs of renal irritation occur (e.g., albuminuria, microhematuria, leukocyturia), hydration should be increased and the dose reduced. These manifestations usually resolve after completion of treatment. If signs of ototoxicity (e.g., dizziness, tinnitus, hearing loss) or nephrotoxicity (e.g., decreased creatinine clearance, oliguria) appear, amikacin should be discontinued or the dose reduced. If azotemia or progressive oliguria develops, treatment should be stopped.

Concomitant administration of amikacin sulfate and potent diuretics, such as ethacrynic acid derivatives, furosemide, or mannitol (especially if the diuretic is administered intravenously), may result in irreversible hearing loss.

Two aminoglycosides should not be administered simultaneously, nor should one drug be replaced by another if the first aminoglycoside was used for 7–10 days. A repeat course should not be initiated earlier than 4–6 weeks.

In the absence of positive clinical response, consider the possibility of development of resistant microorganisms. In such cases, treatment should be discontinued and appropriate therapy initiated.

Use during pregnancy or breastfeeding

Contraindicated during pregnancy or breastfeeding. If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

The effect of Potentox on reaction speed when driving or operating machinery has not been studied; however, it should be considered that adverse reactions affecting the nervous system may occur during treatment.

Administration and Dosage

Prior to administration, skin tests for individual sensitivity to the drug should be performed, provided there are no contraindications to such testing.

The daily dose for adults is 1.25–2.5 g, administered once or twice daily in equal doses, depending on the type and course of the disease.

The appropriate dosage should be calculated based on body weight. Potentox can be administered intravenously or intramuscularly.

Before initiating treatment, serum creatinine levels should be determined and endogenous creatinine clearance calculated. Blood urea nitrogen measurement is not a reliable indicator of renal function. Renal function should be periodically reassessed during prolonged therapy.

It is advisable to calculate the peak and trough serum concentrations of Potentox during treatment. Serum concentration should not exceed 35 mcg/mL (calculated as amikacin sulfate) within 30–90 minutes after injection. The next dose may be administered when the serum concentration of Potentox reaches 10 mcg/mL (calculated as amikacin sulfate).

Intramuscular administration in patients with normal renal function: the recommended daily dose for adults and children aged 12 years and older is 15 mg/kg/day (calculated as amikacin sulfate), divided into two equal doses given at equal intervals. Doses for patients with excess body weight should not exceed 1.5 g/day.

Initial dose for children aged 2 months to 12 years: 10 mg/kg (calculated as amikacin sulfate), followed by 7.5 mg/kg every 12 hours.

Duration of treatment: 7–10 days.

Recommended doses and administration methods for adults are provided in Table 1.

* Intramuscular administration is indicated only for the treatment of urinary tract infections caused by E. coli when this route of administration is considered more appropriate.

Intravenous administration in patients with normal renal function: Potentox is administered intravenously over 30–60 minutes.

In renal insufficiency, the initial dose (calculated as amikacin sulfate) is 7.5 mg/kg. Subsequent doses are determined by the formula:

(1st dose (mg) × CrCl)/100,

where CrCl is creatinine clearance in mL/min/1.73 m².

If only serum creatinine can be determined, the following formulas are used to estimate creatinine clearance:

For males:

For women:

For children:

in renal insufficiency, administer to children from 12 months of age

where k is the age-related conversion coefficient:

• 0.33 — premature children aged 1 to 4 years;
• 0.45 — full-term children aged 1 to 4 years;
• 0.55 — children aged 2–14 years;
• 0.55 — girls aged 14 years and older;
• 0.70 — boys aged 14 years and older.

In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis is eliminated during a 3-hour dialysis session. A repeat dose equal to the initial dose should be administered after completion of each dialysis session.

For patients undergoing long-term continuous ambulatory peritoneal dialysis, Potentox can be administered at the initial standard recommended doses depending on the severity of infection, given every 48 hours.

Potentox should be reconstituted using one of the following diluents: sterile water for injection, 0.9% sodium chloride solution, 5% glucose solution for injection, or sterile bacteriostatic water for injection (containing benzyl alcohol). Solutions should be prepared immediately before use. After adding the diluent, the solution should be visually inspected to ensure complete dissolution of the drug.

For intravenous infusion, take a vial of Potentox, add the appropriate volume of diluent (see Table 2), transfer the solution into an intravenous container with the appropriate intravenous fluid. The resulting solution should be administered over 30–60 minutes. These solutions can be stored for up to 24 hours at room temperature of 20–25 °C.

Preparation of Potentox solutions

Table 2

When administered intramuscularly, the solution should be injected deeply into the upper outer quadrant of the buttock.

The color of Potentox powder and its solution may darken depending on storage conditions. When stored under recommended conditions, the drug's activity remains unchanged.

Children.

Potentox is recommended for use in children aged 2 months and older. Safety of treatment in children under 2 months of age has not been established. Adequate clinical data supporting the use of Potentox for the treatment of children under 2 months of age or children with severe infections caused by Haemophilus influenzae type b are lacking.

Overdose.

Symptoms.

Cefepime

In cases of significant overdose, especially in patients with impaired renal function, adverse effects are intensified. Overdose symptoms include encephalopathy accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptiform seizures, and neuromuscular excitability.

Amikacin

Possible manifestations of ototoxic and nephrotoxic effects of the drug, as well as signs of neuromuscular blockade: tinnitus, hearing loss, auditory disturbances, skin rashes, headache, dizziness, malaise, paresthesia, decreased renal function (up to renal failure), respiratory depression or paralysis, and toxic reactions (ataxia, urinary disorders, thirst, decreased appetite, nausea, vomiting).

Treatment.

The administration of the drug should be discontinued and symptomatic therapy initiated. Hemodialysis is required to enhance elimination of Potentox from the body. Severe immediate-type allergic reactions require administration of epinephrine and other forms of intensive therapy. At the first signs of neuromuscular blockade, Potentox administration must be stopped immediately, and calcium chloride solution should be administered intravenously or proserin and atropine subcutaneously. If necessary, the patient should be switched to artificial ventilation.

Adverse reactions.

The most common adverse effects were gastrointestinal symptoms and hypersensitivity reactions.

Adverse reactions observed during treatment with cefepime and amikacin are presented in Table 3.

* Convulsions, apnea may occur in patients with impaired renal function if Potentox doses have not been adjusted according to creatinine levels. If seizures occur due to Potentox administration, the drug should be discontinued.

** Amikacin primarily affects auditory function. Cochlear damage involves high-frequency irreversible deafness and often occurs before hearing impairment can be clinically detected.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging and in a place inaccessible to children.

Incompatibility.

Do not mix with other medicinal products in the same container. Use only the solvents specified in the section "Administration and dosage".

Packaging. 1 vial in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address and location of business operations.

Hill Top Industrial Estate, Jarmajri, ERIP Phase-I (Ext.), Batholi Kalan, Baddi, Solan District, Himachal Pradesh 173205, India.

Marketing Authorization Holder.

Mili Healthcare Limited.

Address of the Marketing Authorization Holder.

2nd floor, office premises, 4 Charterfield House, Castle Street, Taunton, Somerset, England, TA1 4AS, United Kingdom.