Myzat 200 mg/5ml Powder for oral suspension

Children: 1 year and over (under 45 kg) MYZAT is indicated for pharyngitis/tonsillitis and otitis media caused by susceptible organisms.

Adults and children over 45 kg: MYZAT is indicated 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; and as an alternative to first line therapy of pharyngitis/tonsillitis.

Posology MYZAT 200 mg/5 mL powder for oral suspension should be administered as a single daily dose. MYZAT should be administered to children using the 5 mL oral dosing syringe or the spoon provided MYZAT suspension can be taken with food.

Use in children: 1 year and older The total dose in children is 30 mg/kg which should be given as a single daily dose of 10 mg/kg for 3 days according to the following guidance:

• < 15 kg : 10 mg/kg once daily on days 1 - 3.
• 15 - 25 kg : 200 mg (5 mL) once daily on days 1 - 3.
• 26 - 35 kg : 300 mg (7,5 mL) once daily on days 1 - 3.
• 36- 45 kg : 400 mg (10 mL) once daily on days 1 - 3.
• > 45 kg : Dose as per adults (Refer to azithromycin 500 mg Tablets Professional Information)

Method of administration For oral use. For reconstitution details please refer to section 6.6.

MYZAT is contra-indicated in patients with a known hypersensitivity to azithromycin, erythromycin or any of the macrolide antibiotics, or to any excipients under section 6.1. Because of the theoretical possibility of ergotism, MYZAT and ergot derivatives should not be co-administered.

Use in hepatic impairment As the liver is the principal route of excretion of MYZAT, it should not be used in patients with hepatic disease.

Use in children under 1 year of age The safety and efficacy of MYZAT in children less than 1 year of age have not been established.

Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson syndrome, Acute Generalised Exanthemateous Pustulosis (AGEP), Drug with Eosinophilic and systemic symptoms (DRESS) and toxic epidermal necrolysis have been reported. Some of these reactions with MYZAT have resulted in recurrent symptoms and required a longer period of observation and treatment. If an allergic reaction occurs, MYZAT 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, the use of MYZAT should be undertaken with caution 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 MYZAT immediately if signs and 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 MYZAT. However, because of the theoretical possibility of ergotism, MYZAT 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 MYZAT.

Clostridium difficile -associated diarrhoea: Clostridium difficile- associated diarrhoea (CDAD) due to overgrowth of Clostridium difficile in the gut, has been reported with use of MYZAT, and may range in severity from mild diarrhoea to fatal colitis. If CDAD is suspected or confirmed, ongoing MYZAT 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 MYZAT was observed (see Section 5.2). Acute renal failure and interstitial nephritis have been reported (see Section 4.8).

QT Prolongation Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac dysrhythmia and Torsades de Pointes, have been seen with treatment with macrolides, including MYZAT (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.

Use in children under 1 year of age: The safety and efficacy of oral MYZAT preparations in children less than 1 year have not been established.

Because of the theoretical possibility of ergotism, MYZAT 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 pharmacodynamic 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 MYZAT is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of MYZAT 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 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.

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 MYZAT and antacids, the medicines should not be taken simultaneously. MYZAT should be taken at least 1 hour before or 2 hours after an antacid.

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

No pharmacokinetic interactions were reported in studies of MYZAT co-administered with: Carbamazepine, methylprednisolone, didanosine (dideoxyinosine), theophylline, rifabutin however co-administration of MYZAT and rifabutin was associated with the development of neutropenia. A causal relationship to its combination with MYZAT 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 MYZAT 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 MYZAT 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 MYZAT 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 MYZAT, 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-administered of azithromycin and warfarin. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when MYZAT is used in patients receiving coumarin-type oral anticoagulants.

The safety and efficacy of MYZAT in pregnancy and lactation have 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, MYZAT should be used during pregnancy only if clearly needed.

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 characterised the pharmacokinetics of azithromycin excretion into human breast milk. MYZAT should only be used in lactating women where adequate alternatives are not available.

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

System organ class Frequency Side effects Infections and Infestations Less Frequent Unknown 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 Less Frequent Unknown Leukopenia, Neutropenia, Eosinophilia. Thrombocytopenia, Haemolytic anaemia Immune System Disorders Less Frequent Unknown Angioedema, Hypersensitivity Anaphylactic reaction (see section 4.4) Metabolism and Nutrition Disorders Less Frequent Anorexia Psychiatric Disorders Less Frequent Unknown Nervousness, Insomnia, Agitation Aggression, Anxiety, Delirium, Hallucination Nervous System Disorders Frequent Less Frequent Unknown Headache, Dizziness, Somnolence, Dysgeusia, Paraesthesia. Syncope, convulsion, hypoestheia, Psychomotor hyperactivity, Anosmia, Eye Disorders Unknown Visual impairment, blurred vision Ear and Labyrinth Disorders Less Frequent Unknown Ear disorder, Vertigo Hearing impairment including deafness and/or tinnitus Skin and subcutaneous tissue disorders Less Frequent Unknown Rash, Pruritus, Urticaria, Dermatitis, Dry skin, Hyperhidrosis, Photosensitivity reaction, Acute generalised exanthematous pustulosis (AGEP). Stevens-Johnson syndrome, Toxic epidermal necrolysis, Erythema multiforme Cardiac Disorders Less Frequent Unknown Palpitations Torsades de pointes (see section 4.4), Dysrhythmia (see section 4.4) including ventricular tachycardia, Electrocardiogram QT prolonged (see section 4.4) Vascular Disorders Less Frequent Unknown Hot flush Hypotension Respiratory, thoracic and mediastinal disorders Less Frequent Dyspnoea, Epistaxis Gastrointestinal Disorders Frequent Diarrhoea, Vomiting, Abdominal pain, Nausea Less Frequent Unknown Constipation, Flatulence, Dyspepsia, Gastritis dysphagia, Abdominal distension, Dry mouth, Eructation, Mouth ulceration, Salivary hypersecretion Pancreatitis, Tongue discolouration Hepatobiliary Disorders Less Frequent Unknown Hepatic function abnormal, Jaundice cholestatic Hepatic failure (which has rarely resulted in death) (see section 4.4), Hepatitis fulminant, Hepatic necrosis Musculoskeletal and Connective Tissue Disorders Less Frequent Unknown Osteoarthritis, Myalgia, Back pain, Neck pain Arthralgia Renal and urinary disorders Less Frequent Unknown Dysuria, Renal pain Renal failure acute, Nephritis interstitial Reproductive system and breast disorders Less Frequent Metrorrhagia, Testicular disorder General disorders and administration site conditions Less Frequent Oedema, Asthenia, Malaise, Fatigue, Face oedema, Chest pain, Pyrexia, Pain, Peripheral oedema Investigations Frequent Less Frequent Lymphocyte count decreased, Eosinophil count increased, Blood bicarbonate decreased, Basophils increased, Monocytes increased, Neutrophils increased 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, Hematocrit decreased, Bicarbonate increased abnormal sodium. Injury and poisoning Less Frequent Post procedural complication 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 via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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. General supportive measures are indicated.