(Summary of Product Characteristics)

ZEZOT (Azithromycin)

Capsules / Suspension / Tablets

QUALITATIVE AND QUANTITATIVE COMPOSITION

Zezot 250mg Capsules:

Each capsule contains:
Azithromycin USP ….. 250mg
as Azithromycin dihydrate
(Product Specs.: USP)
“Product contains lactose”

Zezot 500mg Tablets:

Each film coated tablet contains:
Azithromycin USP ….. 500mg
as Azithromycin dihydrate
(Product Specs.: USP)

Zezot 200mg/5mL Suspension:

Each 5mL contains:
Azithromycin USP ….. 200mg
as Azithromycin dihydrate
(Product Specs.: USP)

PHARMACEUTICAL FORM

Powder for Oral Suspension, Capsules, Film Coated Tablets.

CLINICAL PARTICULARS

THERAPEUTIC INDICATIONS:

Zezot can be indicated for the treatment of the following infections.
Acute bacterial sinusitis/ Acute bacterial otitis media (adequately diagnosed) Pharyngitis, tonsillitis, Acute exacerbation of chronic bronchitis (adequately diagnosed) Mild to moderately severe community acquired pneumonia Skin and soft tissue infections Uncomplicated Chlamydia trachomatis urethritis and cervicitis.

POSOLOGY AND METHOD OF ADMINISTRATION

Posology

Zezot (capsules/ tablets/suspension) should be given as a single daily dose.
In common with many other antibiotics, it should be taken at least 1 hour before or 2 hours after food.

Children over 45 kg body weight and adults, including elderly patients:

The total dose is 1500 mg which should be given over three days (500 mg

once daily).

• In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoea the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg ceftriaxone according to guidelines.
• For patients who are allergic to penicillin and/or cephalosporins, consult the treatment guidelines.
• Capsules and Tablets are not suitable for children under 45 kg.

Children and adolescents (< 18 years)

The total dose in children aged 1 year and older is 30 mg/kg administered as 10 mg/kg once daily for three days, or over a period of five days starting with a single dose of 10 mg/kg on the first day, followed by doses of 5 mg/kg per day for the following 4 days.

Renal impairment:

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 – 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min) Hepatic impairment: Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease.

Reconstitution directions for Oral Suspension:

Add a small quantity of pre-boiled cool water in the bottle and shake, after this add more water upto the mark given on the label and shake vigorously to make suspension which should be used within 10 days.

CONTRAINDICATIONS:

Hypersensitivity to the active substance, erythromycin, any macrolide or ketolide antibiotic, lactose.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE:

Product contains Lactose:

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Hypersensitivity

If an allergic reaction occurs, the product should be discontinued and appropriate therapy should be instituted.

Hepatotoxicity

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy. Azithromycin administration should be stopped immediately.

Infantile hypertrophic pyloric stenosis (IHPS) Following the use of azithromycin in neonates (treatment up to 42 days of

life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.

Pseudomembranous colitis

Pseudomembranous colitis has been reported with the use of macrolide antibiotics.

Ergot derivatives

Because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.

Cross resistance

Concomitant use of several medicinal products from the same or related group of antibacterial agents is not recommended. e.g. erythromycin, clarithromycin, lincosamide.

Cardiovascular events

Azithromycin should be used with caution in patients with ongoing pro-arrhythmic conditions (especially women and elderly patients).

Clostridium difficile associated diarrhea (CDAD)

CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antimicrobial agents.

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy

Paediatric population

Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

The following should be considered before prescribing azithromycin:

Skin and soft tissue infections: Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered.

Sexually transmitted disease: In case of sexually transmitted diseases a concomitant infection by T. pallidum should be excluded.

Neurological or psychiatric diseases: Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Superinfection: As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.

Renal impairment

In patients with severe renal impairment (GFR < 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed.

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on azithromycin:

Antacids: In patients receiving both azithromycin and antacids, it should not be taken simultaneously, but with an interval of about 2 hours.

Fluconazole: Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Terfenadine, Cimetidine & Nelfinavir: No clinically significant adverse effects were observed and n o dose adjustment is required.

Effect of azithromycin on other medicinal products:

Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended

Digoxin and colchicine (P-gp substrates): Azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.

Coumarin-Type Oral Anticoagulants: Consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Cyclosporin: Caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Theophylline: As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theophylline levels is advised.

Zidovudine: Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Astemizole, alfentanil: Caution is advised in the co-administration of these medicines with azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolide antibiotic erythromycin.

Cisapride: Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsades de pointes.

Hydroxychloroquine: Azithromycin should be used with caution in patients receiving medicines known to prolong the QT interval with potential to induce cardiac arrhythmia.

Medicinal products known to prolong the QT interval: Azithromycin should not be used co-administered with other medicinal products, known to prolong the QT interval.

Cetirizine: No significant changes in the QT interval.

