Composition, form of production and packaging
Capsules hard gelatinous, size No. 0, opaque, white, with the inscription "400 mg" with black pharmaceutical ink on the body; the contents of the capsules are powder from white to light yellowish brown.
ceftibutene (in the form of dihydrate) 400 mg
Excipients: microcrystalline cellulose - 60 mg, sodium carboxymethyl starch - 134 mg, magnesium stearate - 6 mg.
The composition of the capsule shell: sodium lauryl sulfate - 60 mcg, titanium dioxide - 3.3 mg, gelatin - 97 mg.
The composition of the substance gluing the body and cap: polysorbate 80 - 160 mcg, gelatin - 3.84 mg, purified water - qs
Ink composition: pharmaceutical glaze, iron oxide black (E172), ethylene glycol monoethylate, alcohol SDA 3A, lecithin, simethicone, purified water.
1 PC. - bags of aluminum foil (5) - packs of cardboard.
Powder for the preparation of a suspension for oral administration from light yellow to dark yellow, with a characteristic cherry smell; The homogeneous suspension prepared is a light yellow color with a characteristic cherry smell.
1 ml of ready cusp. 1 g
ceftibutene (in the form of dihydrate) 36 mg 144 mg
Excipients: polysorbate 80 - 400 mcg, simethicone - 800 mcg, xanthan gum - 16 mg, silicon dioxide - 10 mg, titanium dioxide - 18 mg, sodium benzoate - 4 mg, cherry flavor - 3.66 mg, sucrose - up to 1 g.
8.3 g - bottles of dark glass with a capacity of 30 ml (1) complete with a measuring spoon and a measuring cup - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
Cephalosporin III generation. It is a beta-lactam antibiotic, has a bactericidal effect, the mechanism of which is due to the suppression of bacterial cell wall synthesis.The drug acts on many microorganisms that produce ОІ-lactamases and are resistant to penicillins and other cephalosporins.
Ceftibuten is highly resistant to plasmid penicillinases and cephalosporinases. However, it is destroyed by the action of certain chromosomal cephalosporinases, which are produced by microorganisms such as Citrobacter spp., Enterobacter spp., Bacteroides spp., Morganella spp. and Serratia spp. The drug should not be used for infections caused by bacterial strains whose resistance to beta-lactam antibiotics is due to common mechanisms, such as changes in permeability or penicillin-binding proteins (PSB) (eg, penicillin-resistant Streptococcus pneumoniae). Ceftibuten interacts mainly with PSB-3 Escherichia coli, which leads to the formation of filamentous forms at a concentration of 1 / 4-1 / 2 of the MPC and lysis at a concentration of 2-fold higher than the MIC. The minimum bactericidal concentration of ceftibutene for strains of Escherichia coli sensitive and resistant to ampicillin is approximately equal to the MIC.
It is active in vitro and in clinical practice for most strains of the following Gram-positive microorganisms: Streptococcus pyogenes, Streptococcus pneumoniae (excluding penicillin-resistant strains); Gram-negative microorganisms: Haemophilus influenzae and Moraxella (Branhamella) catarrhalis, including strains producing О±-lactamase, Escherichia coli, Klebsiella spp., Morganella morganii.
Not active against Staphylococcus spp., Enterococcus spp., Acinetobacter spp., Listeria spp., Flavobacterium spp., Pseudomonas spp., Hafnia spp.
Slabo is active against most anaerobes, including most strains of Bacteroides spp., Campylobacter spp., Yersinia spp.
Destroyed by cephalosporinases of chromosomal origin of Citrobacter spp., Enterobacter spp., Bacteroides spp.
After taking the drug inside ceftibuten almost completely absorbed from the digestive tract (90%).
After a single dose of 400 mg C max in the capsules in the plasma is achieved after 2-3 hours and is 15-17 Ојg / ml.
Bioavailability of ceftibutene depends on the dose in the therapeutic dose range (? 400 mg) and varies from 75% to 94%.
Simultaneous food intake does not affect the effectiveness of Cedex В® in capsules, but it affects the bioavailability of CEDEX В® in the form of a powder to prepare a suspension of 36 mg / ml. The effect of food on the bioavailability of Cedex В® was studied in 18 healthy male volunteers who took a suspension of 400 mg in the morning on an empty stomach or immediately after breakfast. The results showed a decrease of C max by 26% and a decrease in AUC by 17% after a high-calorie breakfast and, respectively, by 17% and 12% after a low-calorie breakfast.
The degree of binding of ceftibutene to plasma proteins is 62-64%. C ss ceftibutene (when administered every 12 hours) in the plasma are achieved after taking the fifth dose.
