Sanced - 1000

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANCED - 1000 (SANCED - 1000)

Composition:

Active substance: ceftazidime;

One vial contains ceftazidime pentahydrate equivalent to ceftazidime 1000 mg;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physico-chemical properties: crystalline powder, white or almost white.

Pharmacotherapeutic group. Antibacterial agent for systemic use. Third-generation cephalosporins. ATC code J01D D02.

Pharmacological Properties.

Pharmacodynamics.

Ceftazidime is a bactericidal cephalosporin antibiotic whose mechanism of action is related to inhibition of bacterial cell wall synthesis.

Acquired resistance to the antibiotic varies across different regions and may change over time, and can differ significantly among individual strains. It is advisable to use local data on antibiotic susceptibility and information on the prevalence of microorganisms producing extended-spectrum beta-lactamases, especially when treating severe infections.

Susceptible microorganisms

Gram-positive aerobes: Streptococcus pyogenes, Streptococcus agalactiae.

Gram-negative aerobes: Citrobacter koseri, Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Proteus mirabilis, Proteus spp., Providencia spp., Pasteurella multocida.

Strains capable of developing resistance

Gram-negative aerobes: Acinetobacter baumannii, Burkholderia cepacia, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella spp., Pseudomonas aeruginosa, Serratia spp., Morganella morganii.

Gram-positive aerobes: Staphylococcus aureus, Streptococcus pneumoniae, Viridans group streptococci.

Gram-positive anaerobes: Clostridium perfringens, Peptococcus spp., Peptostreptococcus spp.

Gram-negative anaerobes: Fusobacterium spp.

Resistant microorganisms

Gram-positive aerobes: Enterococcus spp., including E. faecalis and E. faecium, Listeria spp.

Gram-positive anaerobes: Clostridium difficile.

Gram-negative anaerobes: Bacteroides spp., including B. fragilis.

Others: Chlamydia spp., Mycoplasma spp., Legionella spp.

Pharmacokinetics.

After intramuscular injection of 500 mg and 1 g, mean peak serum concentrations of 18 and 37 mg/L are rapidly achieved, respectively. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g, mean serum concentrations reach 46, 87, or 170 mg/L, respectively. Therapeutically effective concentrations persist in serum for up to 8–12 hours after both intravenous and intramuscular administration. Plasma protein binding is approximately 10%. Therapeutic concentrations exceeding the minimum inhibitory concentration (MIC) for most common pathogenic microorganisms are achieved in tissues and body fluids such as bone, heart, bile, sputum, intraocular fluid, synovial fluid, pleural fluid, and peritoneal fluid. Ceftazidime rapidly crosses the placenta and is excreted into breast milk. The drug poorly penetrates the intact blood-brain barrier; in the absence of inflammation, concentrations in the central nervous system (CNS) are low. However, during meningitis, CNS concentrations of ceftazidime reach 4–20 mg/L or higher, which corresponds to therapeutic levels. Ceftazidime is not metabolized in the body. After parenteral administration, high sustained serum concentrations are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged and in active form in urine via glomerular filtration; approximately 80–90% of the dose is eliminated in urine within 24 hours. In patients with impaired renal function, ceftazidime elimination is reduced, and dosage adjustment is required. Less than 1% of the drug is excreted in bile, significantly limiting the amount reaching the intestinal tract.

Clinical characteristics.

Indications.

For the treatment of the following infections in adults and children, including newborns:

• hospital-acquired pneumonia;
• respiratory tract infections in patients with cystic fibrosis;
• bacterial meningitis;
• chronic suppurative otitis media;
• malignant external otitis;
• complicated urinary tract infections;
• complicated skin and soft tissue infections;
• complicated intra-abdominal infections;
• bone and joint infections;
• peritonitis associated with dialysis in patients undergoing continuous ambulatory peritoneal dialysis.

For the treatment of bacteremia arising in patients as a result of any of the above-mentioned infections.

Ceftazidime may be used for the treatment of patients with neutropenia and fever caused by bacterial infection.

Ceftazidime may be used for prophylaxis of urinary tract infections in connection with prostate surgery (transurethral resection).

When prescribing ceftazidime, consideration should be given to its antibacterial spectrum, which primarily includes Gram-negative aerobes (see sections "Special precautions" and "Pharmacological properties").

