INSTRUCTION

for medical use of the medicinal product

CEFOTRINE

 

Composition:

Active substance: cefepime hydrochloride USP equivalent to cefepime;

1 vial contains cefepime hydrochloride USP equivalent to cefepime – 1 g;

Excipient: L-arginine.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Beta-lactam antibiotics. The fourth generation cephalosporins. ATC code: J01D E01.

Pharmacological properties.

Pharmacodynamics.

Cefepime inhibits the synthesis of enzymes in a bacterial cell wall and has a wide spectrum of action against various gram-positive and gram-negative bacteria. Cefepime is highly resistant to hydrolysis by the majority of β-lactamases. It has a small affinity for β-lactamases encoded by chromosomal genes and penetrates into gram-negative bacterial cells rapidly.

Cefepime is active against the following microorganisms:

gram-positive aerobes: Staphylococcus aureus and Staphylococcus epidermidis (including their strains producing β-lactamase); other staphylococci strains, including S. hominis, S. saprophyticus; Streptococcus pyogenes (streptococcus group А); Streptococcus agalactiae (streptococcus group В); Streptococcus pneumoniae (including medium penicillin-resistance strains - MIC from 0.1 to 1 μg/ml); other β-hemolytic streptococci (group C, G, F), S. bovis (group D), streptococcus group Viridans. Most enterococcal strains, such as Enterecoccus faecalis, and methicillin-resistant staphylococci, 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 (subsp. anitratus, lwoffi); Aeromonas hydrophila; Capnocytophaga spp.; Citrobacter spp., including C. diversus, C. freundii; Campylobacter jejuni; Gardnerella vaginalis; Haemophilus ducreyi; H. influenzae (including strains that produce b-lactamases); H. parainfluenzae; Hafnia alvei; Legionella spp.; Morganella morganii; Moraxella catarrhalis (Branhamella catarrhalis) (including strains that produce β-lactamase); Neisseria gonorrhoeae (including strains that produce β-lactamase); N. meningitidis; Pantoea agglomerans (known as Enterobacter agglomerans); Providencia spp. (including P. rettgeri, P. stuartii); Salmonella spp.; Serratia (including S. marcescens, S. liquefaciens); Shigella spp.; Yersinia enterocolitica. Cefepim is inactive for many strains of Xanthomonas maltophilia and Pseudomonas  maltophilia;

anaerobes: Bacteroides spp., including B. melaninogenicus and other oral cavity microorganisms that belong to Bacteroides; Clostridium perfringens; Fusobacterium spp.; Mobiluncus spp.; Peptostreptococcus spp.; Veillonella spp. Cefepim is inactive for Bacteroides fragilis and Clostridium difficile.

Pharmacokinetics.

The average concentrations of cefepime in blood plasma in healthy adult men at different times after single intravenous and intramuscular administration are given in the table below.

Average concentrations of cefepime in blood plasma (μg/ml) after intravenous (IV) and intramuscular (IM) administration

Cefepime dose	0.5 hour	1 hour	2 hours	4 hours	8 hours	12 hours
1 g IV	78.7	44.5	24.3	10.5	2.4	0.6
1 g IM	14.8	25.9	26.3	16.0	4.5	1.4

 

Therapeutic concentrations of cefepime are also achieved in the urine, bile, peritoneal fluid, mucosal secretion of the bronchi, sputum, prostate, appendix, and gall bladder.

The average half-life of cefepime is about 2 hours. In healthy volunteers receiving doses up to 2 g intravenously at intervals of 8 hours during 9 days, no accumulation of the drug was observed.

Cefepime is metabolized into N-methylpyrrolidine, which is rapidly transformed into N-methylpyrrolidine oxide. The average total clearance is 120 ml/min. Cefepime is excreted almost solely through renal regulation mechanisms, mainly by glomerular filtration (average renal clearance – 110 ml/min). In urine, unchanged cefepime is approximately 85%, N-methylpyrrolidine – 1%, N-methylpyrrolidine oxide is about 6.8% and cefepime epimer is about 2.5%. The binding of cefepime to plasma proteins is less than 19% and does not depend on the concentration of the drug in blood serum.