Pharmacokinetics interaction with other medicines: In a pharmacokinetic interaction, no significant effect was observed on the plasma levels of Trimethoprim/sulfamethoxazole, Methylprednisolone, Sildenafil, Didanosine (Dideoxyinosine), Triazolam, Midazolam Efaverinz and Indinavir or its active metabolite in patients receiving concomitant azithromycin.

FERTILITY, PREGNANCY AND LACTATION

Pregnancy

Azithromycin should only be used during pregnancy if the benefit outweighs the risk.

Lactation

Azithromycin is excreted in breast milk. A decision should be taken whether breastfeeding is discontinued or that treatment with azithromycin is discontinued/initiated or not, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.

Fertility

The relevance of this finding to humans is unknown.

Effects on ability to drive and use machines

There is no evidence to suggest that azithromycin may have an effect on a patient’s ability to drive or operate machinery. Visual impairment and vision blurred may have an effect on a patient’s ability to drive or operate machinery.

NDESIRABLE EFFECTS:

Adverse reactions identified from post-marketing experience are included in italics. The frequency grouping is defined using the following convention: 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); not known.

PHARMACOLOGICAL PROPERTIES

PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: Antibacterial for systemic use, macrolides, azithromycin.
ATC code: J01FA10

Mechanism of action

Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.

Microbiology:

Aerobic Gram-negative Microorganisms: Haemophilus influenzae, Moraxella catarrhalis

Other Microorganisms: Chlamydophila pneumoniae, Chlamydia trachomatis, Legionella pneumophila, Mycobacterium avium, Mycoplasma pneumonia Species for which acquired resistance may be a problem.

Aerobic Gram-positive Microorganisms: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes Other microorganisms Ureaplasma urealyticum Inherently resistant organisms.

Aerobic Gram-positive Microorganisms: Staphylococcus aureus – methicillin resistant and erythromycin resistant strains Streptococcus pneumoniae – penicillin resistant strains.

Aerobic Gram-negative microorganisms: Escherichia coli, Pseudomonas aeruginosa Klebsiella spp.

Anaerobic Gram-negative microorganisms: Bacteroides fragilis-group

Break Points:

1. Erythromycin can be used to determine susceptibility to azithromycin.
2. Clinical evidence for the efficacy of macrolides in H. influenzae respiratory infections is conflicting due to high spontaneous cure rates.
3. Azithromycin is always used in conjunction with another effective agent

PHARMACOKINETIC PROPERTIES

 Absorption

The biological availability of azithromycin after oral administration is approximately 37%. Peak plasma levels are achieved 2-3 hours after taking the medicinal product.

Distribution

After oral administration, azithromycin is distributed throughout the entire body. The protein binding of azithromycin in serum is variable and varies, depending on the serum concentration, from 52% at 0.05 mg/l to 12% at 0.5 mg/l. The steady state distribution volume is 31.1 l/kg.

Elimination

The terminal plasma-elimination half-life closely follows the tissue depletion half-life from 2 to 4 days.

Pharmacokinetics in special populations:

Renal insufficiency

Following a single oral dose of azithromycin 1 g, mean Cmax and AUC 0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min).

Hepatic insufficiency

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function.

Elderly

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults.

Paediatric Population

Pharmacokinetics have been studied in children aged 4 months – 15 years taking capsules, granules or suspension

PHARMACEUTICAL PARTICULARS

Incompatibilities

Not applicable.

Shelf life

Tablets and Suspension: 2 years
(Reconstituted powder for oral suspension: 10 days).

Capsules: 3 years

Presentation:

Zezot 250mg Capsules: Alu Alu pack of 6 capsules.
Zezot 500mg Tablets: Alu Alu pack of 6 tablets.
Zezot 200mg/5mL Suspension: Powder for oral suspension available in 15mL (after reconstitution).
Zezot 200mg/5mL Suspension: Powder for oral suspension available in 30mL (after reconstitution).

Special precautions for storage

Suspension: Protect from heat, sunlight and moisture, store below 30°C.
Capsules & Tablets: Protect from heat, sunlight and moisture.
Store below 25°C.
The expiration date refers to the product correctly stored at the required condition.
Do not take if seal is broken.
Keep out of the reach of children.
Shake well before use. For oral use only.
Reconstituted suspension to be used within 10 days. Discard any unused suspension. Close the bottle properly after use.
Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
To be sold on the prescription of a registered medical practitioner only.

MARKETING AUTHORISATION HOLDER

Head Office:

Bosch Pharmaceuticals (Pvt.) Ltd.,
8, Modern Society, Tipu Sultan Road, Karachi-75350 (Pakistan)

Manufacturing Site:

Bosch Pharmaceuticals (Pvt.) Ltd.,
Plot No. 221-223, Sector 23 Korangi Industrial area, Karachi (Pakistan).

MARKETING AUTHORISATION NUMBER(S)

Suspension: 027161
Capsules: 027162
Tablets: 067514

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Suspension: 24 July 2001 / 23 July 2021
Capsules: 24 July 2001 / 23 July 2021
Tablets: 05 April 2011 / 04 April 2021

DATE OF REVISION OF THE TEXT

24-10-2023

DESCRIPTION
ZEZOT contain the active ingredient azithromycin, a macrolide antibacterial drug, for intravenous administration. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R, 11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1- oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C₃₈H₇₂N₂O₁₂•2H₂O and a molecular weight of 785.0.

