Zatyp 500 mg FC Tablet

Adults: ZATYP TABLETS are 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. In sexually transmitted diseases in men and women, ZATYP TABLETS are indicated in the treatment of uncomplicated genital infections due to Chlamydia trachomatis and chancroid due to Haemophilus ducreyi.

Children 1 year and over: ZATYP TABLETS are indicated for pharyngitis/tonsillitis and otitis media caused by susceptible organisms in children over 45 kg.

ZATYP TABLETS: ZATYP TABLETS should be administered as a single daily dose with or without food. ZATYP TABLETS should be taken whole. 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

Use in patients with hepatic impairment: ZATYP TABLETS is contraindicated in patients with severe hepatic impairment (see Section 4.3)

Use in the elderly: 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).

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

Method of administration: Oral

ZATYP TABLETS is contraindicated in patients with a known hypersensitivity to azithromycin, erythromycin, any of the macrolide antibiotics, or to any excipient listed under section 6.1. Because of the theoretical possibility of ergotism, ZATYP TABLETS and ergot derivatives should not be co-administered. Use in hepatic impairment: As the liver is the principal route of excretion of ZATYP TABLETS, it should not be prescribed in patients with hepatic diseases.

Hypersensitivity: Serious allergic reactions, including angioedema and anaphylaxis and dermatologic reactions including Stevens-Johnson Syndrome, Acute Generalised Exanthematous Pustulosis (AGEP), Drug with Eosinophilic and systemic symptoms (DRESS) and toxic epidermal necrolysis have been reported. Some of these reactions with ZATYP TABLETS have resulted in recurrent symptoms and required a longer period of observation and treatment. If an allergic reaction occurs, ZATYP TABLETS should be discontinued and appropriate therapy should be instituted. Medical practitioners 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. ZATYP TABLETS 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 ZATYP TABLETS 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 is no data concerning the possibility of an interaction between ergot and ZATYP TABLETS. However, because of the theoretical possibility of ergotism, ZATYP TABLETS 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 ZATYP TABLETS.

Clostridium difficile -associated diarrhoea: Clostridium difficile -associated diarrhoea (CDAD) due to overgrowth of Clostridium difficile in the gut, has been reported with use of ZATYP TABLETS, and may range in severity from mild diarrhoea to fatal colitis. If CDAD is suspected or confirmed, ongoing ZATYP TABLETS 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 ZATYP TABLETS was observed (see: section 5.2). 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 ZATYP TABLETS (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 medicines; 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 ZATYP TABLETS in children less than 1 year have not been established.
• Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicine. Contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus.

Ergot derivatives: Because of the theoretical possibility of ergotism, ZATYP TABLETS 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 1200 mg ZATYP TABLETS did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of ZATYP TABLETS were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in C max (18 %) of ZATYP TABLETS was observed.

Indinavir: Co-administration of a single dose of 1200 mg ZATYP TABLETS 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 ZATYP TABLETS 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 ZATYP TABLETS (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 although a dose adjustment of ZATYP TABLETS is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of ZATYP TABLETS 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 azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 24 %. In patients receiving both ZATYP TABLETS and antacids, the medicines should not be taken simultaneously. ZATYP 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 ZATYP TABLETS had no effect on the pharmacokinetics of ZATYP TABLETS.

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

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 AUC0 -5 was 5 107 and 4 210 u03bcgh/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 ZATYP TABLETS 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 ZATYP TABLETS 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 ZATYP TABLETS 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 ZATYP TABLETS, 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 ZATYP TABLETS and warfarin. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when ZATYP TABLETS is used in patients receiving coumarin-type oral anticoagulants.

The safety and efficacy of ZATYP TABLETS 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, ZATYP TABLETS 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 characterized the pharmacokinetics of azithromycin excretion into human breast milk. ZATYP TABLETS 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 ZATYP TABLETS. These side effects may affect a patientu2019s ability to drive or operate machinery.

a. Tabulated list of adverse reactions

System organ class ZATYP TABLETS Side effects

Blood and lymphatic system disorders Less frequent Neutropenia

Immune system disorders Less frequent Angioedema

Eye disorders Less frequent Abnormal vision

Ear and labyrinth disorders Less frequent Hearing impairment including hearing loss, deafness and/or tinnitus

Cardiac disorders Less frequent Chest pains, dysrhythmias including ventricular tachycardia, palpitations, QT prolongation, Torsade de Pointes

Gastrointestinal disorders Frequent Abdominal discomfort (pain/ cramps), diarrhoea, nausea Less frequent Flatulence, loose stools, vomiting Less frequent Malaena

Hepatobiliary disorders Frequent Less frequent Abnormal liver function

Skin and subcutaneous tissue disorders Less frequent Rash Less frequent Allergic reactions

Renal and urinary disorders Less frequent Nephritis

General disorders and administration site conditions Frequent In post-marketing experience, the following additional undesirable effects have been reported with frequency unknown:

System organ class ZATYP TABLETS Side effects

Infections and infestations Moniliasis, vaginitis

Blood and lymphatic system disorders Thrombocytopenia

Immune system disorders Anaphylaxis

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

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 to SAHPRA via The u20186.04 Adverse Drug Reactions Reporting Formu2019. Found 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 over dosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea. General supportive measures are indicated.