Azithromycin 250mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Azithromycin 250 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Azithromycin 250 mg film-coated tablet 1 film-coated tablet contains: 250 mg azithromycin (as azithromycin monohydrate)
Excipient with known effect:
1 film-coated tablet contains 7,2 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
White, oblong film-coated tablets with breaking notches on both sides and the embossment: “A 250“
The film-coated tablets can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Azithromycin is indicated for the treatment of the following infections, when caused by microorganisms sensitive to azithromycin (see section 4.4 and 5.1):
- acute bacterial sinusitis (adequately diagnosed)
- acute bacterial otitis media (adequately diagnosed)
- pharyngitis/tonsillitis
- acute exacerbation of chronic bronchitis (adequately diagnosed)
- mild to moderately severe community-acquired pneumonia
- skin and soft tissue infections
- uncomplicated Chlamydia trachomatis urethritis and cervicitis
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Posology
Adults
In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1,000 mg as a single oral dose.
For all other indications the dose is 1,500 mg, to be administered as 500 mg per day for three consecutive days.
Elderly patients
The same dose range as in younger patients may be used in the elderly. Children
Azithromycin tablets should only be administered to children weighing more than 45 kg when normal adult dose should be used. For children under 45 kg other pharmaceutical forms of azithromycin, e.g. suspensions, may be used.
Patients with renal impairment:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (see section 4.4).
Patients with hepatic impairment:
A dose adjustment is not necessary for patients with mild to moderately impaired liver function (see section 4.4).
In the Elderly:
The same dosage as in adult patients is used in the elderly. 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).
Method of administration
Azithromycin 250 mg film-coated tablet should be administered as a daily single dose. Azithromycin 250mg film-coated tablet may be taken 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 section 6.1 (see also section 4.4).
4.4 Special warnings and precautions for use
As with erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
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 (see section 4.8). 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 co-administered.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea 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 diarrhea 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 (see Section 5.2).
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 (see section 4.8). 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 hypomagnesaemia
• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency
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).
Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.
Azithromycin film-coated tablets contain Lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Azithromycin film-coated tablets.
4.5 Interaction with other medicinal products and other forms of interaction
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 drugs 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 (P-gp substrates)
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-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 (see section 4.4).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.
Atorvastatin
Coadministration 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 15-mg 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.
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 coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz
Coadministration 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
Coadministration 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 Cmax (18%) of azithromycin was observed.
Indinavir
Coadministration 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, coadministration 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
Coadministration 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
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).
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, coadministration 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
Coadministration 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.
4.6 Fertility, pregnancy and lactation
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.
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.
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.
4.8 Undesirable effects
The table below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency.
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:
Infections and infestations
Uncommon: Candidiasis, vaginal infection, pneumonia, fungal infections, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis Not known: Pseudomembraneous colitis (see section 4.4)
Blood and lymphatic system disorders
Uncommon: Leukopenia, neutropenia, eosinophilia
Not known: Thrombocytopenia, haemolytic anaemia
Immune system disorders
Uncommon: Angioedema, hypersensitivity
Not known: Anaphylactic reaction (see section 4.4)
Metabolism and nutrition disorders Uncommon: Anorexia
Psychiatric disorders
Uncommon: Nervousness, insomnia
Rare: Agitation
Not known: Aggression, anxiety, delirium, hallucination
Nervous system disorders Common: Headache
Uncommon: Dizziness, somnolence, dysgeusia, paraesthesia
Not known: Syncope, convulsion, hypoaesthesia, psychomotor
hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis (see section 4.4)
Eye disorders
Uncommon: Visual impairment
Ear and labyrinth disorders Uncommon: Ear disorder, vertigo
Not known: Hearing impairment including deafness and/or tinnitus
Cardiac disorders Uncommon: Palpitations
Not known: Torsades de pointes (see section 4.4), arrhythmia (see section
4.4) including ventricular tachycardia, electrocardiogram QT prolonged (see section 4.4)
Vascular disorders Uncommon: Hot flush Not known: Hypotension
Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnoea, epistaxis
Gastrointestinal disorders Very common: Diarrhea
Common: Vomiting, abdominal pain, nausea
Uncommon: Constipation, flatulence, dyspepsia, gastritis, dysphagia,
abdominal distension, dry mouth, eructation, mouth ulceration, salivary hypersecretion
Not known: Pancreatitis, tongue discoloration Hepatobiliary disorders
Rare: Hepatic function abnormal, jaundice cholestatic
Not known: Hepatic failure (which has rarely resulted in death) (see section
4.4) , hepatitis fulminant, hepatic necrosis
Skin and subcutaneous disorders
Uncommon: Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis Rare: Photosensitivity reaction
Not known: Stevens-Johnson syndrome, Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders Uncommon: Osteoarthritis, myalgia, back pain, neck pain Not known: Arthralgia
Renal and urinary disorders Uncommon: Dysuria, renal pain
Not known: Renal failure acute, nephritis interstitial
Reproductive system and breast disorders
Uncommon: Metrorrhagia, testicular disorder
General disorders and administration site conditions
Uncommon: Oedema, asthenia, malaise, fatigue, face edema, chest pain, pyrexia, pain, peripheral edema
Investigations
Common: Lymphocyte count decreased, eosinophil count increased, blood
bicarbonate decreased, basophils increased, monocytes increased, neutrophils increased
Uncommon: Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal, blood alkaline phosphatase increased, chloride increased, glucose increased, platelets increased, hematocrit decreased, bicarbonate increased, abnormal sodium
Injury and poisoning
Uncommon: post procedural complication
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:
Metabolism and nutrition disorders Common: Anorexia
Nervous system disorders
Common: Dizziness, headache, paraesthesia, dysgeusia
Uncommon: Hypoaesthesia
Eye disorders
Common: Visual impairment
Ear and labyrinth disorders
Common: Deafness
Uncommon: Hearing impaired, tinnitus
Cardiac disorders Uncommon: Palpitations
Gastrointestinal disorders Very common:
Diarrhea, abdominal pain, nausea, flatulence, abdominal discomfort, loose stools
Hepatobiliary disorders Uncommon: Hepatitis
Skin and subcutaneous tissue disorders Common: Rash, pruritus
Uncommon: Stevens-Johnson syndrome, photosensitivity reaction
Musculoskeletal and connective tissue disorders Common: Arthralgia
General disorders and administration site conditions Common: Fatigue
Uncommon: Asthenia, malaise
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 (www.mhra.gov.uk/yellowcard).