COMPOSITION:

Each vial contains:
Azithromycin U.S.P. ….. 500mg as Azithromycin dihydrate
(Product Specs.: U.S.P.)

Clinical Pharmacology:
Pharmacodynamic Properties:
Pharmacotherapeutic group: Antibacterial for systemic use, macrolides.

ATC code: J01FA10.

Mechanism of Action:
Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.

INDICATIONS AND USAGE
ZEZOT (azithromycin for injection) is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below. As recommended dosages, durations of therapy, and applicable patient populations vary among these infections.

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, or Streptococcus pneumoniae in patients who require initial intravenous therapy.

Pelvic inflammatory disease due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with ZEZOT.

CONTRAINDICATIONS
ZEZOT is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic.

PRECAUTIONS
General: Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing azithromycin in these patients. ZEZOT (azithromycin for injection) should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. Local I.V. site reactions have been reported with the intravenous administration of azithromycin. The incidence and severity of these reactions were the same when 500 mg azithromycin were given over 1 hour (2 mg/mL as 250 mL infusion) or over 3 hours (1 mg/mL as 500 mL infusion). All volunteers who received infusate concentrations above 2.0 mg/mL experienced local I.V. site reactions and, therefore, higher concentrations should be avoided. Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization. Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. Prescribing ZEZOT (azithromycin) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found.

Pregnancy: Teratogenic Effects. Pregnancy Category B: There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Nursing Mothers: It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.

ADVERSE REACTIONS
Clinical side effects leading to discontinuations from these studies were most commonly gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), and rashes; laboratory side effects leading to discontinuation were increases in transaminase levels and/or alkaline phosphatase levels. Overall, the most common side effects associated with treatment in adult patients who received I.V./P.O. ZEZOT in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%) being the most frequently reported. Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation (3.1%). The most common side effects associated with treatment in adult women who received I.V./P.O.

Azithromycin in studies of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most commonly reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was coadministered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%). No other side effects occurred in patients on the multiple dose I.V./P.O. regimen of Azithromycin in these studies with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:

Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis,

Nervous System: headache, somnolence

Allergic: bronchospasmm
Special Senses: taste perversion

DOSAGE AND ADMINISTRATION
The recommended dose of ZEZOT (azithromycin for injection) for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250-mg tablets to complete a 7 to 10 day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. The recommended dose of ZEZOT (azithromycin) for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7-day course of therapy. ZEZOT (azithromycin for injection) should not be given as a bolus or as an intramuscular injection.

Reconstitution
Prepare the initial solution of ZEZOT (azithromycin for injection) by adding 5 mL of Sterile Water for Injection to the 500 mg vial and shaking the vial until all of the drug is dissolved. Since ZEZOT (azithromycin for injection) is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 5 mL of Sterile Water is dispensed. Each mL of reconstituted solution contains 100 mg azithromycin. Reconstituted solution is stable for 24 hours when stored below 30°C or 86°F. Parenteral drug products should be inspected visually for particulate matter prior to administration.

If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

Dilute this solution further prior to administration as instructed below.

Dilution To provide azithromycin over a concentration range of 1.0-2.0 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below:

• Normal Saline (0.9% sodium chloride)
• 1/2 Normal Saline (0.45% sodium chloride)
• 5% Dextrose in Water
• Lactated Ringer’s Solution
• 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl
• 5% Dextrose in Lactated Ringer’s Solution
• 5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)
• 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)
• Normosol®-M in5% Dextrose
• Normosol®-R in 5% Dextrose

It is recommended that a 500-mg dose of ZEZOT (azithromycin for injection), diluted as above, be infused over a period of not less than 60 minutes.

ZEZOT (azithromycin for injection) should not be given as a bolus or as an intramuscular injection.

Other intravenous substances, additives, or medications should not be added to ZEZOT (azithromycin for injection), or infused simultaneously through the same intravenous line.

STORAGE AND DIRECTIONS:

• Dry powder store at controlled room temperature (15-30OC). When diluted according to the instructions (1.0 mg/mL to 2.0 mg/mL), ZEZOT (azithromycin for injection) is stable for 24 hours at or below 30°C, or for 72 hrs. if stored under refrigeration 5°C.
• Add provided Solvent to prepare solution.
• For single use only. Discard any unused portion after use.
• Dosage: As directed by the physician.
• Protect from heat, sunlight and moisture. Keep out of the reach of children.
• The expiration date refers to the product correctly stored at the required condition.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

HOW SUPPLIED
ZEZOT (Azithromycin for injection) is supplied in lyophilized powder form under a vacuum in a 8ml vial equivalent to 500 mg of azithromycin for intravenous administration with 1 ampoule of 5ml sterile water for injection.