Azithromycin

Azithromycin 250 mg Capsules

Each capsule contains azithromycin dihydrate equivalent to 250 mg of azithromycin.

For a full list of excipients, see section 6.1.

Capsules, hard.

White cap and white body, size “0” hard gelatin opaque capsules, imprinted in black ink with “250” on cap and body, containing white to off white granular powder.

Treatment of the following bacterial infections induced by micro-organisms susceptible to azithromycin (see sections 5.1):

- bronchitis

- community-acquired pneumonia

- sinusitis

- pharyngitis/tonsillitis (see 4.4 regarding streptococcal infections)

- otitis media

- infections of the skin and soft tissues

- uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

Azithromycin capsules should be given as a single daily dose.

In common with many other antibiotics Azithromycin Capsules should be taken at least 1 hour before or 2 hours after food.

Children and adolescents with a body weight above 45 kg, adults and the elderly:

The total dose of azithromycin is 1500 mg, which should be given over three days (500 mg once daily).

In the case of uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin 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.

Paediatric population:

Children and adolescents with a body weight below 45 kg:

Azithromycin Capsules are not suitable for children under 45kg.

Renal impairment:

Dose adjustment is not required 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 – Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties)

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 Special warnings and precautions for use).

Method of administration

Azithromycin Capsules are for oral administration only.

The use of azithromycin is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients (listed in Section 6.1).

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 drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware reappearance of 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 Undesirable effects). Some patients may have had pre-existing hepatic disease or may have been taken 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.

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.

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. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see section 4.8 Undesirable effects); therefore caution is required when treating patients:

- With congenital or documented QT prolongation

- Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of classes IA and III,cisapride and terfenadine- With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesemia

- With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency

Superinfections:

As with any antibiotic preparation, observation for signs of superinfection with nonsusceptible 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.

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. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

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.

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).

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).

Azithromycin capsules are for oral administration only.

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 cetirizine 20 mg 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 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.

Digoxinand 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-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate 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 derivative:

Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4 Special warnings and special precautions for use).

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).

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 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.

Ciclosporin:

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 ciclosporin, the resulting ciclosporin C_max and 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 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 coadministration 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 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 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 Undesirable effects).

Sildenafil:

In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500mg 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 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 DS (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.

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 foetus 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.

Breast-feeding

There are no data on secretion in breast milk. As many drugs are excreted in human milk, azithromycin should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.

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 table 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:

Hearing impairment,

*ADR identified post-marketing

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard), or search for MHRA Yellow Card in the Google Play or Apple App Store.

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

General properties:

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.

The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the ribosomal 50S sub-unit and thus inhibiting the translocation of peptides.

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). Coadministration 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:

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, beta-haemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant Staphylococcus aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

Breakpoints

Azithromycin susceptibility breakpoints for typical bacterial pathogens:

NCCLS:

• Susceptible ≤ 2mg/l; resistant ≥ 8mg/l

• Haemophilus spp.: susceptible ≤ 4mg/l

• Streptococcus pneumoniae and Streptococcus pyogenes:

Susceptible ≤ 0.5 mg/l; resistant ≥ 2 mg/l

Susceptibility

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

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

Absorption:

Following oral administration, the bioavailability of azithromycin is approximately 37 %. Peak plasma levels are reached after 2-3 hours after taking the medicinal product.

Distribution:

Orally administered azithromycin is widely distributed over the whole body.

Pharmacokinetic studies have shown considerably higher azithromycin concentrations in the tissues (up to 50 times the maximum concentration observed in the plasma) than in the plasma. This indicates that the substance is extensively bound in the 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 follows the tissue depletion half-life of 2 to 4 days.

Approximately 12 % of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days.Particually high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites have been identified (formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by cleavage of the 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 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 foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.

Cellulose, microcrystalline (E460)

Pregelatinised starch (maize)

Magnesium stearate (E470b)

Sodium laurilsulfate

Gelatin

Black Ink (Shellac, propylene glycol, black iron oxide, potassium hydroxide)

Not applicable.

2 years.

Store below 25°C. Store in the original package.

White opaque, PVC-Al blister.

Blister: 2, 4 or 6 capsules

Not all pack sizes may be marketed.

No special requirements.

Zentiva Pharma UK Limited

12 New Fetter Lane

London EC4A 1JP

United Kingdom

PL 17780/0873

30/11/2016

24/12/2019