Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see section 5.1):

§ bronchitis

§ community-acquired pneumonia

§ sinusitis

§ pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections)

otitis media

§ skin and soft tissue infections

§ uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae.

Considerations should be given to official guidance regarding the appropriate use of antibacterial agents

Posology:

Azomycin should be given as a single daily dose.

Azomycin Suspension can be taken with food.

Children over 45 kg body weight and adults, including elderly patients: The total dose of azithromycin 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 gonorrhea the recommended dose is 2000mg of azithromycin as a single dose together with 500 mg of ceftriaxone intramuscularly as a single dose according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

The Elderly:

The same dosage as in adult patients is used in the elderly. However, since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes (see section 4.4).

Paediatric population

In children under 45 kg body weight: Azomycin Suspension should be used for children under 45 kg. There is no information on children less than 6 months of age. The dose in children is 10mg/kg as a single daily dose for 3 days:

Up to 15 kg (less than 3 years): Measure the dose as closely as possible using the measuring dropper provided. 

For children weighing more than 15 kg, Azomycin Suspension should be administered using teaspoon according to the following guidance:

§ 15-25 kg (3-7 years): 5 ml (200 mg), once daily for 3 days.

§ 26-35 kg (8-11 years): 7.5 ml (300 mg), once daily for 3 days.

§ 36-45 kg (12-14 years): 10 ml (400 mg), once daily for 3 days.

Over 45 kg: Dose as per adults.

See section 6.5 for appropriate pack size to use depending on age/body weight of child.

The specially supplied measure should be used to administer azithromycin suspension to children.

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) (see section 4.4 and section 5.2).

Hepatic impairment:

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin (see section 4.4).

Method of administration

Azomycin Suspension is for oral administration only

Hypersensitivity

As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), Dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) (rarely fatal) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Hepatotoxicity

Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.

In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/ investigations should be performed immediately. Azithromycin administration should be stopped if liver dysfunction has emerged.

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 and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.

Ergot derivatives

In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.

Superinfection

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

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity form mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. 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 2 months after the administration of antibacterial agents.

Renal impairment

In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

Prolongation of the QT interval

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides, including azithromycin. (see section 4.8) The following situations may lead to an increased risk for ventricular arrhythmias (including torsades de pointes) which can lead to cardiac arrest (possibly fatal). Azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:

With congenital or documented QT prolongation

§ Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of Class IA (quinidine and procainamide) and III, (dofetilide, amiodarone and sotalol), cisapride and terfenadine, antipsychotic agents such as pimozide, antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin.

§ With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia

§ With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

§ Elderly patients: elderly patients may be more susceptible to drug-associated effects on the QT interval

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Paediatric population

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

Diabetes

Caution in diabetic patients as the suspension contains sugar. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Azomycin Suspension is for oral administration only

Antacids: When studying the effect of simultaneously administered antacid on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak concentrations of azithromycin measured in the plasma fell by 24%. In patients receiving azithromycin and antacids, azithromycin should be taken at least 1 hour before or 2 hours after the antacid. Co-administration of azithromycin prolonged release granules for oral suspension with a single dose of 20 ml co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.

Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with 20 mg cetirizine at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosine (Dideoxyinosine): Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared to placebo.

Digoxin and colchicine: concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.

Zidovudine: Single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).

Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.

Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.

Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.

Coumarin-type oral anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single dose of 15mg warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers who were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of ciclosporin, the resulting ciclosporin C_maxand AUC_0-5 were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC_0-∞. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a single dose of 600mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole: Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life

of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.

Indinavir: Co-administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.

Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

Midazolam: In healthy volunteers, co-administration of 500 mg/day azithromycin for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15 mg midazolam.

Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment was required.

Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8.).

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and C_max, of sildenafil or its major circulating metabolite.

Terfenadine: Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.

Triazolam: In 14 healthy volunteers, co-administration of 500mg azithromycin on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with 1200mg azithromycin on Day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.

Pregnancy

There are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed. The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.

Breast-feeding

Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

In fertility studies conducted in rats, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.

There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery.

