Ceftazidime

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

Composition:

Active substance: ceftazidime;

1 vial contains ceftazidime pentahydrate equivalent to ceftazidime 1 g;

Excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical characteristics: white to cream-colored powder.

Pharmacotherapeutic group. Antibacterial agents 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 regions and may change over time, with significant differences possible among individual strains. It is advisable to use local data on antibiotic susceptibility and 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 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, Staphylococcus pneumoniae, Viridans group streptococcus.

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 mg/L and 37 mg/L, respectively, are rapidly achieved in patients. Within 5 minutes after intravenous bolus administration of 500 mg, 1 g, or 2 g of the drug, mean serum concentrations reach 46 mg/L, 87 mg/L, 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 of ceftazidime exceeding the 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, CNS concentrations are low. However, during meningitis, ceftazidime concentrations in the CNS reach 4–20 mg/L or higher, which corresponds to therapeutic levels.

Ceftazidime is not metabolized in the body. After parenteral administration, high and sustained serum concentrations of ceftazidime are achieved. The elimination half-life is approximately 2 hours. The drug is excreted unchanged in active form in urine via glomerular filtration; about 80–90% of the dose is recovered 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 instructions").

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 for the use of antibacterial agents.

Contraindications.

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

Hypersensitivity to cephalosporin antibiotics.

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.

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

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 determining glucosuria; however, a minor interference may occur when using copper reduction methods (Benedict, Fehling, Clinitest).

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

Special precautions for use.

As with other beta-lactam antibiotics, severe and occasionally fatal hypersensitivity reactions have been reported. If serious hypersensitivity reactions occur, ceftazidime therapy should be discontinued immediately and appropriate emergency measures initiated. Prior to starting therapy, patients should be questioned about previous 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 the causative organism has been shown to be susceptible to ceftazidime or until there is a high likelihood that the probable pathogen will be susceptible to ceftazidime. This is particularly important when considering treatment of patients with bacteremia, bacterial meningitis, skin and soft tissue infections, and bone and joint infections. Additionally, 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 phenomenon 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, and dosage should be reduced according to the degree of renal impairment. Cases of neurological complications have been reported when dosage was not appropriately reduced (see sections "Dosage and administration" and "Side effects").

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. Careful and ongoing monitoring of the patient is essential.

Cases of pseudomembranous colitis, ranging in severity from mild to life-threatening, have been reported with the use of antibiotics. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after antibiotic therapy. If prolonged and significant diarrhea or abdominal cramping occurs, 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 peristalsis 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.

Ceftazidime contains sodium (one vial containing 1 g of ceftazidime contains 52 mg of sodium), which should be taken into consideration 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 postnatal development. The drug should be administered to pregnant women only if the potential benefit justifies the potential risk.

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.

Data on the effect on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. However, certain side effects (e.g., dizziness) may occur, which could affect the ability to drive or operate machinery (see section "Side effects").

Administration method and dosage.

Adults and children ≥ 40 kg

Intermittent administration

Infection	Dose administered
respiratory tract infections in patients with cystic fibrosis	100–150 mg/kg body weight per day every 8 hours, maximum up to 9 g per day1
febrile neutropenia	2 g every 8 hours
hospital-acquired pneumonia
bacterial meningitis
bacteremia*
bone and joint infections	1–2 g every 8 hours
complicated skin and soft tissue infections
complicated intra-abdominal infections
peritonitis associated with continuous ambulatory peritoneal dialysis
complicated urinary tract infections	1–2 g every 8 or 12 hours
prophylaxis of urinary tract infections during surgery on the prostate gland (transurethral resection)	1 g at the time of induction of anesthesia, and a second dose at the time of catheter removal
chronic otitis media	1–2 g every 8 hours
malignant external otitis
Continuous infusion
Infection	Dose administered
febrile neutropenia	Administer a loading dose of 2 g followed by continuous infusion of 4–6 g every 24 hours1
hospital-acquired pneumonia
respiratory tract infections in patients with cystic fibrosis
bacterial meningitis
bacteremia*
bone and joint infections
complicated skin and soft tissue infections
complicated intra-abdominal infections
peritonitis associated with continuous ambulatory peritoneal dialysis
1 In adult patients with normal renal function, 9 g of the drug per day has been administered without adverse reactions.