Patients aged 65 years and older with normal kidney function do not need the drug dose adjustment, despite a smaller renal clearance compared to younger patients.

In patients with different stages of renal failure, studies have shown the increased half-life of the drug. In patients with severe renal failure requiring dialysis, the average half-life is 13 hours in hemodialysis and 19 hours in peritoneal dialysis.

The pharmacokinetics of cefepime is unchanged in patients with impaired liver function or cystic fibrosis. Dosage adjustment for such patients is not required.

Clinical particulars.

Indications.

Adults.

Infections caused by microflora susceptible to the drug:

- infections of the respiratory tract, including pneumonia, bronchitis;

- infections of the skin, subcutaneous tissue and soft tissues;

- intra-abdominal infections, including peritonitis and infections of the biliary tract;

- gynaecological infections;

- septicemia.

Empirical therapy of patients with neutropenic fever.

Prevention of postoperative complications in intra-abdominal surgery.

Children.

- pneumonia;

- urinary tract infections, including pyelonephritis;

- skin and subcutaneous tissue infections;

- septicemia;

- empirical therapy of patients with neutropenic fever;

- bacterial meningitis.

Contraindications.

Hypersensitivity to cefepime or L-arginine, as well as to cephalosporin antibiotics, penicillins or other β-lactam antibiotics.

Interaction with other drugs and other types of interactions. 

When Cefotrin is co-administrated with high doses of aminoglycosides, the renal function should be closely monitored due to potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity was observed after co-administration of other cephalosporins with diuretics, such as furosemide.

Cefepime concentrations from 1 to 40 mg/ml are compatible with the following parenteral solutions:

0.9% solution of sodium chloride for injection; 5 and 10% glucose solution for injection; 6M sodium lactate solution for injection, 5% glucose and 0.9% sodium chloride solution for injections; Ringer's lactate solution and 5% glucose solution for injection.

To avoid possible drug interactions with other drugs, cefepime solutions (like most other β-lactam antibiotics) should not be co-administered with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulphate and netilmicin sulphate. Each of these antibiotics is administrated separately if these drugs are prescribed along with Cefotrine.

Effects on clinical laboratory tests.

The use of cefepime may cause a false-positive reaction to urine glucose test when using Benedict's reagent. It is recommended to use glucose tests based on the enzymatic reaction of glucose oxidation.

Precautions for use. 

In patients with high risk of severe infections (e.g. patients with a history of bone marrow transplantation with its reduced activity occurring against a background of malignant hemolytic disease with severe progressive neutropenia), monotherapy may be insufficient and therefore, a complex antimicrobial therapy is indicated.

It is necessary to determine whether the patient had immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins or other β-lactam antibiotics before. Antibiotics should be prescribed with caution to all patients with any form of allergies, especially to medicinal products. In the event of an allergic reaction, the use of the drug should be discontinued. Severe immediate hypersensitivity reactions may require the use of adrenaline and other forms of therapy.

Pseudomembranous colitis was reported when using almost all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of developing this pathology in the event of diarrhoea during the treatment with Cefotrin. Pseudomembranous colitis from mild diarrhea to colitis with a fatal outcome is possible. Mild colitis might disappear after the drug administration; moderate or severe conditions may require special treatment.

The drug should be used with caution in patients with the digestive tract diseases, especially colitis.

In long-term treatment, it is necessary to regularly monitor the functional parameters of liver, kidneys and hemopoiesis organs.

In patients with renal impairment (creatinine clearance <60 ml/min), the dose of cefepime should be adjusted to compensate for the slow rate of renal excretion. Since prolonged antibiotic concentrations in blood serum are possible at normal doses in patients with renal insufficiency or other conditions that may impair renal function, the maintenance dose should be lowered when cefepime is administered to such patients. The stage of renal dysfunction, severity of the infection and its susceptibility to bacteria that caused the infection, should be taken into account when determining the next dose.