Azithromycin is well tolerated with a low incidence of side effects.

The section below lists the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency. 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); and Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:

*ADR identified post-marketing

§ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3”.

Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment based on clinical trial experience and post-marketing surveillance. These adverse reactions differ from those reported with immediate release or the prolonged release formulations, either in kind or in frequency:

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via:

§ Saudi Arabia:

  The National Pharmacovigilance Centre (NPC):

-   SFDA Call Centre: 19999

-   E-mail: npc.drug@sfda.gov.sa

-   Website: https://ade.sfda.gov.sa/

§ Other GCC States:

-   Please contact the relevant competent authority.

By reporting side effects, you can help provide more information on the safety of this medicine.

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

General properties

Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10

Mode of action:

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0. Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation / translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.

Cardiac electrophysiology:

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

Mechanism of resistance:

The two most frequently encountered mechanisms of resistance to macrolides, including azithromycin, are target modification (most often by methylation of 23S rRNA) and active efflux. The occurrence of these resistance mechanisms varies from species to species and, within a species, the frequency of resistance varies by geographical location.

The most important ribosomal modification that determines reduced binding of macrolides is post-transcriptional (N6) -dimethylation of adenine at nucleotide A2058

(Escherichia. coli numbering system) of the 23S rRNA by methylases encoded by erm (erythromycin ribosome methylase) genes. Ribosomal modifications often determine cross resistance (MLSB phenotype) to other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramin B (which include, for example, the quinupristin component of quinupristin/dalfopristin). Different erm genes are present in different bacterial species, in particular streptococci and staphylococci. Susceptibility to macrolides can also be affected by less frequently encountered mutational changes in nucleotides A2058 and 

A2059, and at some other positions of 23S rRNA, or in the large subunit ribosomal proteins L4 and L22.

Efflux pumps occur in a number of species, including Gram-negatives, such as Haemophilus influenzae (where they may determine intrinsically higher minimal inhibitory concentrations [MICs]) and staphylococci. In streptococci and enterococci, an efflux pump that recognizes 14- and 15-membered macrolides (which include, respectively, erythromycin and azithromycin) is encoded by mef (A) genes.

Methodology for determining the in vitro susceptibility of bacteria to azithromycin

Susceptibility testing should be conducted using standardized laboratory methods, such as those described by the Clinical and Laboratory Standards Institute (CLSI). These include dilution methods (MIC determination) and disk susceptibility methods. Both CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) provide interpretive criteria for these methods.

Based on a number of studies, it is recommended that the in vitro activity of azithromycin be tested in ambient air, to ensure physiological pH of the growth medium. Elevated CO2 tensions, as often used for streptococci and anaerobes, and occasionally for other species, result in a reduction in the pH of the medium. This has a greater adverse effect on the apparent potency of azithromycin than on that of other macrolides.

The CLSI susceptibility breakpoints, based on broth microdilution or agar dilution testing, with incubation in ambient air, are given in the table below.

Absorption

Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2-3 hours after taking the medicinal product.

Distribution

Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues.

Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.

Elimination

The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.

Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine – and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.

In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and for humans is unknown.

Carcinogenic potential:

Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.

Mutagenic potential:

There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.

Reproductive toxicity:

In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50mg/kg/day azithromycin and above was observed.

** Quantity of Castor Sugar may vary to adjust the quantity (desired potency) of Azithromycin and Sodium benzoate.

Not applicable.

Before reconstitution, store below 30ºC, in a dry place

After reconstitution, store in a refrigerator and use within 7 days.

Pack of 15mL: pack of 15mL (when reconstituted) in a sealed, labelled amber coloured glass bottle with mark and an ampoule of 7mL water for reconstitution, in a printed carton along with a leaflet and provided with CRC cap and measuring device.

Pack of 30mL: pack of 30mL (when reconstituted) in a sealed, labelled amber coloured glass bottle with mark and an ampoule of 14mL water for reconstitution, in a printed carton along with a leaflet and provided with CRC cap and measuring device.

Any unused product or waste material should be disposed of in accordance with local requirements.