Claribax 500 mg FC tablets

u2022 Lower respiratory tract infections, e.g. bronchitis, pneumonia.

u2022 Upper respiratory tract infections, e.g. pharyngitis, sinusitis.

u2022 Skin and soft tissue infections, e.g. folliculitis, cellulitis, erysipelas.

u2022 Eradication of Helicobacter pylori ( H. pylori) , resulting in decreased recurrence of duodenal ulcer when used in combination with a proton- pump inhibitor to suppress acid secretion and another antibiotic. CLARIBAX has been used in treatment regimens which include CLARIBAX plus amoxicillin and omeprazole; CLARIBAX plus tinidazole and omeprazole; and CLARIBAX plus tetracycline and bismuth subsalicylate.

u2022 There is some evidence that disseminated and localised mycobacterial infections in human immunodeficiency virus-positive (HIV-positive) adults, due to Mycobacterium avium or Mycobacterium intracellulare respond to CLARIBAX. Based on bacteriological results, CLARIBAX should be used in conjunction with other antimycobacterials. Localised infections due to Mycobacterium chelonae and Mycobacterium kansasii have responded to CLARIBAX to a lesser extent.

Adults and children older than 12 years

The recommended dosage of CLARIBAX is one 250 mg tablet twice daily. In more severe infections, the dosage can be increased to 500 mg twice daily.

Renal impairment

In patients with renal impairment with creatinine clearance of less than 30 mL/min, the dosage of CLARIBAX should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

Eradication of H. pylori : To decrease recurrence of duodenal ulcer in combination with a proton-pump inhibitor and another antibiotic: CLARIBAX 500 mg twice daily in combination with amoxicillin 1 000 mg twice daily and omeprazole 20 mg daily for 7 u2013 10 days.

Dosage in HIV patients with mycobacterial infections: The recommended treatment for adults with disseminated or localised mycobacterium infections ( M. avium, M. intracellulare, M. chelonae, M. kansasii ) is 500 mg twice daily.

Treatment of disseminated Mycobacterium avium complex infections in acquired immunodeficiency disease (AIDS) patients should continue as long as clinical and microbiological benefit is demonstrated. A decrease in efficacy has been noted in patients on treatment exceeding 12 weeks. CLARIBAX should be used in conjunction with other antimycobacterial medicines.

Treatment of other non-tuberculous mycobacterial infections should continue at the discretion of the physician.

Paediatric population

CLARIBAX should not be used in children younger than 12 years.

Method of administration

Oral.

u2022 Hypersensitivity to clarithromycin, other macrolide antibacterial medicine or to any of the excipients listed in section 6.1.

u2022 Concomitant administration of clarithromycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine), as this may result in ergot toxicity (see section 4.5).

u2022 Concomitant administration of clarithromycin and oral midazolam (see section 4.5).

u2022 Concomitant administration of clarithromycin and any of the following drugs: astemizole, cisapride, domperidone, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsadeu2019s de pointes (see section 4.4 and 4.5).

u2022 Concomitant administration with ticagrelor or ranolazine.

u2022 Concomitant administration with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).

u2022 As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients taking colchicine (see sections 4.4 and 4.5).

u2022 Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsadeu2019s de pointes (see sections 4.4 and 4.5).

u2022 Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).

u2022 Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

u2022 Concomitant administration of CLARIBAX and atypical antipsychotics that are predominantly metabolised through the CYP3A4: quetiapine, cariprazine and aripiprazole.

Helicobacter pylori infections

Use of any antimicrobial therapy, such as CLARIBAX, to treat H. pylori infection may select for medicine-resistant organisms.

Hepatic impairment

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. Cases of fatal hepatic failure have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicines. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Renal impairment

Caution is advised in patients with moderate to severe renal impairment taking CLARIBAX.