Ceftibuten easily penetrates into liquid media and body tissues. In a skin bladder fluid that has been experimentally induced in healthy volunteers receiving ceftibutene at a daily dose of 400 mg, the concentration of ceftibutene is comparable to or greater than that in plasma (AUC-based comparison). Ceftibuten is determined in the middle ear fluid in children with acute otitis media, where its concentration is approximately equal to or greater than its concentration in the plasma. The concentration of ceftibutene in the lung tissue is approximately 40% of the concentration in the plasma. In the nasal, tracheal and bronchial secretions, the bronchoalveolar lavage fluid and its cellular suspension, ceftibutene concentrations are approximately 46, 20, 24, 6, and 81% of the plasma concentrations, respectively.
There is no data on the concentration of ceftibutene in the cerebrospinal fluid, however, when using other cephalosporins, their content in the cerebrospinal fluid usually does not reach the therapeutic level.
Metabolism and excretion
The main ceftibutene derivative circulating in the plasma (ceftibuten-trans) appears to be formed by direct conversion of ceftibutene (cis-form). Ceftibuten-trans does not possess microbiological activity in vitro and in vivo for staphylococci, enterococci, Acinetobacter spp., Bordeiella, Listeria spp., Flavobacterium spp., Pseudomonas spp., Campylobacter spp., Yersinia spp., Hafnia spp. The concentration of ceftibutene-trans in plasma or urine is usually about 10% or less of the concentration of ceftibutene.
T 1/2 of ceftibutene from the plasma is 2 to 4 hours (2.5 hours on the average) and does not depend on the dose or scheme of application. It is excreted mostly unchanged in the urine. Ceftibuten is found in urine within 24 hours after admission at a dose of 400 mg; C max in urine is 264 Ојg / ml and is reached within the first 4 hours; After 20-24 hours after a single dose, the concentration of ceftibutene in the urine is 10.5 Ојg / ml.
Pharmacokinetics in special clinical cases
In the elderly, C ss ceftibutene (when administered every 12 hours) is achieved after taking the fifth dose. The average AUC in this group was slightly higher than in young adults. With repeated use of ceftibutene in elderly people, cumulation was negligible.
With mild renal insufficiency, pharmacokinetics ceftibutene does not change significantly.
Treatment of infectious-inflammatory diseases caused by sensitive microorganisms:
- infections of the upper respiratory tract (including pharyngitis, tonsillitis, acute sinusitis in adults);
acute otitis media in children;
- Infections of the lower respiratory tract in adults (including exacerbation of chronic bronchitis and community-acquired pneumonia) in those cases when it is possible to take the drug inside;
- Urinary tract infection (acute and chronic pyelitis, cystopyelitis, cystitis, urethritis).
The drug is taken orally. Cedex В® in the form of capsules can be taken regardless of food. Suspension is recommended to be taken about 2 hours before or 1 hour after eating. Before using the preparation, the vial with the finished suspension should be vigorously shaken.
The duration of treatment with the drug on average is from 5 to 10 days. In the treatment of infections caused by Streptococcus pyogenes, Cedex В® should be used at a therapeutic dose for at least 10 days.
The recommended dose is 400 mg / day (1 capsule or 11.1 ml of suspension).
Cedex В® in capsules can be taken regardless of food intake.
With acute bacterial sinusitis, exacerbation of chronic bronchitis and infections of the urinary tract (acute and chronic pyelitis, cystopyelitis, cystitis, urethritis), thedrug can be used at a dose of 400 mg 1 time / day.
With community-acquired pneumonia and the possibility of taking the drug inside, the recommended dose of CedexВ® is 200 mg (5.6 ml of suspension) every 12 hours.
The duration of therapy is 5-10 days, depending on the severity and type of the disease.
With mild renal insufficiency, the pharmacokinetics of the Cedex В® drug does not change significantly, so a dose change is only required when the CK is lowered to less than 50 ml / min . With QC 30-49 ml / min, the daily dose should be reduced to 200 mg; at KK 5-29 ml / min the recommended daily dose is 100 mg (2.8 ml of suspension). If a change in the frequency of application is preferred, then with CK 30-49 ml / min, CEDEX В® at a dose of 400 mg can be administered every 48 hours, with a QC of 5-29 ml / min - every 96 hours (after 3 days).
Patients on hemodialysis (frequency of the procedure 2 or 3 times a week), Cedex В® can be prescribed 400 mg at the end of each hemodialysis session.
The recommended dose of the drug in the form of a suspension is 9 mg / kg / day (0.25 ml / kg / day). The maximum dose is 400 mg / day.
With pharyngitis (including tonsillitis), acute otitis media and urinary tract infections (acute and chronic pyelitis, cystopyelitis, cystitis, urethritis) the drug can be applied 1 time / day.
Children from 12 years of age and a body weight of? 45 kg can take CEDEX В® in the form of capsules in a dose recommended for adults.
Safety and efficacy of Tzedex in children under 6 months of age, incl. in newborns, not established.
