ZENITH Azithromycin Monohydrate 500mg Film-Coated Tablet 1's

For the treatment of the following infections caused by microorganisms sensitive to azithromycin (see Precautions and Pharmacology: Pharmacodynamics under Actions): Mild to moderate community-acquired pneumonia, in particular pneumonia caused by Mycoplasma pneumoniae, Chlamydophila psittaci (ornithosis) or Chlamydophila pneumoniae (TWAR); Acute exacerbation of chronic bronchitis (adequately diagnosed); Acute bacterial sinusitis (adequately diagnosed); Tonsillitis, pharyngitis and acute otitis media in patients with hypersensitivity to beta-lactam antibiotics or when such treatment is not suitable for other reasons; Skin and soft tissue infections such as furunculosis, pyoderma, impetigo and erysipelas in patients with hypersensitivity to beta-lactam antibiotics or when such treatment is not suitable for other reasons; Uncomplicated genital infections caused by Chlamydia trachomatis or Neisseria gonorrhoeae (non-multidrug-resistant strains).
Considerations should be given to official guidance on the appropriate use of antibacterial agents.

 

Azithromycin differs from other antibiotics by its high tissue affinity. Azithromycin reaches levels up to 50 times higher in tissue than in plasma and tissue elimination half-life ranges between 2 to 4 days. Thus, azithromycin dose regimen differs from that of other antibiotics.
Dosage: Adults: In uncomplicated genital infections due to Chlamydia trachomatis or sensitive Neisseria gonorrhoeae, the dose is 1,000 mg azithromycin (given 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. As an alternative, the same total dosage (1,500 mg) can also be administered over a period of five days with 500 mg on the first day and then 250 mg on the second to the fifth day.
A 5-day treatment regimen of azithromycin was shown to have sufficient efficacy in the treatment of pneumonia. In most cases, use of a 3-day treatment regimen also seems to be sufficient.
Older people: The same dose as in adult patients is used in older people. Since older 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 Precautions).
Paediatric population: 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.
In patients with renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 mL/min) (see Precautions and Pharmacology: Pharmacokinetics under Actions).
In patients with hepatic impairment: A dose adjustment is not necessary for patients with mild to moderately impaired liver function (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Method of administration: Azithromycin should be swallowed whole with liquid as a single daily dose. The tablets may be taken with food.

 

Overdosage

May be taken with or without food: Swallow whole, do not chew/crush.

Hypersensitivity to the active substance, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients.

Hypersensitivity: As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), and dermatologic reactions including acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, 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 medicinal product should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Hepatotoxicity: Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see Adverse Reactions). 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.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
Infantile hypertrophic pyloric stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.
Pseudomembranous colitis: Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should therefore be considered in patients who get diarrhoea after starting treatment with azithromycin.
Ergot derivatives: In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered.
Superinfection: As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi, is recommended.
Cross resistance: Because of existing cross-resistance with erythromycin-resistant gram-positive strains and most strains of methicillin resistant staphylococci, use of azithromycin is not recommended. Local epidemiology and susceptibility patterns should be taken into consideration.
Serious infections: Azithromycin is not intended to treat suitable severe infections where fast high blood concentrations of antibiotic have to be achieved.
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.
Renal impairment: In patients with severe renal impairment (GFR <10 mL/min), a 33% increase in systemic exposure to azithromycin was observed (see Pharmacology: Pharmacokinetics under Actions).
Cardiovascular events: Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides including azithromycin (see Adverse Reactions). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsades 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 that prolong QT interval such as antiarrhythmics of classes 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.
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including azithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin.
Myasthenia gravis: Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see Adverse Reactions).
Long-term use: There is no experience on safety and effectiveness of long-term use of azithromycin in indications mentioned before. At fast recurrent infections, treatment with other antibiotics should be considered.
Neurological and psychiatric disorders: Azithromycin should be used with caution in patients with neurological and psychiatric disorders.
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.
However, certain adverse reactions, visual impairment and vision blurred may have an effect on a patient's ability to drive or operate machinery (see Adverse Reactions).
Use in Children: Safety and efficacy for the prevention or treatment of Mycobacterium avium complex in children have not been established.

 

Use In Pregnancy & Lactation

Below the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency are listed.
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); Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Approximately 13% of the patients in clinical trials reported adverse events, wherein gastrointestinal disorders were the most common.
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: Pseudomembranous colitis (see Precautions).
Blood and lymphatic system disorders: Uncommon: Leukopenia, neutropenia, eosinophilia. Not known: Thrombocytopenia, haemolytic anaemia.
Immune system disorders: Uncommon: Angioedema, hypersensitivity reaction. Not known: Severe (partly fatal) anaphylactic reaction e.g. anaphylactic shock (see Precautions).
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 Precautions).
Eye disorders: Uncommon: Visual impairment. Not known: Blurred vision.
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 Precautions), arrhythmia (see Precautions) including ventricular tachycardia, electrocardiogram QT prolonged (see Precautions).
Vascular disorders: Uncommon: Hot flush. Not known: Hypotension.
Respiratory, thoracic and mediastinal disorders: Uncommon: Dyspnoea, epistaxis.
Gastrointestinal disorders: Very common: Diarrhoea. 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 Precautions), hepatitis fulminant, hepatic necrosis.
Skin and subcutaneous disorders: Uncommon: Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis. Rare: Photosensitivity reaction, acute generalised exanthematous pustulosis (AGEP). Very rare: DRESS (drug reaction with eosinophilia and systemic symptoms)*. Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
*Frequency estimated with the "rule of three".
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 oedema, chest pain, pyrexia, pain, peripheral oedema.
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 creatinine increased, blood potassium abnormal, blood alkaline phosphatase increased, chloride increased, glucose increased, platelets increased, haematocrit 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: Diarrhoea, 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.

 

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 medicinal products 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 1,200 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 and colchicine (P-gp substrates): 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.
Ergot derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see Precautions).
Zidovudine: Single 1,000 mg doses and multiple 1,200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Pharmacokinetic studies have been conducted between azithromycin and the following medicinal products known to undergo significant cytochrome P450 mediated metabolism.
Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).
However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
Cimetidine: In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Coumarin-type oral anticoagulants: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 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. Consequently, caution should be exercised before considering concurrent administration of these medicinal products. If co-administration of these medicinal products 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 1,200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg Fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C_max (18%) of azithromycin was observed.
Indinavir: Co-administration of a single dose of 1,200 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 (1,200 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 medicinal product.
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 Adverse Reactions).
Sildenafil: In normal healthy 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, 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 variable for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1,200 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.
Other antibiotics: On a possible co-resistance between macrolide antibiotics and azithromycin (e.g. erythromycin) as well as lincomycin and clindamycin is to look at. Concomitant use of several medicinal products from the same group of substances is not recommended.
Medicinal products known to prolong the QT interval: Azithromycin should not be co-administered with other medicinal products known to prolong the QT interval (see Precautions).

 

Caution For Usage

Storage

Action

Macrolides