Azromax 250mg Film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 250 mg azithromycin (as azithromycin monohydrate).

Excipients:
Each film-coated tablet contains 0.18 mg of soya lecithin.

For a the full list of excipients, see section 6.1.

4.2 Posology and method of administration

For oral usePosology:

Azithromycin tablets should be given as a single daily dose. The tablets can be taken with or without food. The duration of treatment in each of the infectious diseases is given below.

Method of administration
For oral use.
The tablets can be taken with or without food.

4.3 Contraindications

The use of this product in contraindicated in patients with hHypersensitivity to the active substance azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients listed in section 6.1 or to erythromycin or any macrolide or ketolide antibiotic.

Azithromycin contains soya oil. If you allergic to peanut or soya, do not use this medicinal product.

4.4 Special warnings and precautions for use

Allergic reactions
As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal) have been reported alongside dermatological reactions, including Stevens-Johnson syndrome (SJS),. toxic epidermal necrolysis (TEN) (rarely fatal) and DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms). A certain number of these reactions resulted in recurring symptoms and required an extended period of Some of these reactions with azithromycin have caused recurrent symptoms and have required longerobservation and treatment.

If an allergic reaction occurs, use of this medicinal product must be discontinued and the appropriate treatment initiated. Doctors must be aware that allergic symptoms can recur if symptomatic treatment is discontinued.

Renal impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance > 40 m/min). GFR 30-80 ml/min/1.73 m2). Caution is advised Iin patients with severe renal function impairment (GFR < 10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed < 30 ml/min/1.73 m2) as systemic exposure may be increased (see section 5.2).

Hepatic impairment
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, or 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.

Liver function disorders, hepatitis, cholestatic jaundice, liver necrosis and renal failure have been reported and have been fatal in a number of cases. Discontinue the use of azithromycin if signs and symptoms of hepatitis occur.

Pseudomembranous colitis has been reported following use of macrolide antibiotics. This diagnosis should therefore be taken into consideration in patients who develop diarrhoea after starting treatment with azithromycin.

Infantile hypertrophic pyloric stenosis

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.

QT prolongation
Prolonged cardiac repolarisation and a prolonged QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other 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:

• Patients with congenital or documented acquired QT prolongation.
• Patients currently receiving treatmentconcurrently with other active substances that 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 (see section 4.5).
• Patients with a disrupted electrolyte balancedisturbance, particularly in cases of hypokalaemia and hypomagnesaemia
• Patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

The following should be considered before prescribing azithromycin:

This medicinal product contains soya oil

Azithromycin contains soya oil. Patients who are allergic to peanut or soya, must not use this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Cisapride
Cisapride is metabolized metabolised 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.

Protease inhibitors
There are no data available about a possible interaction with protease inhibitors.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequate data from 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 passes into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized characterised the pharmacokinetics of azithromycin excretion into human breast milk. Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.

4.8 Undesirable effects

 

	Very Common	Common	Uncommon	Rare	Very Rare	Not Known
Infections and Infestations			Candidiasis, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory  disorder, rhinitis, oral candidiasis			Pseudomembranous colitis (see section 4.4)
Blood and Lymphatic System Disorders			Leukopenia, neutropenia, eosinophilia			Thrombocytopenia, haemolytic anaemia
Immune System Disorders			Angioedema, hypersensitivity			Anaphylactic reaction (see section 4.4)
Metabolism and Nutrition Disorders			Anorexia
Psychiatric Disorders			Nervousness, insomnia	Agitation		Aggression, anxiety, delirium, hallucination
Nervous System Disorders		Headache	Dizziness, somnolence, dysgeusia, paraesthesia			Syncope, convulsion, hypoaesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis (see Section section 4.4)
Eye Disorders			Visual impairment
Ear and Labyrinth Disorders			Ear disorder, vertigo			Hearing impairment including deafness and/or tinnitus
Cardiac Disorders			Palpitations			Torsades de pointes (see section 4.4), arrhythmia (see section 4.4) including ventricular tachycardia, Electrocardiogram QT prolonged (see section 4.4)
Vascular Disorders			Hot flushes			Hypotension
Respiratory, thoracic and mediastinal disorders			Dyspnoea, epistaxis
Gastrointestinal Disorders	Diarrhoea	Vomiting, abdominal pain, nausea	Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulceration, salivary hypersecretion			Pancreatitis, tongue discolouration
Hepatobiliary Disorders			Hepatitis	Hepatic function abnormal, jaundice cholestatic		Hepatic failure (which has rarely resulted in death) (see section 4.4), Hepatitis hepatitis fulminant, Hepatic hepatic necrosis
Skin and Subcutaneous Tissue Disorders			Rash, pruritus, urticarial Urticaria, dermatitis, dry skin, hyperhidrosis	Photosensitivity reaction	DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)	Stevens-Johnson syndrome, toxic Toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and Connective Tissue Disorders			Osteoarthritis, myalgia, back pain, neck pain			Arthralgia
Renal and Urinary Disorders			Dysuria, renal pain			Renal failure acute, nephritis interstitial

* for powder for solution for infusion only


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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie. 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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

FREEPOST
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanisn Mechanism of action
The action mechanism of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the 50 S subunit and thus inhibiting the translocation of peptides.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core:
Microcrystalline cCellulose, microcrystalline (E460)
Pregelatinised maize starch (maize starch)
Sodium starch glycolate (Type A)
Colloidal Aanhydrous colloidal silica (E551)
Sodium lauryl sulphate sulfate
Magnesium stearate (E470b)

Tablet Film-coating:
Poly(vinyl) alcohol (partially hydrolysed)
Titanium dioxide (E171)
Talc (E553b)
Soya lecithin
Xanthan gum (E415).

