Azithromycin New Formulation Aspen 500 mg Tablets

AZITHROMYCIN NEW FORMULATION ASPEN is indicated in adults for:

• Mild to moderate infections caused by susceptible organisms in:
  • Lower respiratory tract infections including bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae or Staphylococcus aureus and pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae;
  • Uncomplicated skin and soft tissue infections;
  • Sinusitis due to Haemophilus influenzae, Streptococcus pneumoniae or Staphylococcus aureus;
• An alternative to first line therapy of pharyngitis/tonsillitis.
• Sexually transmitted diseases in men and women in the treatment of:
  • Uncomplicated genital infections due to Chlamydia trachomatis;
  • Chancroid due to Haemophilus ducreyi.

AZITHROMYCIN NEW FORMULATION ASPEN is indicated in children aged 1 year and older for:

• Pharyngitis/tonsillitis and otitis media caused by susceptible organisms in children over 45 kg. (An azithromycin suspension is recommended in children under 45 kg).

Posology

Adults: For all indications other than sexually transmitted diseases, the total dose is 1,5 g which should be given as 500 mg daily for 3 days. For sexually transmitted diseases caused by Chlamydia trachomatis or Haemophilus ducreyi, the dose is 1 g given as a single dose.

Special populations

Elderly population: Normal adult dosage is recommended. Elderly patients may be more susceptible to development of Torsade de Pointes dysrhythmia than younger patients (see section 4.4).

Hepatic impairment: AZITHROMYCIN NEW FORMULATION ASPEN is contraindicated in patients with severe hepatic impairment (see section 4.3).

Paediatric population: Children over 45 kg - dose as per adults. This formulation is not suitable for children under 45 kg.

Method of administration

AZITHROMYCIN NEW FORMULATION ASPEN should be administered as a single daily dose with or without food. AZITHROMYCIN NEW FORMULATION ASPEN should be taken whole.

AZITHROMYCIN NEW FORMULATION ASPEN is contraindicated in:

• Patients with hypersensitivity to azithromycin, erythromycin, any of the macrolide or ketolide antibiotics or to any excipients in AZITHROMYCIN NEW FORMULATION ASPEN (see section 6.1).
• Because of the theoretical possibility of ergotism, AZITHROMYCIN NEW FORMULATION ASPEN and ergot derivatives should not be co-administered.
• Hepatic impairment: As the liver is the principal route of excretion of azithromycin, as contained in AZITHROMYCIN NEW FORMULATION ASPEN, it should not be prescribed in patients with hepatic disease.

Hypersensitivity: Serious allergic reactions, including angioedema and anaphylaxis and dermatologic reactions including Stevens-Johnson syndrome, Acute Generalised Exanthemateous Pustulosis (AGEP), Drug Reaction with Eosinophilic and systemic symptoms (DRESS) and toxic epidermal necrolysis have been reported. Some of these reactions with AZITHROMYCIN NEW FORMULATION ASPEN have resulted in recurrent symptoms and required a longer period of observation and treatment. If an allergic reaction occurs, AZITHROMYCIN NEW FORMULATION ASPEN should be discontinued, and appropriate therapy should be instituted. Medical practitioners to 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, AZITHROMYCIN NEW FORMULATION ASPEN should not be used in patients with hepatic disease (see section 4.3). Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure, some of which have resulted in death, have been reported. Discontinue AZITHROMYCIN NEW FORMULATION ASPEN immediately if signs and/or symptoms of hepatitis occur.

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 NEW FORMULATION ASPEN. However, because of the theoretical possibility of ergotism, AZITHROMYCIN NEW FORMULATION ASPEN and ergot derivatives should not be co-administered (see section 4.3).

Superinfection: Observation for signs of superinfection with non-susceptible organisms, including fungi, is recommended.

Pseudomembranous colitis: Pseudomembranous colitis has been reported and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients with diarrhoea subsequent to administration of AZITHROMYCIN NEW FORMULATION ASPEN.