Rules for the preparation of oral suspension
Before opening the vial with powder, shake it. The powder can have a specific odor, which is not a sign of unfitness. After mixing the powder with water, the finished suspension acquires a characteristic cherry smell.
Measure the required amount of water (28 ml) by pouring water into a measuring cup (supplied) to the level of the hole. Pour approximately half of the measured water into the vial of powder and shake to moisten the powder well, then add the remaining amount of water to the vial and shake well again until the powder is completely dissolved and 33 ml of a homogeneous suspension is obtained.
To dispense the prepared suspension it is recommended to use a measuring spoon included in the kit and having a calibration of 1.25 ml, 2.5 ml. 3.75 ml and 5 ml suspension, or other medical dosing product available to the patient.
In clinical trials involving about 3,000 patients, the most common side effects were nausea (3%), diarrhea (3%), and headache (2%).
Undesirable reactions are given with the indication of organ systems and are classified according to frequency of occurrence as follows: often (? 1/100, <1/10);infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1000); very rarely (<1/10 000); frequency is not set (can not be determined based on available data).
Side effects observed during clinical trials or in the postmarketing period
Infectious and parasitic diseases: infrequently - candidiasis (oral cavity), vaginitis; rarely - colitis caused by Clostridium difficile; frequency not established - superinfection.
On the part of the hematopoiesis system: infrequently - eosinophilia, lowering of hemoglobin level; rarely - leukopenia, thrombocythemia, aplastic anemia, hemolytic anemia, pancytopenia, neutropenia, agranulocytosis.
From the coagulation system of the blood: infrequently - prolongation of prothrombin time, increase in MHO; rarely - a clotting disorder.
Allergic reactions: frequency not established - serum sickness, anaphylactic reactions, bronchospasm, skin rash, hives, reaction of increased photosensitivity, itching, angioedema, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
Mental disorders: very rarely - agitation and insomnia (in children); frequency not established - psychotic disorders.
From the nervous system: often - headache; rarely convulsions; very rarely - paresthesia, drowsiness, hyperkinesia in children; frequency not established - aphasia.
From the side of the hearing organ and labyrinthine disturbances: very rarely - vertigo.
From the respiratory system: infrequent - nasal congestion, shortness of breath.
From the digestive system: often - nausea, diarrhea; infrequently - anorexia, taste change, gastritis, vomiting, abdominal pain, constipation, dry mouth, indigestion, flatulence, stool incontinence; frequency is not set - melena.
From the liver and bile ducts: infrequently - hyperbilirubinemia, increased activity of ALT, AST in the blood serum; rarely - an increase in LDH activity in the blood serum; frequency not established - hepatobiliary disorders, jaundice.
From the urinary system: infrequently - dysuria, in children - hematuria, impaired renal function, toxic nephropathy.
From the skin and subcutaneous tissues: infrequently - in children diaper dermatitis.
On the part of laboratory indicators: infrequently - glucosuria, ketonuria, Coombs positive reaction.
Other: very rarely - fatigue, children - fever and irritability.
Side effects of all cephalosporins
From the hemopoietic system: aplastic anemia, pancytopenia, neutropenia, agranulocytosis, hemolytic anemia.
From the side of the liver and bile ducts: hyperbilirubinemia, cholestasis.
From the urinary system: dysfunction of the kidneys, toxic nephropathy.
Laboratory indicators: positive Coombs reaction, glucosuria, ketonuria.
Other: drug fever, internal bleeding.
Side effects in children, common to all cephalosporins
From the digestive system: anorexia, dyspepsia, diarrhea, vomiting, abdominal pain, loose stool, nausea.
From the nervous system: agitation, insomnia, irritability, headache, dizziness, hyperkinesia, agitation.
From the skin and subcutaneous tissues: diaper dermatitis, itching, rash.
Other: dehydration, fever, hematuria, urticaria.
- Children's age to 6 months (safety and efficacy of the drug in patients of this age group, including those in newborns, are not established);
- Children under 12 years of age and body weight up to 45 kg due to the impossibility of correct dosing in young children (for the preparation in the form of capsules);
- congenital disorders of carbohydrate metabolism: fructose intolerance, glucose / galactose absorption impairment or sugarase / isomaltase insufficiency (for the preparation in the form of a powder for the preparation of a suspension for oral administration);
- Hypersensitivity to the components of the drug and to other cephalosporins.
Caution should be given to patients with known or suspected allergies to penicillins; complicated by gastrointestinal diseases, especially chronic colitis in the anamnesis; renal insufficiency of moderate and severe degree (CK less than 50 ml / min) and patients on hemodialysis; allergic reactions, incl. in the anamnesis.
