Azitus XL 100 and 200 Suspension

Azithromycin Oral Suspension IP

Each 5 ml contains :

Azithromycin IP (as Dihydrate)

equivalent to Azithromycin 100 mg

Excipients q.s

Colour : Quinoline Yellow

Flavoured syrupy base

Each 5 ml contains :

Azithromycin IP (as Dihydrate

equivalent to Azithromycin 200 mg

Excipients q.s.

Flavoured syrupy base

Oral suspension 100 / 200 mg

4.1 Therapeutic indication

For susceptible infections including community acquired pneumonia, pelvic inflammatory disease.

4.2 Posology and method of administration

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, according to the tables shown below. There are limited data on use in children younger than 1 year.

The dose for the treatment of pharyngitis caused by Streptococcus pyogenes is an exception : in the treatment of pharyngitis caused by Streptococcus pyogenes Azithromycin has proved to be effective when it is administered to children as a single dose of 10 mg/kg or 20 mg/kg for 3 days with a maximum daily dose of 500 mg. At these two doses a comparable clinical effect was observed, even if the eradication of the bacteria was more significant at a daily dose of 20 mg/kg. Penicillin is however the drug of first choice in the treatment of pharyngitis caused by Streptococcus pyogenes and the prevention of subsequent rheumatic fever

Patients with renal impairment :

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min).

Patients with hepatic impairment :

A dose adjustment is not necessary for patients with mild to moderately impaired liver function

Method of administration

After taking the suspension a bitter after-taste can be avoided by drinking fruit juice directly after swallowing. Azithromycin oral suspension should be given in a single daily dose. The suspension may be taken together with food.

4.3 Contraindications

The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients listed in the formulation.

4.4 Special warnings and precautions for use Hypersensitivity

As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised 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 medicinal product 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.

Since 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. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. 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. In patients receiving ergot derivatives, ergotism has been precipitated by coadministration 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 coadministered. As with any antibiotic preparation, observation for signs of superinfection with non- susceptible organisms, including fungi is recommended.

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from 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 two months after the administration of antibacterial agents. In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed.

Cardiovascular Events

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including azithromycin. Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, 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 class 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

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including azithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin. Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy. Safety and efficacy for the prevention or treatment of Mycobacterium aviumcomplex in children have not been established.

The following should be considered before prescribing azithromycin :

Azithromycin oral suspension is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

Azithromycin is not the first choice for the empiric treatment of infections in areas where the prevalence of resistant isolates is 10% or more.

In areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics.

As for other macrolides, high resistance rates of Streptococcus pneumoniae (> 30 %) have been reported for azithromycin in some European countries. This should be taken into account when treating infections caused by Streptococcus pneumoniae.

Pharyngitis / tonsilitis

Azithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.

Sinusitis

Often, azithromycin is not the substance of first choice for the treatment of sinusitis

Acute otitis media

Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.

Skin and soft tissue infections

The main causative agent of soft tissue infections, Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered a precondition for treatment of soft tissue infections with azithromycin.

Infected burn wounds

Azithromycin is not indicated for the treatment of infected burn wounds

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.

Neurological or psychiatric diseases

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

4.5 Drugs interactions

Antacids

In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously.

Cetirizine

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

Didanosine (Dideoxyinosine)

Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Digoxin and colchicine (P-gp substrates)

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-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered

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

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended. Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism. Ergotamine derivatives : Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended. Astemizole, alfentanil There are no known data on interactions with astemizole or 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 macrolid antibiotic erythromycin.

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.

Cisapride

Cisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsades de pointes

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 15 mg dose of 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.

Cyclosporin

In a pharmacokinetic study with healthy volunteers that 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 cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, 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.

Efavirenz

Co-administration of a 600 mg single dose of 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 Cmax (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 azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of 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 is required

Rifabutin

Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product. 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.

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 Cmax 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 azithromycin 500 mg 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 (160 mg/800 mg) for 7 days with azithromycin 1200 mg 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. Substances that prolong the QT interval Azithromycin should not be used concomitantly with other active substances that prolong the QT interval

4.6 Use in special populations

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.

Breastfeeding

Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in breastfeeding women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk.

Fertility

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

4.7 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.

4.8 Undesirable effects

Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment base 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 :

5.1 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, RNAdependent protein synthesis in sensitive organisms is prevented.

5.2 Pharmacodynamic properties

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Table : Antibacterial spectrum of Azithromycin

* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.

5.3 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. Pharmacokinetic studies have shown clearly higher azithromycin levels in the tissues than in the plasma (up to 50 times the maximum observed concentration in plasma). This indicates that the substance is bound in the tissues in considerable quantities. Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher than the MRC90 of the most frequently occurring pathogens after a single dose of 500 mg. 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. Approximately 12% of an intravenously administered dose of azithromycin is, over a period of 3 days, excreted unchanged in the urine. High concentrations of unchanged azithromycin were found in human bile. In this, ten metabolites were also detected (formed by N- and O- desmethylation, by hydroxylation of the desosamin and aglycon rings and by splitting the cladinose conjugate). A comparison of fluid chromatography and microbiological assessment methods shows that the metabolites are microbiologically inactive.

6.1 Animal toxicology or pharmacology

In animal tests in which the doses used amounted to 40 times the clinical therapeutic doses, azithromycin was found to have caused reversible phospholipidosis, but as a rule no true toxicological consequences were observed which were associated with this. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown. Electrophysiological investigations have shown that azithromycin prolongs the QT interval. 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 embryotoxicity studies in mice and rats no teratogenic effects were observed. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to slight retardations in fetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, slight retardations in physical development and delay in reflex development were observed following treatment with 50 mg/kg/day azithromycin and above.

Azithromycin suspension contains the active ingredient azithromycin, a macrolide antibacterial drug, for oral 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-ribohexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)- βD-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.

Molecular formula : C₃₈H₇₂N₂O₁₂

Molecular weight : 749.0 g/mol

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

30 Months

8.3 Packaging information

A bottle of 30 ml.

8.4 Storage and handing instructions

Store below 25°C. Protect from light.

Keep out of reach of children.

• Azithromycin suspension may be taken with or without food. However, increased tolerability has been observed when tablets are taken with food.
• Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously.
• The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.
• Patients should be counselled that antibacterial drugs, including azithromycin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by azithromycin or other antibacterial drugs in the future
• Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.