Clostridium difficile-associated diarrhoea: Clostridium difficile-associated diarrhoea (CDAD) due to overgrowth of Clostridium difficile in the gut, has been reported with use of AZITHROMYCIN NEW FORMULATION ASPEN, and may range in severity from mild diarrhoea to fatal colitis. If CDAD is suspected or confirmed, ongoing AZITHROMYCIN NEW FORMULATION ASPEN use should be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridium difficile, and surgical evaluation should be instituted as clinically indicated.

Renal impairment: In patients with a creatinine clearance < 30, a 33 % increase in systemic exposure to AZITHROMYCIN NEW FORMULATION ASPEN was observed (see section 5). Acute renal failure and interstitial nephritis have been reported (see section 4.8).

Prolongation of the QT interval: Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac dysrhythmia and Torsade de Pointes, have been seen in treatment with other macrolides including AZITHROMYCIN NEW FORMULATION ASPEN (see section 4.8). Prescribers should specifically consider the risk of QT prolongation, which can be fatal in at-risk groups including:

• Patients with congenital or documented QT prolongation.
• Patients currently receiving treatment with other active substances known to prolong QT interval such as antidysrhythmics of classes IA and III; antipsychotic agents; antidepressants; and fluoroquinolones.
• Patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia.
• Patients with clinically relevant bradycardia, cardiac dysrhythmia or cardiac insufficiency.
• Elderly patients: elderly patients may be more susceptible to medicine-associated effects on the QT interval.

Myasthenia gravis: Exacerbation of symptoms of myasthenia gravis and new-onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy.

Paediatric population: The safety and efficacy of AZITHROMYCIN NEW FORMULATION ASPEN has not been established in children less than 1 year of age.

Ergot derivatives: Because of the theoretical possibility of ergotism, AZITHROMYCIN NEW FORMULATION ASPEN and ergot derivatives should not be co-administered (see section 4.3 and section 4.4).

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. Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to be associated with the pharmacokinetic medicine interactions seen with erythromycin. 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 medicines 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.
• 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.
• Midazolam: In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetic properties and pharmacodynamics properties 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 although a dose adjustment of AZITHROMYCIN NEW FORMULATION ASPEN is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of AZITHROMYCIN NEW FORMULATION ASPEN is warranted.
• 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 C max, of sildenafil or its major circulating metabolite.

Triazolam: In 14 healthy volunteers, co-administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0,125 mg triazolam on day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Co-administration of trimethoprim/sulfamethoxazole (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.

Special administration advised with the following:

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacids with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 24 %. In patients receiving both AZITHROMYCIN NEW FORMULATION ASPEN and antacids, the medicines should not be taken simultaneously. AZITHROMYCIN NEW FORMULATION ASPEN tablets should be taken at least 1 hour before or 2 hours after an antacid.

Cimetidine: A single dose of cimetidine administered 2 hours before AZITHROMYCIN NEW FORMULATION ASPEN had no effect on the pharmacokinetics of AZITHROMYCIN NEW FORMULATION ASPEN.

No pharmacokinetic interactions were reported in studies of AZITHROMYCIN NEW FORMULATION ASPEN co-administered with: Carbamazepine, methylprednisolone, didanosine (dideoxyinosine), theophylline, rifabutin (however co-administration of AZITHROMYCIN NEW FORMULATION ASPEN and rifabutin was associated with the development of neutropenia. A causal relationship to its combination with AZITHROMYCIN NEW FORMULATION ASPEN has not been established (see section 4.8)) and 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).

Special precautionary monitoring is advised with the following:

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 (C max increase by 24 % and AUC 0-5 was 5 107 and 4 210 ngh/mL with and without azithromycin, respectively, p u2264 0,05). Consequently, caution should be exercised before co-administration of these two medicines. If co-administration is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.