When using cefepime, including other drugs of this group, the serious adverse reactions such as reversible encephalopathy (confusion, including ocular consciousness), myoclonia, convulsions and/or renal failure, were observed more frequently in patients with renal insufficiency, who received the doses higher than recommended, and in elderly patients with renal insufficiency at recommended doses of cefepime. Some cases occurred in patients who received the doses adjusted for their renal function. In most cases, the symptoms of nephrotoxicity were reversible and disappeared after discontinuation of cefepime and/or after hemodialysis.

The pharmacokinetics of cefepime is unchanged in patients with impaired liver function. Dosage adjustment for such patients is not required.

The use of antibacterial agents causes a change in the normal microflora of the large intestine and may cause clostridium growth. Studies have shown that the toxin produced by Clostridium difficile is a major cause of antibiotic-associated colitis. After confirmation of pseudomembranous colitis diagnosis, it is necessary to take therapeutic measures. Moderate pseudomembranous colitis may disappear after discontinuation of the drug. In case of moderate and severe conditions, it is necessary to consider the expediency of the fluids and electrolytes use, proteins replenishment and the use of an antibacterial drug effective against Clostridium difficile.

Warnings.

It is unlikely that the prescription of cefepime in the absence of proven or suspected bacterial infection or prophylactic use will be effective, but this may increase the risk of bacteria that are not susceptible to this drug. Prolonged administration of cefepime (including other antibiotics) may cause the development of superinfection. It is necessary to carry out a re-examination of the patient's condition. In the event of a superinfection, appropriate measures should be taken.

Many cephalosporins, including cefepime, are associated with a decreased prothrombin activity. The risk group includes patients with impaired liver or kidney function, patients with a poor diet, and those who take a long course of antimicrobial therapy. It is necessary to control prothrombin in patients at risk and, if necessary, to prescribe vitamin K.

When using cefepime, a positive direct Coombs test results can be obtained. When haematological or transfusion procedures for determining the blood group by cross-linking method are performed, and when an antiglobulin test or Coombs test for newborns whose mothers received cephalosporin group antibiotics before childbirth is performed, it should be taken into account that a positive Coombs test may be the result of the drug administration.

When using lidocaine as a solvent, lidocaine safety information should be taken into account.

It has been shown that L-arginine changes glucose metabolism and simultaneously increases potassium levels in blood serum at doses that 33 times exceed the maximum recommended dose of cefepime. At this time the lower dose effects are not known.

Utilization.

Environment pollution with the medicinal product should be minimized. Avoid entering the medicinal product into the sewage system or household waste.

Pregnancy and lactation.

There are no adequate and well controlled studies for pregnant women. Therefore, Cefotrin can only be prescribed during pregnancy when the expected benefit to the mother outweighs the potential risk to the fetus.

Cefepime penetrates breast milk in a very small amount, but during the treatment breastfeeding should be discontinued.

Effects on reaction rates while driving vehicles or operating other mechanisms.

Taking into account the possibility of the drug to affect the central nervous system, it is recommended to refrain from driving and working with other mechanisms when using Cefotrin.

Route of administration and Dosages.

The usual dosage for adults is 1 g. Cefotrin should be administered intravenously or intramuscularly at 12 hours interval. Usual duration of the treatment is 7-10 days; severe infections may require longer treatment.

However, the dosage and route of administration vary depending on pathogens susceptibility, infection severity and the patient’s kidneys functional state.

Recommendations for the dosage of Cefotrin for adults are given in the following table.