Ceftazidime should be used in combination with other antibacterial agents if microorganisms causing the infection are expected to fall outside the spectrum of ceftazidime activity.

The drug should be prescribed in accordance with current official recommendations for the use of antibacterial agents.

Contraindications.

Hypersensitivity to ceftazidime or to other cephalosporin antibiotics or to any of the excipients of the medicinal product.

History of severe hypersensitivity (e.g., anaphylactic reactions) to other beta-lactam antibiotics (penicillins, monobactams, and carbapenems).

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only with probenecid and furosemide.

Concomitant administration of high doses of the drug with nephrotoxic medicinal products may adversely affect renal function (see section "Special precautions").

Chloramphenicol is an in vitro antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is unknown; however, if concomitant use of ceftazidime with chloramphenicol is considered, the possibility of antagonism should be taken into account.

Special precautions for use

Severe skin adverse reactions (SSARs) have been reported during treatment with ceftazidime, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or lead to fatal outcomes, with an incidence rate of "unknown".

Patients should be informed about the signs and symptoms, and careful monitoring for skin reactions is required.

If signs or symptoms suggestive of these reactions occur, ceftazidime should be discontinued immediately, and alternative therapy should be considered.

If a patient develops a serious reaction such as SJS, TEN, DRESS, or AGEP during treatment with ceftazidime, ceftazidime therapy must not be restarted under any circumstances.

As with other beta-lactam antibiotics, severe and sometimes fatal hypersensitivity reactions have been reported. In the event of a severe hypersensitivity reaction, ceftazidime therapy should be discontinued immediately and appropriate emergency measures should be initiated.

Prior to initiating therapy, patients should be questioned about previous history of severe hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other beta-lactam antibiotics. The drug should be administered with caution to patients who have experienced mild hypersensitivity reactions to other beta-lactam antibiotics.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections until it has been established that the causative pathogen is susceptible to ceftazidime, or there is a high probability that the likely pathogen will be susceptible. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Furthermore, ceftazidime is susceptible to hydrolysis by certain extended-spectrum beta-lactamases. Therefore, when selecting ceftazidime for therapy, information regarding the prevalence of microorganisms producing extended-spectrum beta-lactamases should be taken into account.

Concomitant administration of high doses of cephalosporins and nephrotoxic agents such as aminoglycosides or potent diuretics (e.g., furosemide) may adversely affect renal function. Clinical experience with ceftazidime has shown that this is unlikely when recommended dosages are followed. There are no data indicating that ceftazidime adversely affects renal function at usual therapeutic doses.

Ceftazidime is eliminated by the kidneys; therefore, the dose should be reduced according to the degree of renal impairment. Cases of neurological complications have been reported when the dose was not appropriately reduced (see sections "Dosage and administration" and "Adverse reactions").

As with other broad-spectrum antibiotics, prolonged treatment with ceftazidime may result in overgrowth of non-susceptible microorganisms (e.g., Candida, Enterococci); in such cases, discontinuation of therapy or other necessary interventions may be required. Continuous monitoring of the patient's condition is essential.

Ceftazidime does not interfere with enzymatic methods for glucose in urine. However, a slight interference (false-positive results) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).

Ceftazidime does not interfere with the alkaline picrate method for creatinine determination.

A positive Coombs test reaction occurs in approximately 5% of patients, which may interfere with blood group determination.

The medicinal product contains sodium, which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Data on the use of ceftazidime in pregnant women are limited. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonal or postnatal development. The drug should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ceftazidime is excreted in breast milk in small amounts, but with therapeutic doses, no effect on the breastfed infant is expected. Ceftazidime may be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Specific studies have not been conducted. However, certain adverse reactions (e.g., dizziness) may occur, which could affect the ability to drive or operate machinery (see section "Adverse reactions").

Method of administration and dosage.

Adults and children weighing ≥ 40 kg

Children weighing < 40 kg

Infants and children older than 2 months of age with body weight < 40 kg

*If this is associated or suspected to be associated with infections listed in the section "Indications".

Infants and children aged ≤ 2 months

Children

The safety and efficacy of administering ceftazidime by continuous intravenous infusion in infants and children aged ≤ 2 months have not been established.

Geriatric Patients

Due to reduced ceftazidime clearance, the total daily dose for elderly patients with acute infections should generally not exceed 3 g, particularly in patients aged 80 years and older.

