Skyzed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SKYZED (SKYZED)

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate equivalent to ceftazidime 1000 mg;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical 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 the inhibition of bacterial cell wall synthesis.

Acquired resistance to the antibiotic varies across different regions and may change over time, with significant differences observed among individual strains. It is advisable to use local data on antibiotic susceptibility and the prevalence of microorganisms producing extended-spectrum β-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 with possible acquired 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%. 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, and concentrations in the CNS are low in the absence of inflammation. However, during meningitis, CNS concentrations of ceftazidime range from 4–20 mg/L or higher, reaching therapeutic levels. Ceftazidime is not metabolized in the body. After parenteral administration, high and 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, elimination of ceftazidime 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.

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.

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 resulting from bacterial infection.

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

When prescribing ceftazidime, its antibacterial spectrum, primarily directed against gram-negative aerobes, should be taken into account (see sections "Pharmacological properties" and "Special warnings and precautions for use").

Ceftazidime should be used in combination with other antibacterial agents if it is expected that some of the microorganisms causing the infection are not covered by the spectrum of ceftazidime.

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

Contraindications.

Hypersensitivity to ceftazidime or to any of the excipients of the drug.

Hypersensitivity to other cephalosporin antibiotics.

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

Interaction with other medicinal products and other forms of interaction.

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

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

Like other antibiotics, ceftazidime may affect intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives. Ceftazidime does not interfere with enzymatic methods for glucose in urine; however, a minor interference may be observed when using copper reduction methods (Benedict, Fehling, Clinitest).

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

Special precautions for use.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported during treatment with ceftazidime. These reactions may be life-threatening or fatal, and their frequency is unknown.

Patients should be informed about the signs and symptoms, and skin reactions should be closely monitored.

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

If a serious reaction such as SJS, TEN, DRESS, or AGEP develops during treatment with ceftazidime, re-administration of ceftazidime is contraindicated under any circumstances.

As with other β-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 hypersensitivity reactions to ceftazidime, cephalosporin antibiotics, or other β-lactam antibiotics. The drug should be administered with caution to patients who have had non-severe hypersensitivity reactions to other β-lactam antibiotics.

Ceftazidime has a limited antibacterial spectrum. It is not an appropriate agent for monotherapy of certain types of infections until the causative pathogen has been shown to be susceptible to ceftazidime, or there is a high likelihood 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 β-lactamases. Therefore, when selecting ceftazidime for treatment, information on the prevalence of microorganisms producing extended-spectrum β-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 phenomenon is unlikely when the recommended dosage is followed. There is no evidence 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 measures may be required. Continuous monitoring of the patient is essential.

Cases of pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with antibiotic use. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. If prolonged or significant diarrhea occurs, or if abdominal cramps develop, treatment should be discontinued immediately, further diagnostic evaluation should be performed, and specific therapy for Clostridium difficile should be initiated if necessary. Medicinal products that inhibit intestinal motility should not be administered.

As with other broad-spectrum cephalosporins and penicillins, some previously susceptible strains of Enterobacter spp. and Serratia spp. may become resistant during treatment with ceftazidime. In such cases, periodic susceptibility testing should be performed.

The medicinal product contains 2.39 mmol of sodium carbonate per dose, 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 have not shown any direct or indirect harmful effects on pregnancy, embryonal or fetal development, or postnatal development. The drug should be administered during pregnancy only if the expected benefit outweighs the potential risk.

Ceftazidime is excreted in breast milk in small amounts, but effects on the breastfed infant are not expected with therapeutic doses. Ceftazidime may be used during breastfeeding.

Ability to affect the speed of reactions while driving or operating machinery.

No specific studies have 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").

Dosage and administration.

Adults and children with body weight ≥ 40 kg

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

Children with body weight < 40 kg

*If this is associated or there is suspicion of association with infections listed in the section "Indications".

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, in elderly patients with acute infections, the daily dose generally should not exceed 3 g, particularly in patients aged 80 years and older.