Children <40 kg

Infants and children aged > 2 months and body weight < 40 kg	Infection	Usual dose
Intermittent administration
	complicated urinary tract infections	100–150 mg/kg body weight per day in 3 divided doses, maximum – 6 g per day
	chronic otitis media
	malignant external otitis
	neutropenia in children	150 mg/kg body weight per day in 3 divided doses, maximum – 6 g per day
	respiratory tract infections in patients with cystic fibrosis
	bacterial meningitis
	bacteremia*
	bone and joint infections	100–150 mg/kg body weight per day in 3 divided doses, maximum – 6 g per day
	complicated skin and soft tissue infections
	complicated intra-abdominal infections
	peritonitis associated with continuous ambulatory peritoneal dialysis
Continuous infusion
	febrile neutropenia	Administer a loading dose of 60–100 mg/kg body weight, followed by continuous infusion of 100–200 mg/kg body weight per day, maximum – up to 6 g per day
	hospital-acquired pneumonia
	respiratory tract infections in patients with cystic fibrosis
	bacterial meningitis
	bacteremia*
	bone and joint infections
	complicated skin and soft tissue infections
	complicated intra-abdominal infections
	peritonitis associated with continuous ambulatory peritoneal dialysis
Infants aged ≤ 2 months	Infection	Usual dose
Intermittent administration
	Most infections	25–60 mg/kg body weight per day in 2 divided doses1
1In infants and children aged ≤ 2 months, the serum elimination half-life may be 2–3 times longer than in adults

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

Children

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

Geriatric patients

Due to reduced ceftazidime clearance, for 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 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. Maintenance dosing should be based on creatinine clearance.

Recommended maintenance doses of ceftazidime in renal impairment – intermittent administration

Adults and children ≥ 40 kg body weight

Creatinine clearance (ml/min)	Approximate serum creatinine level, µmol/L (mg/dL)	Recommended single dose of ceftazidime (g)	Dosing interval (hours)
50-31	150-200 (1.7-2.3)	1	12
30-16	200-350 (2.3-4)	1	24
15-6	350-500 (4-5.6)	0.5	24
< 5	> 500 (>5.6)	0.5	48

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 < 40 kg

Creatinine clearance (mL/min**)	Approximate serum creatinine level* (μmol/L (mg/dL))	Recommended individual dose (mg/kg body weight)	Dosing frequency (hours)
50–31	150–200 (1.7–2.3)	25	12
30–16	200–350 (2.3–4)	25	24
15–6	350–500 (4–5.6)	12.5	24
<5	>500 (>5.6)	12.5	48

*This is the serum creatinine level calculated according to recommendations and may not precisely correspond to the degree of renal function impairment in all patients with kidney disease;

** 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 impairment – continuous infusion

Adults and children ≥ 40 kg body weight

Creatinine clearance (ml/min)	Approximate serum creatinine level, µmol/L (mg/dL)	Dosing frequency (hours)
50-31	150-200 (1.7-2.3)	Administer a loading dose of 2 g followed by continuous infusion of 1 to 3 g every 24 hours
30-16	200-350 (2.3-4)	Administer a loading dose of 2 g followed by continuous infusion of 1 g every 24 hours
≤15	> 350 (4-5.6)	Not studied

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

Children < 40 kg

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

If 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 is 3–5 hours.

A recommended maintenance dose of ceftazidime should be administered after each hemodialysis session (see table below).

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis, including 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 into several doses. For low-flux hemofiltration, doses should be adjusted as in impaired renal function.

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

Dosage recommendations for ceftazidime in patients undergoing prolonged venovenous hemofiltration

Residual renal function (creatinine clearance, ml/min)	Maintenance dose (mg) according to ultrafiltration rate (ml/min)a
	5	16.7	33.3	50
0	250	250	500	500
5	250	250	500	500
10	250	500	500	750
15	250	500	500	750
20	500	500	500	750

The maintenance dose should be administered every 12 hours.