Hepatic Impairment

Dosage adjustment is not required for patients with mild to moderate hepatic impairment. Clinical studies in patients with severe hepatic impairment have not been conducted. Careful clinical monitoring of efficacy and safety is recommended.

Renal Impairment

Ceftazidime is eliminated unchanged by the kidneys. Therefore, the dose should be reduced in patients with impaired renal function.

The initial loading dose should be 1 g. The maintenance dose should be based on creatinine clearance.

Recommended maintenance doses of ceftazidime in renal impairment — intermittent administration

Adults and children weighing ≥ 40 kg

For patients with severe infections, the single dose may be increased by 50% or the frequency of administration correspondingly increased. In such patients, monitoring of ceftazidime serum levels is recommended.

In children, creatinine clearance should be adjusted according to body surface area or body weight.

Children weighing < 40 kg

*This is the serum creatinine level calculated according to recommendations and may not precisely reflect the degree of renal function impairment in all patients with renal insufficiency.

** Creatinine clearance calculated based on body surface area or measured.

Careful clinical monitoring of efficacy and safety of use is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency — continuous infusion

Adults and children weighing ≥ 40 kg

Dose selection should be cautious. Careful clinical monitoring of efficacy and safety of use is recommended.

Children weighing < 40 kg

The safety and efficacy of ceftazidime administered by continuous intravenous infusion in children with impaired renal function and body weight < 40 kg have not been established. Careful clinical monitoring of efficacy and safety of use is recommended.

If administration of ceftazidime by continuous intravenous infusion is required in children with impaired renal function, creatinine clearance should be adjusted according to the child's body surface area or body weight.

Hemodialysis

The serum half-life of ceftazidime during hemodialysis ranges from 3 to 5 hours.

A maintenance dose of ceftazidime as recommended in the table below should be administered after each hemodialysis session.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis in standard regimens as well as during continuous ambulatory peritoneal dialysis.

In addition to intravenous administration, ceftazidime can be added to dialysis fluid (usually 125 to 250 mg per 2 L of dialysis solution).

For patients with renal impairment undergoing prolonged arteriovenous hemodialysis or high-flux hemofiltration in intensive care units, the recommended dose is 1 g per day as a single dose or divided doses. For low-flux hemofiltration, doses should be used as for renal impairment.

Dosing recommendations for patients undergoing venovenous hemofiltration and venovenous hemodialysis are provided in the tables below.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration

The medicinal product is administered intravenously by injection or infusion, or by deep intramuscular injection. Recommended sites for intramuscular administration are the upper outer quadrant of the gluteus maximus muscle or the lateral aspect of the thigh.

Solutions of ceftazidime may be administered directly into the vein or into an intravenous infusion system, if the patient is receiving parenteral fluids.

The dose depends on the severity of the disease, sensitivity, location and type of infection, as well as the patient's age and renal function.

Preparation of solution

Ceftazidime is compatible with most commonly used intravenous infusion solutions. However, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibilities").

Vials of all sizes are produced under reduced pressure. During dissolution of the drug, carbon dioxide is released and the pressure inside the vial increases. Small bubbles of carbon dioxide in the dissolved preparation can be disregarded.

*Note. Reconstitution for intravenous infusion should be performed in two steps (see below).

The solution color varies from light yellow to amber depending on concentration, diluent, and storage conditions. When recommendations are followed, the drug's efficacy is not affected by variations in its coloration.

Ceftazidime at concentrations from 1 mg/mL to 40 mg/mL is compatible with the following solutions: 0.9% sodium chloride solution; M/6 sodium lactate solution; Hartmann's solution; 5% glucose solution; 0.225% sodium chloride and 5% glucose solution; 0.45% sodium chloride and 5% glucose solution; 0.9% sodium chloride and 5% glucose solution; 0.18% sodium chloride and 4% glucose solution; 10% glucose solution; 10% glucose 40 and 0.9% sodium chloride solution; 10% glucose 40 and 5% glucose solution; 6% dextran 70 and 0.9% sodium chloride solution; 6% dextran 70 and 5% glucose solution.

Ceftazidime at concentrations from 0.05 mg/mL to 0.25 mg/mL is compatible with peritoneal dialysis fluid (lactate).

Ceftazidime for intramuscular administration may be dissolved in 0.5% or 1% lidocaine hydrochloride solution.