Infection severity	Dosage and route of administration	Frequency
Urinary tract infections of mild and moderate severity	500 mg - 1 g intravenously or intramuscularly	Every 12 hours
Other infections of mild and moderate severity	1 g intravenously or intramuscularly	Every 12 hours
Severe infections	2 g intravenously	Every 12 hours
Very serious and life-threatening infections	2 g intravenously	Every 8 hours

 

For preventing the development of infections during surgical interventions. 60 minutes before the surgery, adults should be given 2 g of the drug intravenously for 30 minutes. Then add additional 500 mg of metronidazole intravenously. Solutions of metronidazole should not be concurrently administered with Cefotrine. Before the introduction of metronidazole the system for infusion should be washed.

During long (more than 12 hours) surgical operations, it is recommended to reintroduce the same dose of Cefotrin with the subsequent administration of metronidazole 12 hours after the first dose.

Renal impairment. In patients with impaired renal function (creatinine clearance is less than 30 ml/min), the dose of Cefotrin should be adjusted.

Recommended doses of cefepime for adults

Creatinine clearance (ml/min)	Recommended doses
> 50	The usual dosage which is adequate for the infection severity (see previous table), dose adjustment is not required.
	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	500 mg every 12 hours
30-50	Dose adjustment according to creatinine clearance
	2 g every 12 hours	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours
11-29	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
£ 10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Hemodialysis	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

If only the creatinine concentration in blood serum is known, then creatinine clearance can be calculated by the following formula:

Men:

                                                             body weight (kg) ´ (140 - age)

creatinine clearance (ml/min) = ---------------------------------------------------

                                                            72 ´ serum creatinine (mg/dl)

Women:

Creatinine clearance (ml/min) = above mentioned value ´ 0.85

 

In hemodialysis, about 68% of the dose of the drug is excreted from the body within 3 hours. After completion of each dialysis session, a repeated dose equal to the initial dose should be administered. In continuous outpatient peritoneal dialysis, the drug can be used at initial normal recommended doses of 500 mg, 1 or 2 g depending on the infection severity at 48 hours interval.

Children from 1 to 2 months. Prescribe only according to life-indications at a dose of 30 mg/kg body weight every 12 or 8 hours, depending on the infection severity. The state of children with body weight up to 40 kg treated with Cefotrin should be monitored continuously.

In children with impaired kidney function, it is recommended to lower the dose or increase the interval between injections.

Creatinine clearance in children is calculated by the following formula:

 

                                                                       0.55 ´ height (cm)

creatinine clearance (ml/min/1.73 m²) = ---------------------------------

                                                                    serum creatinine (mg/dl)

or

 

                                                                      0.52 ´ height (cm)

creatinine clearance (ml/min/1.73 m²) = ------------------------------------------   - 3.6

                                                                 serum creatinine (mg/dl)

 

Children from 2 months. The maximum dose for children should not exceed the recommended adult dose. The usual recommended dose for children with body weight up to 40 kg, in the case of complicated or uncomplicated urinary tract infections (including pyelonephritis), with uncomplicated skin infections, pneumonia, as well as in the case of empirical treatment of febrile neutropenia, is 50 mg/kg every 12 hours (patients with febrile neutropenia and bacterial meningitis – every 8 hours). The usual duration of treatment is 7-10 days; severe infections may require longer treatment.

Cefotrine is prescribed for children with a body weight of 40 kg or more same as for adults.

Routes of administration. Cefotrine can be administered intravenously or by deep intramuscular injection into a large muscle mass (e.g. into the upper outer quadrant of the sphincter muscle – gluteus maximus).

Intravenous administration. Intravenous route of administration is best for patients with severe or life-threatening infections.

For intravenous administration, Cefotrin is dissolved in sterile water for injection, in 5% glucose solution for injection or in 0.9% sodium chloride solution, as indicated in the table below. It should be slowly administered for 3-5 minutes intravenously or via a system for intravenous administration.

Intramuscular administration. Cefotrine can be dissolved in sterile water for injection, 0.9% sodium chloride solution for injection, 5% glucose solution for injections, bacteriostatic water for injections with parabens or benzyl alcohol, 0.5% or 1 % solution of lidocaine hydrochloride in the concentrations indicated in the table below.