P-glycoprotein substrates: Concomitant administration of AZITHROMYCIN NEW FORMULATION ASPEN with P-glycoprotein substrates such as digoxin or dabigatran has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if AZITHROMYCIN NEW FORMULATION ASPEN and P-glycoprotein substrates such as digoxin or dabigatran are administered concomitantly, the possibility of elevated serum medicine concentrations should be considered. Clinical monitoring and serum monitoring of digoxin levels during treatment with AZITHROMYCIN NEW FORMULATION ASPEN and after its discontinuation are necessary. 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 AZITHROMYCIN NEW FORMULATION ASPEN, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.

Warfarin: In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. However, there have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and warfarin. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when AZITHROMYCIN NEW FORMULATION ASPEN is used in patients receiving coumarin-type oral anticoagulants.

The safety of AZITHROMYCIN NEW FORMULATION ASPEN in pregnancy and lactation has not been established.

Pregnancy: Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the foetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, AZITHROMYCIN NEW FORMULATION ASPEN should be used during pregnancy only if clearly needed.

Breastfeeding: 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 characterised the pharmacokinetics of azithromycin excretion into human breast milk. AZITHROMYCIN NEW FORMULATION ASPEN should only be used in lactating women where adequate alternatives are not available.

Fertility: No data.

Side effects such as dizziness, convulsions, vertigo, somnolence, and syncope have been reported with usage of AZITHROMYCIN NEW FORMULATION ASPEN. These side effects may affect a patientu2019s ability to drive or operate machinery.

a. Tabulated list of adverse reactions

System organ class

• Frequent
• Less frequent
• Frequency unknown

Blood and lymphatic system disorders

• Neutropenia

Immune system disorders

• Angioedema

Eye disorders

• Abnormal vision

Ear and labyrinth disorders

• Hearing impairment including hearing loss, deafness and/or tinnitus

Cardiac disorders

• Chest pains, dysrhythmias including ventricular tachycardia, palpitations, QT prolongation, Torsade de Pointes

Gastrointestinal disorders

• Abdominal discomfort (pain/cramps), diarrhoea, nausea
• Flatulence, loose stools, vomiting
• Melaena

Hepato-biliary disorders

• Abnormal liver function

Skin and subcutaneous tissue disorders

• Rash
• Allergic reactions

Renal and urinary disorders

• Nephritis

In post-marketing experience, the following additional undesirable effects have been reported with frequency unknown:

System organ class

• Frequency unknown

Infections and infestations

• Moniliasis, vaginitis

Blood and lymphatic system disorders

• Thrombocytopenia

Immune system disorders

• Anaphylaxis, angioedema

Metabolism and nutrition disorders

• Anorexia

Psychiatric disorders

• Nervousness, aggressive reaction, agitation, anxiety

Nervous system disorders

• Dizziness, convulsions, headache, hyperactivity, hypoesthesia, paraesthesia, somnolence, syncope, taste/smell perversion and/or loss

Ear and labyrinth disorders

• Deafness, tinnitus, impaired hearing, vertigo

Cardiac disorders

• Palpitations, dysrhythmias including ventricular tachycardia, QT prolongation, Torsade de Pointes

Vascular disorders

• Hypotension

Gastrointestinal disorders

• Vomiting/diarrhoea (rarely resulting in dehydration), dyspepsia, constipation, pseudomembranous colitis, pancreatitis, tongue discolouration

Hepatobiliary disorders

• Hepatitis and cholestatic jaundice, hepatic necrosis and hepatic failure, which have rarely resulted in death

Skin and subcutaneous tissue disorders

• Allergic reactions including pruritus, rash, photosensitivity, oedema, urticaria, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal disorders

• Arthralgia

Renal and urinary disorders

• Interstitial nephritis, acute renal failure

General disorders

• Asthenia, fatigue, malaise

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/ Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms: Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. Typical symptoms of overdosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea.

Treatment: In the event of overdose, general symptomatic and supportive measures are indicated as required.