ZITHROMAX™ CAPSULES

ZITHROMAX™ SUSPENSION

Active ingredient: azithromycin.

Zithromax Capsules contain azithromycin dihydrate 262.05mg equivalent to 250mg azithromycin base.

Zithromax Powder for Oral Suspension is a dry blend of azithromycin dihydrate 209.64mg/5ml containing the equivalent of 200mg azithromycin base per 5ml on reconstitution with water.

Zithromax Capsules are white, hard gelatin capsules marked Pfizer and ZTM 250.

Zithromax Powder for Oral Suspension is a dry powder which reconstitutes with water to give a cherry/banana flavoured suspension with a slight vanilla odour.

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 Pharmacodynamic properties):

- bronchitis

- community-acquired pneumonia

- sinusitis

- pharyngitis/tonsillitis (see Section 4.4 regarding streptococcal infections)

- otitis media

- skin an dsoft tissue infections

- uncomplicated genital infections due to Chlamydia trachomatis.

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

Method of administration:

Zithromax should be given as a single daily dose. In common with many other antibiotics Zithromax Capsules should be taken at least 1 hour before or 2 hours after food.

Zithromax Suspension can be taken with food.

Children over 45kg body weight and adults, including elderly patients: The total dose of azithromycin is 1500mg which should be given over three days (500mg once daily). In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000mg as a single oral dose.

In children under 45kg body weight: Zithromax Capsules are not suitable for Children under 45kg. Zithromax Suspension should be used for children under 45kg. 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 15kg (less than 3 years): Measure the dose as closely as possible using the 10ml oral dosing syringe provided. The syringe is graduated in 0.25ml divisions, providing 10mg of azithromycin in every graduation.

For children weighing more than 15kg, Zithromax Suspension should be administered using the spoon provided according to the following guidance:

15-25 kg (3-7 years): 5ml (200mg) given as 1 x 5ml spoonful, once daily for 3 days.

26-35 kg (8-11 years): 7.5ml (300mg) given as 1 x 7.5ml spoonful, once daily for 3 days.

36-45 kg (12-14 years): 10ml (400mg) given as 1 x 10ml spoonful, once daily for 3 days.

Over 45 kg: Dose as per adults.

See Nature and contents of container, 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 Zithromax suspension to children.

Renal failure:

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 - Special warnings and precautions for use).

Hepatic failure:

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.

Zithromax Suspension is for oral administration only.

Zithromax Capsules are for oral Administration only.

Zithromax is contra-indicated in patients with a known hypersensitivity to azithromycin or any of the macrolide or ketolide antibiotics, erythromycin or to any excipients thereof as (for example) listed in Section 6.1 List of excipients.

Because of the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be coadministered.

As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with Zithromax have resulted in recurrent symptoms and required a longer period of observation and treatment.

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).

As with any antibiotic preparation, observation of signs of superinfection with non-susceptible organisms, including fungi is recommended. there is a possibility that superinfections could occur (e.g. fungal infections).

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.

Use in 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. Pharmacokinetic properties).

Zithromax capsules and suspension are for oral administration only.

Antacids: In patients receiving Zithromax and antacids, Zithromax should be taken at least 1 hour before or 2 hours after the antacid.

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

Cimetidine: A single dose of cimetidine administered 2 hours before Zithromax had no effect on the pharmacokinetics of azithromycin.

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 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 coadministration of these two drugs. If coadministration is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.

Digoxin: Some of the macrolide antibiotics have been reported to impair the metabolism of digoxin (in the gut) in some patients. Therefore, in patients receiving concomitant Zithromax and digoxin the possibility of raised digoxin levels should be borne in mind, and digoxin levels monitored.

Ergot derivatives: Because of the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be coadministered.

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

Nelfinavir: A study based on 12 healthy volunteers receiving co-administration of azithromycin (1200mg) and nelfinavir at a steady state (750mg three times daily) resulted in a 100% increase in azithromycin absorption and bioavailability. There was no significant effect upon the rate of absorption or the rate of clearance. The clinical consequences of this interaction are unknown, caution should be exercised when prescribing azithromycin to patients taking nelfinavir.