The stability of both drugs is maintained when ceftazidime at a concentration of 4 mg/mL is mixed with the following agents: hydrocortisone (hydrocortisone sodium phosphate) 1 mg/mL in 0.9% sodium chloride injection or 0.5% glucose solution; cefuroxime (cefuroxime sodium) 3 mg/mL in 0.9% sodium chloride injection; cloxacillin (cloxacillin sodium) 4 mg/mL in 0.9% sodium chloride injection; heparin 10 IU/mL or 50 IU/mL in 0.9% sodium chloride injection; potassium chloride 10 mEq/L or 40 mEq/L in 0.9% sodium chloride injection.

Preparation of solutions for intramuscular or intravenous bolus injection

1. Insert the syringe needle through the vial stopper and add the recommended volume of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Invert the vial. With the syringe plunger fully depressed, insert the needle into the vial. Withdraw the entire solution into the syringe, keeping the needle submerged in the solution at all times. Small bubbles of carbon dioxide gas may be disregarded.

Preparation of solutions for intravenous infusion

1. Insert the syringe needle through the vial stopper and add 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert an air-vent needle through the stopper until the drug is completely dissolved. After complete dissolution, insert an air-vent needle through the stopper into the vial to relieve internal pressure.
4. Add the resulting solution to an intravenous infusion system, ensuring the total volume is at least 50 mL, and administer by intravenous infusion over 15–30 minutes.

Note. To maintain sterility of the product, it is essential not to insert an air-vent needle through the stopper before the drug is fully dissolved.

Children.

Can be administered to children from the first days of life.

Overdose.

Overdose may lead to neurological complications such as encephalopathy, seizures, and coma. Symptoms of overdose may occur in patients with renal impairment if the dose is not appropriately reduced (see sections "Administration and Dosage" and "Special Warnings and Precautions"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse Reactions

Adverse effects are classified by organ systems and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known.

Infections and infestations

Uncommon — candidiasis (including vaginal candidiasis and candidal stomatitis).

Blood and lymphatic system disorders

Common — eosinophilia and thrombocytosis.

Uncommon — leukopenia, neutropenia, and thrombocytopenia.

Frequency not known — lymphocytosis, hemolytic anemia, and agranulocytosis.

Immune system disorders

Frequency not known — anaphylaxis (including bronchospasm and/or hypotension).

Nervous system disorders

Uncommon — dizziness, headache.

Frequency not known — neurological complications¹, paresthesia.

Vascular disorders

Common — phlebitis or thrombophlebitis at the injection site.

Gastrointestinal disorders

Common — diarrhea.

Uncommon — antibiotic-associated diarrhea or colitis² (see section "Special precautions"), nausea, vomiting, abdominal pain, and colitis.

Frequency not known — taste disturbances.

Renal and urinary disorders

Uncommon — transient elevation in blood urea, blood urea nitrogen (BUN), and/or serum creatinine.

Very rare — interstitial nephritis, acute renal failure.

Hepatobiliary disorders

Common — transient increase in one or more liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), alkaline phosphatase).

Frequency not known — jaundice.

Skin and subcutaneous tissue disorders

Common — maculopapular rash or urticaria.

Uncommon — pruritus.

Frequency not known — angioedema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP).

Common — pain and/or inflammation at the site of intramuscular injection.

Uncommon — fever.

Laboratory findings

Common — positive Coombs test³.

¹ Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who did not receive appropriate dose reduction of ceftazidime.

² As with other cephalosporins, colitis may be related to Clostridium difficile and may present as pseudomembranous colitis (see section "Special precautions").

³ A positive Coombs test occurs in approximately 5% of patients and may interfere with blood grouping.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Incompatibilities

Ceftazidime is less stable in solutions of sodium bicarbonate for injection than in other intravenous infusion solutions; therefore, sodium bicarbonate is not recommended as a solvent.

Ceftazidime and aminoglycosides should not be mixed in the same infusion system or syringe.

Precipitation has been observed when vancomycin was added to a solution of ceftazidime. Therefore, infusion systems and intravenous catheters should be flushed between administration of these two drugs.

Packaging

1 vial per cardboard pack.

Prescription category

Prescription only.

Manufacturer

Sens Laboratories Pvt. Ltd.

Manufacturer's address and location of business operation

VI/51B, Post No. 2, Kozhuvanal, Pala, Kottayam – 686 573, Kerala, India.