AZITHROMYCIN 500

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Azithromycin 500

Prescription only.

Read the instruction thoroughly before use.

Please inform your doctor of all undesirable effects upon drug administration.

Keep out of reach of children.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient: Azithromycin (as azithromycin dihydrate) ... 500 mg

Excipients: Dibasic calcium phosphate dihydrate, pregelatinized starch, hypromellose 2208, croscarmellose sodium, magnesium stearate, sodium laurilsulfate, hypromellose 2910 (6cp), hypromellose 2910 (15cp), polyethylene glycol 6000, titanium dioxide, talc.

PHARMACEUTICAL FORM: Film coated tablet.

Product description: A white to off-white, oval, film-coated tablet, a plain on one side and a score line on the other, intact edges. 

THERAPEUTIC INDICATIONS

Azithromycin is indicated for infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis and pneumonia, in odontostomatological infections, in skin and soft tissue infections, in acute otitis media and in upper respiratory tract infections including sinusitis and pharyngitis/tonsillitis. (Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin is generally effective in the eradication of streptococci from the oropharynx; however, data establishing the efficacy of azithromycin and the subsequent prevention of rheumatic fever are not available at present).

In sexually transmitted diseases in men and women, azithromycin is indicated for the treatment of uncomplicated genital infections due to Chlamydia trachomatis. It is also indicated for the treatment of chancroid due to Haemophilus ducreyi; and uncomplicated genital infections due to non-multiresistant Neisseria gonorrhoea; concurrent infection with Treponema pallidum should be excluded.

Azithromycin is indicated, either alone or in combination with rifabutin, for prophylaxis against Mycobacterium avium-intracellulare complex (MAC) infection, an opportunistic infection prevalent in patients with advanced human immunodeficiency virus (HIV).

Azithromycin is indicated in combination with ethambutol for the treatment of disseminated MAC (DMAC) infection in patients with advanced HIV infection.

POSOLOGY AND METHOD OF ADMINISTRATION

Oral azithromycin should be administered as a single daily dose. Duration of the treatment for the different infection diseases is given below. Azithromycin tablets can be taken with or without food.

In adults

For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis and Haemophilus ducreyi, 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 as a single dose in combination with 250 mg or 500 mg ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

For prophylaxis against MAC infections in patients infected with the human immunodeficiency virus (HIV), the dose is 1200 mg once per week.

For the treatment of DMAC infections in patients with advanced HIV infection, the recommended dose is 600 mg once a day. Azithromycin should be administered in combination with other antimycobacterial agents that have shown in vitro activity against MAC, such as ethambutol at the approved dose. For all other indications in which the oral formulation is administered, the total dosage of 1500 mg should be given as 500 mg daily for 3 days. As an alternative, the same total dose can be given over 5 days with 500 mg given on Day 1, then 250 mg daily on Days 2 to 5.

In children: The maximum recommended total dose for any treatment is 1500 mg for children.

Weight (kg)

3-day regimen

5-day regimen

>45

Dose as per adults.

Dose as per adults.

Azithromycin tablets should only be administered to children weighing more than 45 kg.

In the elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to the development of torsades de pointes arrhythmia than younger patients (see section Special Warnings and Precautions for use).

In patients with 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 Special Warnings and Precautions for use and section Pharmacokinetic properties).

In patients with hepatic impairment: The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment (see section Special Warnings and Precautions for use).

Or as directed by a physician.

CONTRAINDICATIONS

The use of this product is contraindicated in patients with a hypersensitivity to azithromycin, erythromycin, any other macrolide or ketolide antibiotic, or to any of the excipients listed in section Qualitative and Quantitative Composition.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Hypersensitivity

As with erythromycin and other macrolides, rare serious allergic reactions, including angiooedema 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 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.

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.

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 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.

  1. 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 Pharmacokinetic properties).

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 macrolides, including azithromycin (see section Undesirable effects). Prescribers should consider the risk of QT prolongation, which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including:    

  • Patients with congenital or documented QT prolongation
  • Patients currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of Classes IA and III, antipsychotic agents, antidepressants, and fluoroquinolones.
  • Patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia.
  • Patients with clinically relevant bradycardia, cardiac arrhythmia or 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 have been reported in patients receiving azithromycin therapy.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially “sodium-free”.

USE IN PREGNANCY AND LACTATION

Pregnancy

Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the fetus due to azithromycin was found. 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.

Lactation

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

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE 

There is no evidence to suggest that azithromycin may have an effect on a patient's ability to drive or operate machinery. However, undesirable effects such as dizziness, seizures, vertigo, drowsiness and syncope have been reported during azithromycin therapy and can affect the ability to drive and use machines.

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 24%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.

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.

Digoxin: Concomitant administration of macrolide antibiotics, including azithromycin with P-glycoprotein substrates such as digoxin, 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.

Ergot: There is a theoretical possibility of interaction between azithromycin and ergot derivatives (see section Special Warnings and Precautions for use).

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.

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 15 mg 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 single dose of 600 mg 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 dose of 15 mg midazolam.

Nelfinavir: Co-administration of azithromycin (1200 mg) and nelfinavir at steady sta

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