Terfenadine: Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other anti-infectives in conjunction with terfenadine, pharmacokinetic interaction studies have been performed. These 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. As with other macrolides, Zithromax should be administered with caution in combination with terfenadine.

Theophylline: Theophylline levels may be increased in patients taking Zithromax.

Coumarin-Type Oral Anticoagulants: In a pharmacodynamic interaction study, Zithromax did not alter the anticoagulant effect of a single 15mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration 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.

Zidovudine: Single 1000mg doses and multiple 1200mg or 600mg doses of azithromycin did not affect 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.

Didanosine: Coadministration of daily doses of 1200mg azithromycin with didanosine in 6 subjects did not appear to affect the pharmacokinetics of didanosine as compared with placebo.

Rifabutin: Coadministration 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).

Use in pregnancy: Animal reproduction studies are insufficient with respect to effects on pregnancy, embryonal/ foetal development, parturition and post natal development (see Section 5.3 Preclinical safety data). The potential risks for humans is unknown. Zithromax should not be used during pregnancy unless clearly necessary.

Use in lactation: There is insufficient/ limited information on the excretion of azithromycin in human or animal breast milk. A risk to the suckling child cannot be excluded. A decision on whether to continue/ discontinue breast-feeding or to continue/ discontinue therapy with Zithromax should be made taking into account the benefit of breast-feeding to the child and the benefit of Zithromax therapy to the woman.

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

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

Blood and lymphatic system disorders

Rare (> 1/10000, < 1/1000)

Thrombocytopenia

In clinical trials there have been occasional reports of periods of transient, mild neutropenia. However, a causal relationship with azithromycin treatment has not been confirmed.

Psychiatric disorders

Rare (> 1/10000, < 1/1000)

Aggressiveness, agitation, anxiety and nervousness

Nervous system disorders

Uncommon (> 1/1000, < 1/100)

Dizziness/vertigo, somnolence, headache, convulsions (which have also been found to be caused by other macrolides), taste perversion, syncope

Rare (> 1/10000, < 1/1000)

Paraesthesia and asthenia

Insomnia and hyperactivity

Ear and labyrinth disorders

Rare (> 1/10000, < 1/1000)

Macrolide antibiotics have been reported to have caused hearing damage. In some patients receiving azithromycin impaired hearing, deafness and ringing in the ears have been reported. Many of these cases relate to experimental studies in which azithromycin was used at large doses over prolonged periods. According to available follow-up reports, the majority of these problems however were reversible.

Cardiac disorders

Rare (> 1/10000, < 1/1000)

Vascular disorders

Rare (> 1/10000, < 1/1000)

Hypotension

Gastrointestinal disorders

Common (> 1/100, < 1/10)

Nausea, vomiting, diarrhoea, abdominal discomfort (pain/cramps)

Uncommon (> 1/1000, < 1/100)

Loose stools, flatulence, digestive disorders, anorexia, dyspepsia

Rare (> 1/10000, < 1/1000)

Constipation, discoloration of the tongue, pancreatitis

Pseudomembranous colitis has been reported

Hepato-biliary disorders

Rare (> 1/10000, < 1/1000)

Hepatitis and cholestatic jaundice have been reported, including abnormal liver function test values, as well as rare cases of hepatic necrosis and hepatic dysfunction, which in rare instances have resulted in death

Skin and subcutaneous tissue disorders

Uncommon (> 1/1000, < 1/100)

Allergic reactions including pruritus and rash

Rare (> 1/10000, < 1/1000)

Allergic reactions including angioneurotic oedema, urticaria and photosensitivity; serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders

Uncommon (> 1/1000, < 1/100)

Arthralgia

Renal and urinary disorders

Rare (> 1/10000, < 1/1000)

Interstitial nephritis and acute renal failure

Reproductive system and breast disorders

Uncommon (> 1/1000, < 1/100)

Vaginitis

General disorders

Rare (> 1/10000, < 1/1000)

Anaphylaxis including oedema (leads in rare cases to death, see section 4.4 Special warnings and precautions for use), candidiasis, fatigue, malaise

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:

Zithromax 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 means of binding to the ribosomal 50s sub-unit and inhibition of peptide translocation.