Hepatic impairment

Dosage adjustment is not required in patients with mild to moderate hepatic impairment. Clinical studies have not been conducted in patients with severe hepatic impairment. Close clinical monitoring of efficacy and safety of use 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 with body weight ≥ 40 kg

For patients with severe infections, the single dose may be increased by 50% or the frequency of administration correspondingly increased. For 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 with body weight < 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 administration is recommended.

Recommended maintenance doses of ceftazidime in renal insufficiency – continuous infusion

Adults and children with body weight ≥ 40 kg

Dose selection should be performed cautiously. Careful clinical monitoring of the efficacy and safety of the drug is recommended.

Children with body weight < 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 the efficacy and safety of the drug is recommended.

If continuous intravenous infusion of the drug 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 elimination half-life of ceftazidime in serum during hemodialysis is 3 to 5 hours.

After each hemodialysis session, a maintenance dose of ceftazidime as recommended in the table below should be administered.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis in the standard regimen and during continuous ambulatory peritoneal dialysis.

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

For patients with renal insufficiency 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 administered as for impaired renal function.

For patients undergoing venovenous hemofiltration and venovenous hemodialysis, dosing recommendations are provided in the tables.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

The maintenance dose should be administered every 12 hours.

Dosage recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

The maintenance dose should be administered every 12 hours.

Administration

The drug should be 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 part 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 on the patient's age and renal function.

Preparation instructions

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

All vial sizes are manufactured under reduced pressure. As the drug dissolves, carbon dioxide is released and pressure in the vial increases. Small bubbles of carbon dioxide in the reconstituted solution may be disregarded.

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

The color of the solution may vary from light yellow to amber depending on concentration, diluent, and storage conditions. When following the recommended guidelines, the drug's efficacy is not affected by variations in its coloration.

Ceftazidime at concentrations from 1 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 to 0.25 mg/mL is compatible with peritoneal dialysis fluid (lactate).

For intramuscular administration, ceftazidime may be reconstituted with 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 or 50 IU/mL in 0.9% sodium chloride injection; potassium chloride 10 or 40 mEq/L – in 0.9% sodium chloride injection.

Preparation of solutions for intramuscular or intravenous bolus injection

1. Insert the needle of the syringe 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 withdrawn, insert the needle into the vial. Draw the entire solution into the syringe, keeping the needle tip 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 needle of the syringe 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 to achieve a total solution volume of at least 50 mL and administer by intravenous infusion over 15–30 minutes.

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

Children.

May be used in neonates 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 "Special precautions", "Dosage and administration"). Serum concentrations of ceftazidime can be reduced by hemodialysis or peritoneal dialysis.

Adverse reactions.

Adverse effects were classified by frequency of occurrence – from very common to uncommon, and by organ systems: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – candidiasis (including vaginal vaginitis 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 arterial hypotension).

Nervous system disorders: uncommon – dizziness, headache; frequency not known – paresthesia.

Cases of 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.

Vascular disorders: common – phlebitis or thrombophlebitis at the injection site.

Gastrointestinal disorders: common – diarrhea; uncommon – nausea, vomiting, abdominal pain, and colitis.

As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis (see section "Special precautions"); frequency not known – taste disturbances.

Renal and urinary disorders: uncommon – transient increase in blood urea levels; very rare – interstitial nephritis, acute renal failure.

Hepatobiliary disorders: common – transient increase in one or more liver enzymes (ALT, AST, LDH, GGT, alkaline phosphatase); frequency not known – jaundice.

Skin and subcutaneous tissue disorders: common – maculopapular rash or urticaria; uncommon – pruritus; frequency not known – angioneurotic edema, polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP).

General disorders and administration site conditions: common – pain and/or inflammation at the site of intramuscular injection; uncommon – fever.

Investigations: common – positive Coombs test.

Uncommonly, as with other cephalosporins, transient increases in blood urea, blood urea nitrogen, and/or serum creatinine have occasionally been observed.

A positive Coombs reaction 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 of children.

Incompatibilities.

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

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

Instances of precipitate formation have been observed when vancomycin was added to a ceftazidime solution. Therefore, it is recommended to flush infusion systems and intravenous catheters between administration of these two drugs.

Packaging.

1 vial per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sens Laboratory Pvt. Ltd.

Manufacturer's address and place of business.

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