Dosing recommendations for ceftazidime in patients undergoing prolonged venovenous hemodialysis

Residual renal function (creatinine clearance, mL/min)	Replacement dose (mg) for dialysate at flow rate (mL/min)a
	1 L/hour			2 L/hour
	Ultrafiltration rate (L/hour)			Ultrafiltration rate (L/hour)
	0.5	1	2	0.5	1	2
0	500	500	500	500	500	750
5	500	500	750	500	500	750
10	500	500	750	500	750	1000
15	500	750	750	750	750	1000
20	750	750	1000	750	750	1000

The maintenance dose should be administered every 12 hours.

Administration.

Ceftazidime 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 gluteal 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 commonly used intravenous solutions. However, sodium bicarbonate for injection should not be used as a solvent (see section "Incompatibility").

Vials are manufactured under reduced pressure. As the drug dissolves, carbon dioxide is released and the pressure inside the vial increases. Small bubbles of carbon dioxide in the dissolved preparation can be disregarded.

Dose administered		Required amount of diluent (ml)	Approximate concentration (mg/ml)
1 g	Intramuscular Intravenous bolus Intravenous infusion	3 10 50*	260 90 20

*Note. Reconstitution should be performed in two steps (see text).

The color of the solution varies from light yellow to amber depending on concentration, diluent, and storage conditions. Provided that the recommendations are followed, the drug's activity 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 (with lactate).

Ceftazidime for intramuscular injection can 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 substances: 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 needle of the syringe through the vial stopper and inject 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 may be disregarded.

Preparation of solutions for intravenous infusion (1 g and 2 g vials) in two steps:

1. Insert the needle of the syringe through the vial stopper and inject 10 mL of diluent.
2. Remove the syringe needle and shake the vial until a clear solution is obtained.
3. Do not insert the air vent needle through the stopper until the drug is completely dissolved. Insert the 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 ensure sterility of the product, it is essential not to insert the air vent needle through the stopper before the drug is fully dissolved.

The reconstituted solution can be stored for up to 24 hours at temperatures below 25°C or for up to 7 days at temperatures up to 4°C.

Children.

Can be used in 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 "Special Instructions" and "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 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known.

Infections and infestations

Uncommon – candidiasis (including 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.

Neurological complications such as tremor, myoclonia, seizures, encephalopathy, and coma have been reported in patients with renal impairment who received unadjusted doses 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 Clostridium difficile-associated and may present as pseudomembranous colitis (see section "Special precautions").

Frequency not known – taste disturbances.

Renal and urinary disorders

Very rare – interstitial nephritis, acute renal failure.

Uncommon – transient increase in blood urea levels.

Hepatobiliary disorders

Common – transient elevation of 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, and toxic epidermal necrolysis.

General disorders and administration site conditions

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

Uncommon – fever.

Investigations

Common – positive Coombs test.

Uncommon – as with some other cephalosporins, transient elevations in blood urea, blood urea nitrogen, and/or serum creatinine have occasionally been observed.

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

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

The reconstituted solution is chemically and physically stable for 6 hours at room temperature. To prevent microbiological contamination, the solution should ideally be used immediately after reconstitution.

If not used immediately, the storage duration and conditions are the responsibility of the physician. The total time between reconstitution, dilution, refrigerated storage at 2–8 °C, and administration should not exceed 24 hours.

Incompatibilities.

Ceftazidime is less stable in sodium bicarbonate injection solution than in other intravenous diluents and therefore 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 ceftazidime solution. Therefore, infusion systems and intravenous catheters should be flushed between administration of these two drugs.

Packaging.

Vials of 1000 mg, pack of 1 or 10 vials in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Zeiss Pharmaceuticals Pvt. Ltd.

Manufacturer's address.

Plot No. 72, EPIP, Phase-I, Jharmajri, Baddi, Distt. Solan, (H. P.), India

Marketing Authorization Holder.

AAR PHARMA FZ-LLC, United Arab Emirates

Address of Marketing Authorization Holder.

Premises 702, 7th Floor, Building: DSC Tower, P.O. Box – 478837, Dubai, United Arab Emirates