8. MARKETING AUTHORISATION NUMBER(S)

PA PA0577/122/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 4th June 2010
Date of last renewal: 01st January 2012


10. DATE OF REVISION OF THE TEXT

November 2013February 2017

• 4.2 - Elderly New information added,

  Patients with renal impairment,  GFR changed

• 4.3, formatting

• 4.4, Allergic reactions  grammer, comparing to other macrolides QT prolongation, refer to document Myasthenia gravis and azithromycin, Superinfections, Clostridium difficile associated diarrhoea were added, information about paediatric population added

• 4.5, Antacids - reduction by 25% in peak concentration change. Digoxin - text added, Astemizole - spelling change, atorvastatin - rhabdomylosis mentioned, ciclosporin - spelling change, theophylline - text deleted,

• 4.6, Fertility added, breastfeeding info edited,

• 4.8, refer to new table, reporting of side effects, new IMB guidelines

• 5.1, mode changed to Mechanism, breakpoints, refer to table

• 5.2, metabolism changed to biotransformation, insufficiency changed to impairment, paediatric population

• Date of revision changed



4.1     Therapeutic indications

 

For treatment of the following infections, when caused by micro-organisms 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

·      Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas

·      Uncomplicated Chlamydia trachomatis urethritis and cervicitis

 

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

 

4.3     Contraindications

 

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

 

Azithromycin contains soya oil.  If you allergic to peanut or soya, do not use this medicinal product.

 

4.4     Special warnings and precautions for use

 

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).

 

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.

 

Azithromycin is not the first choice for the empirical treatment of infections in areas where the prevalence of resistant isolates is 10% or more (see section 5.1).

 

               4.5       Interaction with other medicinal products and other forms of interaction

 

Antacids

When studying the effect of simultaneously administered antacid on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak concentrations of azithromycin measured in the plasma did fall by 30 %. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

 

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

Some of the macrolide antibiotics have been reported to impair the microbial metabolism of digoxin in the gut in some patients. In patients receiving concomitant azithromycin, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.

 

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 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.

 

 

Astemizol and alfentanil

No data are available on interactions with astemizol and alfentanil. Caution should be exercised with concomitant use of these agents and azithromycin in view of the described potentation of its effect during concomitant use of the macrolide antibiotic erythromycin.

 

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).

 

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 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 (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. As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theoophylline levels is advised.

 

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 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

 

4.8     Undesirable 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:

 

System Organ Class	Adverse reaction	Frequency
Infections and Infestations	Candidiasis, oral candidiasis, vaginal infection	Uncommon
	Pseudomembranous colitis (see section 4.4)	Not known
Blood and Lymphatic System Disorders	Leukopenia, neutropenia	Uncommon
	Thrombocytopenia, haemolytic anaemia	Not known
Immune System Disorders	Angioedema, hypersensitivity	Uncommon
	Anaphylactic reaction (see section 4.4)	Not known
Metabolism and Nutrition Disorders	Anorexia	Common
Psychiatric Disorders	Nervousness	Uncommon
	Agitation	Rare
	Aggression, anxiety	Not known
Nervous System Disorders	Dizziness, headache, paraesthesia, dysgeusia	Common
	Hypoaesthesia, somnolence, insomnia	Uncommon
	Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia Myasthenia gravis (see Section 4.4)	Not known
Eye Disorders	Visual impairment	Common
Ear and Labyrinth Disorders	Deafness	Common
	Hearing impaired, tinnitus	Uncommon
	Vertigo	Rare
Cardiac Disorders	Palpitations	Uncommon
	Torsades de pointes (see section 4.4), arrhythmia (see section 4.4) including ventricular tachycardia	Not known
Vascular Disorders	Hypotension	Not known
Gastrointestinal Disorders	Diarrhea, abdominal pain, nausea, flatulence	Very common
	Vomiting, dyspepsia	Common
	Gastritis, constipation	Uncommon
	Pancreatitis, tongue discolouration	Not known
Hepatobiliary Disorders	Hepatitis	Uncommon
	Hepatic function abnormal	Rare
	Hepatic failure (see section 4.4)**, hepatitis fulminant, hepatic necrosis, jaundice cholestatic	Not known
Skin and Subcutaneous Tissue Disorders	Rash, pruritus	Common
	Stevens-Johnson syndrome, photosensitivity reaction, urticaria	Uncommon
	Toxic epidermal necrolysis, erythema multiforme	Not known
Musculoskeletal and Connective Tissue Disorders	Arthralgia	Common
Renal and Urinary Disorders	Renal failure acute, nephritis interstitial	Not known
General Disorders and Administration Site Conditions	Injection site pain                ,* injection site inflammation,* fatigue	Common
	Chest pain, oedema, malaise, asthenia	Uncommon
Investigations	Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased	Common
	Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal	Uncommon
	Electrocardiogram QT prolonged (see section 4.4)	Not known

* for powder for solution for infusion only

**which has rarely resulted in death

 

                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

10.     DATE OF REVISION OF THE TEXT

 

August 2012