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, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

Breakpoints

Azithromycin susceptibility breakpoints for typical bacterial pathogens are:

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

* 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.

Absorption

Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attaned 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.

In animal tests in which the doses used amounted to 40 times the clinical therapeutic dose, azithromycin caused reversible phospholipidosis but, as a rule, no true toxicological consequences were observed in association with this. Azithromycin has not been found to cause toxic reactions in patients when administered in accordance with the recommendations.

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 50 mg/kg/day azithromycin and above was observed.

Zithromax Capsules contain: Lactose, magnesium stearate, maize starch, and sodium lauryl sulphate. The capsule shells contain: Gelatin, iron oxide-black (E172), shellac, sulphur dioxide and titanium dioxide.

Zithromax Powder for Oral Suspension contains: Hydroxypropylcellulose, sodium phosphate tribasic anhydrous, sucrose, xanthan gum. Flavours: artificial banana, artificial cherry, artificial creme de vanilla.

None known

Zithromax Capsules 60 months.

Powder for Oral Suspension 3 years.

Once reconstituted with water, Zithromax Suspension has a shelf-life of 5 days.

No special storage conditions required.

Zithromax Capsules are available as:

Packs of 4 capsules. Aluminium/PVC blister strips, 4 capsules per strip, 1 strip in a carton box.

Pack of 6 capsules. Aluminium/PVC blister strips, 6 capsules per strip, 1 strip in a carton box.

Zithromax Powder for Oral Suspension is available as:

600mg (15ml) Pack: (Recommended for use in children up to 7 years (25kg)).

Packs of powder equivalent to 600mg azithromycin in a polypropylene container with child resistant screw cap (with or without a tamper evident seal), in a carton box. Pack contains a double-ended multi-dosing spoon and 10ml oral dosing syringe with detachable adaptor. A sticker for the syringe is appended to the bottle label. Reconstitute with 9ml of water to give 15ml suspension.

900mg (22.5ml) Pack: (Recommended for use in children aged from 8-11 years (26-35kg)). Packs of powder equivalent to 900mg azithromycin in a polypropylene container with child resistant screw cap (with or without a tamper evident seal), in a carton box. Pack contains a double-ended multi-dosing spoon. Reconstitute with 12ml of water to give 22.5ml suspension.

1200mg (30ml) Pack:(Recommended for use in children aged from 12-14 years (36-45kg) ). Packs of powder equivalent to 1200mg azithromycin in a polypropylene container with child resistant screw cap (with or without a tamper evident seal), in a carton box. Pack contains a double-ended multi-dosing spoon. Reconstitute with 15ml of water to give 30ml suspension.

Multi-dosing spoon delivers doses as follows:

Each pack contains a Patient information/instruction leaflet.

When dispensing the 15ml pack, advice should be given as to whether the dose should be measured using the oral dosing syringe or the spoon provided and on correct usage.

If the dose is to be given using the oral dosing syringe, before dispensing, the syringe adaptor should be detached from the syringe and inserted into the bottle neck and the cap replaced.

The sticker provided should be used to mark the syringe at the appropriate level once the correct daily dosage has been calculated.

When dispensing 22.5ml and 30ml packs, advice should be given as to the correct usage of the multi-dosing spoon.

Zithromax Capsules should be swallowed whole.

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

Zithromax Capsules 250mg PL0057/0335

Zithromax Powder for Oral Suspension 200mg/5ml PL0057/0336

Zithromax Capsules 250mg: 22 December 2005

Zithromax Powder for Oral Suspension 200mg/5ml: 22 December 2005

March 2008

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