When lidocaine is used as a solvent, it is advisable to do a skin test for its tolerance before administration.

 

 

Route of administration	Volume of solution for dilution (ml)	Approximate volume of derived solution (ml)	Approximate concentration of cefepime (mg/ml)
Intravenous administration: 1 g/vial	10	11.4	90
Intramuscular administration: 1 g/vial	3	4.4	230

 

 

 

 

 

 

 

 

 

 

 

Like other parenterally administered drugs, the prepared solutions of the drug should be checked for the absence of particular matters before administration.

To identify a pathogen (pathogens) and determine its susceptibility to cefepime, appropriate microbiological tests should be performed. However, Cefotrin can be used as monotherapy even before the pathogen is identified, because Cefotrin has a wide range of antibacterial activity against gram-positive and gram-negative bacteria. Patients at risk of mixed aerobic-anaerobic infection (including Bacteroides fragilis) can be treated with Cefotrin in combination with a drug that affects anaerobes.

Children.

It can be applied to children from 1 month.

Overdose.

Symptoms: Manifestations of side effects increase in cases of significant excess of recommended doses, especially in patients with impaired renal function. Symptoms of overdose include encephalopathy, accompanied by hallucinations, abnormal consciousness, stupor, coma, myoclonus, epileptic seizures and neuromuscular arousal.

Therapy. It is necessary to discontinue the drug’s administration and to initiate a symptomatic therapy. Haemodialysis accelerates the elimination of cefepime from the body; peritoneal dialysis is ineffective. Severe immediate allergic reactions require the use of adrenaline and other forms of intensive care.

Adverse reactions.

Immune system disorders: hypersensitivity, including anaphylaxis, anaphylactic shock, angioneurotic oedema;

Respiratory system disorders: cough, sore throat, shortness of breath, breathing difficulties;

Cardiovascular system disorders: tachycardia, vasodilation;

Digestive system disorders: nausea, vomiting, dyspepsia, oral candidiasis, dysgeusia, diarrhoea, colitis (including pseudomembranous colitis), abdominal pain, constipation;

Nervous system disorders: headache, insomnia, anxiety, convulsions, dizziness, paresthesia, epileptic seizures;

Hepatobiliary system disorders: hepatitis, cholestatic jaundice;

Skin and subcutaneous tissue disorders: rash, itching, urticaria;

Reproductive system disorders:  genital itching, candidiasis;

Other: asthenia, sweating, fever, vaginitis, erythema, chest pain, back pain, peripheral oedema.

Local reactions at the site of administration:

intravenous – phlebitis and inflammation;

intramuscular – pain, inflammation.

Post marketing research:

- encephalopathy (loss of consciousness, hallucinations, stupor, coma), epileptic seizures, myoclonia, renal failure;

- anaphylaxis, including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia.

Laboratory findings: increased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin, as well as anaemia, eosinophilia, increased prothrombin time or partial thromboplastin time (PTT), and a positive Coombs test without haemolysis. Temporary increase in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia were observed in less than 0.5% of patients. Also, transient leukopenia and neutropenia were observed.

Possible adverse reactions which are typical for cephalosporin group antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, toxic nephropathy, aplastic anaemia, haemolytic anaemia, haemorrhage, liver function disorders, cholestasis and pancytopenia.

Storage life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

Do not mix with other medicines in one container. Use the solvents listed in the section "Routes of administration and Dosage".

Package.

1 vial in a cardboard box.

Terms of dispensing.

On prescription.

Manufacturer.

Venus Remedies Limited.

Manufacturer’s registered address.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-1 (Extn), Bhatoli Kalan, Baddi, Distt.Solan, Himachal Pradesh, 173205, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s and/or declarant’s representative registered address

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

Date of last review. 14.07.17.