PREGNANCY AND LACTATION
Controlled studies of drug use in pregnant women have not been conducted. In experimental animal studies, no negative effects of ceftibutene on pregnancy or childbirth, embryonic or postnatal development have been identified. However, with the appointment of CedexВ®, pregnant women should evaluate the ratio of benefit to mother and risk to the fetus.
CedexВ® is not recognized in breast milk in nursing women, but use of the drug in women during lactation should be carried out with caution only if the intended benefit to the mother exceeds the potential risk to the child.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be given to patients with renal insufficiency of moderate and severe degree (QC less than 50 ml / min) and patients on hemodialysis.
APPLICATION FOR CHILDREN
Contraindicated in childhood to 6 months (safety and efficacy of the drug in patients of this age group, including those in newborns, not established).
The drug in the form of capsules is contraindicated in children under 12 years (due to the inability of adequate dosing in young children).
Long-term treatment with broad-spectrum antibiotics can lead to the development of resistance of microorganisms to the drug.
Patients with diabetes should be informed that 1 teaspoon of the suspension contains 1 g of sucrose.
When developing seizures or an anaphylactic reaction, it is necessary to cancel the drug and begin the appropriate treatment.
It is recommended to exercise extreme caution when prescribing Cedex В® to patients with allergic reactions of any kind (eg, hay fever and bronchial asthma these patients are at increased risk of severe hypersensitivity reactions.
In connection with the content of Cedex В® in the form of a powder for the preparation of a suspension for ingestion of sodium benzoate, hypersensitivity reactions can occur, manifested in the form of inflammation of the skin, eyes and mucous membrane. Infants may have an increased risk of jaundice.
Approximately 10% of patients with penicillin allergy have a cross-reaction to cephalosporins. In patients who received both penicillins and cephalosporins, hypersensitivity reactions (anaphylaxis) were recorded; There are cases of cross-reactivity with the development of anaphylaxis. If severe anaphylactic reactions shown emergency treatment (e.g., epinephrine, corticosteroids, / in fluid administration, airway management, the introduction of oxygen, antihistamines, dynamic observation).
With antibiotic treatment of a broad spectrum of action (including drug Tsedeks В® ) breach of intestinal flora may result in diarrhea, including pseudomembranous colitis associated with the generation of toxin Clostridium difficile. In mild cases enough discontinuation of treatment and use of ion exchange resins (colestyramine, colestipol), in severe cases shown compensation fluid loss, electrolytes, protein, vancomycin, metronidazole or bacitracin. You can not use drugs that violate the intestinal peristalsis.
The severity of diarrhea, accompanied or not by dehydration, can vary from mild to severe or life-threatening. Diarrhea can occur during or after antibiotic treatment.This diagnosis should be discussed in all cases where there is persistent diarrhea during treatment with any broad-spectrum antibiotic. in t.ch. preparation Tsedeks В® .
Ceftibuten influence on the results of chemical and laboratory tests did not reveal. The use of other cephalosporins sometimes recorded false positive direct Coombs test. However, the results of studies using healthy erythrocytes have not confirmed the ability to cause a positive Coombs ceftibuten in vitro assay even at concentrations up to 40 .mu.g / ml.
Impact on the ability to drive vehicles and manage mechanisms
There is no evidence that the reception of the drug Tsedeks В® affects pas ability to drive and use machines have been detected. Patients should be warned of the possibility of dizziness, seizures, when they appear, should refuse to carry out these activities.
Accidental overdose Tsedeks В® signs of toxicity were not observed. In healthy adult volunteers who received Tsedeks В® single dose of 2 g, serious adverse reactions were not, and all of the clinical and laboratory parameters were within normal limits.
Treatment: the specific antidote ceftibuten does not exist, so an overdose is possible to gastric lavage. A significant portion of the drug dose Tsedeks В® can be removed from the blood via hemodialysis. The efficiency of peritoneal dialysis has not been established.
In certain studies have investigated the interaction of ceftibuten with the following drugs: antacids that contain aluminum hydroxide and magnesium at high doses, ranitidine and theophylline (single in / introduction). Evidence of significant interactions have been identified. Effect ceftibuten drug concentration in the blood or plasma pharmacokinetics of theophylline when taken orally is not known. Information about the interaction with other drugs has not yet been received.
Cephalosporins, including ceftibuten, in rare cases may reduce the activity of prothrombin, which leads to an increase in prothrombin time, especially in patients who were stabilized on oral anticoagulation therapy. In patients at risk, should regularly monitor the prothrombin time or INR and apply, if necessary, vitamin K.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The capsules should be stored at a temperature not higher than 25 В° C. Powder for oral suspension should be stored in a dry, dark place at a temperature not higher than 25 В° C. Shelf life - 2 years.
The obtained suspension can be stored for 14 days in refrigerator (at a temperature of from 2 В° to 8 В° C).
The drug should be stored out of the reach of children.