4.9 Overdose
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
General properties
Pharmacotherapeutic group: antibacterials for systemic use, macrolides, azithromycin,
ATC code: J01FA10
Mode of action
The mechanism of action of azithromycin is based on the suppression of bacterial protein synthesis, that is to say that it binds to the ribosomal 50s sub-unit and inhibits the translocation of peptides. Azithromycin acts bacteriostatic.
PK/PD Relationship
The efficacy of azithromycin is best described by the relationship AUC/MIC, where AUC describes the area under the curve and MIC represents the mean inhibitory concentration of the microbe concerned.
Mechanism of resistance
Resistance to azithromycin may be natural or acquired. There are 3 main mechanisms of resistance affecting azithromycin:
- Efflux: resistance may be due to an increase in the number of efflux pumps on the cell membrane. In particular, 14- and 15-link macrolides are affected. (M-phenotype)
- Alterations of the cell structure: methylisation of the 23 s rRNS may reduce the affinity of the ribosomal binding sites, which can result in microbial resistance to macrolides, lincosamides and group B streptogramins (SB) (MLSB-phenotype).
- Enzymatic deactivation of macrolides is only of limited clinical significance.
In the presence of the M-phenotype, complete cross resistance exists between azithromycin and clarithomycin, erythromycin and roxithromycin. With the MLSB-phenotype, additional cross resistance exists with clindamycin and streptogramin B.
A partial cross resistance exists with spiramycin.
Breakpoints
According to EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for azithromycin (2009-06-01):
|
Species |
Susceptible |
Resistant |
|
Staphylococcus spp. |
< 1 mg/l |
> 2 mg/l |
|
Streptococcus (Group A,B,C,G) |
< 0,25 mg/l |
> 0,5 mg/l |
|
Streptococcus pneumoniae |
< 0,25 mg/l |
> 0,5 mg/l |
|
Haemophilus influenzae |
< 0,12 mg/l |
> 4 mg/l |
|
Moraxella catarrhalis |
< 0,5 mg/l |
> 0,5 mg/l |
|
Neisseria gonorrhoeae |
< 0,25 mg/l |
> 0,5 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.
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union.
Table of Susceptibility_
Commonly susceptible species
Aerobic Gram-negative microorganisms
Haemophilus influenzae *
Moraxella catarrhalis *
Neisseria gonorrhoeae
Other microorganisms
Chlamydophila pneumoniae Chlamydia trachomatis
Legionella pneumophila_
Mycobacterium avium_
Species for which acquired resistance may be a problem
Aerobic Gram-positive microorganisms
Staphylococcus aureus 2
Streptococcus agalactiae Streptococcus pneumoniae 2
Streptococcus pyogenes 2
Other microorganisms
Ureaplasma urealyticum_
Inherently resistant organisms
Staphylococcus aureus - methicillin resistant and erythromycin resistant strains Streptococcus pneumoniae - penicillin resistant strains Escherichia coli Pseudomonas aeruginosa
same source, 10 metabolites were also detected, which were formed through N- and O-demethylation, hydroxylation of desosamine- and aglycone rings and degradation 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 than are released from inactive phagocytes. In animal models the azithromycin concentrations measured in inflammation foci were high.
Pharmacokinetics in Special Populations
Renal insufficiency
Following a single oral dose of azithromycin 1 g, mean Cmax and AUC0-120 increased by 5.1 % and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min). In subjects with severe renal impairment, the mean Cmax and AUC0-120 increased 61% and 33% respectively compared to normal.
Hepatic insufficiency
In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly
The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.
Infants, toddlers, children and adolescents
Pharmacokinetics have been studied in children aged 4 months - 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.65 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The tJ/2 of 36 h in the older children was within the expected range for adults.
5.3 Preclinical safety data
In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, 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.
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 of the embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation in physical development and delay in reflex development following treatment with 50 mg/kg/day azithromycin and above were observed.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
Microcristalline cellulose Maize starch Sodium starch glycollate Silicium dioxide Magnesium stearate Sodium laurylsulphate
Film-coating Lactose monohydrate Hypromellose Macrogol 4000 Titanium dioxide
6.2. Incompatibilities Not applicable
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
The film-coated tablets are packed in aluminium/polyvinylchloride blisters. Azithromycin 250 mg Tablets
Packs containing 2, 3, 4, 6, 9, 12 and 24 film-coated tablets.
6.6. Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Sandoz Ltd
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04416/1235
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28/05/2008
10 DATE OF REVISION OF THE TEXT
19/02/14
Klebsiella spp._
Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indication.
5.2 Pharmacokinetic properties Absorption
Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma 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.
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.
Binding to serum proteins varies in dependence on exposure in concentration range from 12% in 0.5 microgram/ml up to 52% in 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
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. In the