Pseudomembranous colitis and Clostridium difficile-associated diarrhoea

Pseudomembranous colitis has been reported and may range in severity from mild to life threatening. Clostridium difficile -associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial medicines including CLARIBAX, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial medicines alters the normal flora of the colon, which may lead to overgrowth of C. difficile . 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 medicines. Therefore, discontinuation of CLARIBAX therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Medicines inhibiting peristalsis should be avoided.

Colchicine toxicity

There have been post-marketing reports of colchicine toxicity with concomitant use of CLARIBAX and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of CLARIBAX and colchicine is contraindicated.

Benzodiazepine medicines

Caution is advised regarding concomitant administration of CLARIBAX and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5).

Cardiovascular events

Prolongation of the QT interval, reflecting effects on cardiac repolarisation imparting a risk of developing cardiac dysrhythmia and Torsades de Pointes, have been seen in patients treated with macrolides including CLARIBAX (see section 4.8). Due to increased risk of QT prolongation and ventricular dysrhythmias (including Torsades de Pointes), the use of clarithromycin is contraindicated in patients taking any of astemizole, cisapride, domperidone, pimozide and terfenadine; in patients who have hypokalaemia; and in patients with a history of QT prolongation or ventricular cardiac arrhythmia (see section 4.3).

Caution is advised with the use of CLARIBAX in the following patients:

• Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.
• Patients with hypomagnesaemia.
• Patients concomitantly taking other medicines associated with QT prolongation other than those which are contraindicated.

Variable results have been obtained from epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides. A rare short-term risk of dysrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides have been identified in some observational studies. These findings must be taken into consideration when prescribing CLARIBAX.

Pneumonia

Considering the emerging resistance of Streptococcus pneumoniae to macrolide antibiotics, sensitivity testing is essential when prescribing CLARIBAX for the treatment of community-acquired pneumonia. In hospital- acquired pneumonia, CLARIBAX should be combined with additional and appropriate antibiotics.

Skin and soft tissue infections or mild to moderate severity

Staphylococcus aureus and Staphylococcus pyogenes are the predominant pathogens causing skin and soft tissue infections. Both of these pathogens may be resistant to macrolide antibiotics and sensitivity testing is therefore advised before prescribing CLARIBAX. In cases where beta-lactam antibiotics cannot be used (e.g., allergy), other antibiotics, such as clindamycin may be the first choice. Currently, macrolide antibiotics are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum , acne vulgaris, erysipelas and in situations where penicillin treatment cannot be used.

Hypersensitivity reactions

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS)), CLARIBAX therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Cytochrome P3A4 (CYP3A4) inducing medicines

CLARIBAX should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking CLARIBAX and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot, be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see section 4.5).

Hypoglycaemic medicines (oral and insulin)

Clinically significant hypoglycaemia may result from the concomitant use of CLARIBAX and oral hypoglycaemic medicines (such as sulphonylureas) or insulin. Careful monitoring of glucose levels is recommended (see section 4.5).

Oral anticoagulant medicines

There is a risk of serious haemorrhage and significant elevations in International Normalised Ratio (INR) and prothrombin time when CLARIBAX is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving CLARIBAX and oral anticoagulants concurrently.

Resistance and superinfections

Long-term use:

Long-term use may result in colonisation with increased numbers of non- susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

Cross resistance

Attention should also be paid to the possibility of cross resistance between CLARIBAX and other macrolide medicines, as well as lincomycin and clindamycin.

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:

Astemizole, cisapride, domperidone, pimozide, and terfenadine

Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsadeu2019s de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see section 4.3).

Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsadeu2019s de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in 2 - 3 - fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Ergot alkaloids

There have been post-marketing reports indicating acute ergot toxicity characterised by vasospasm and ischaemia of the extremities and other tissues (including the central nervous system), following the concomitant use with ergotamine or dihydroergotamine. Concomitant administration of CLARIBAX and ergot alkaloids is contraindicated (see section 4.3).

Oral midazolam

A 7-fold increase in the area under the curve (AUC) of midazolam has been reported following the co-administration of CLARIBAX with oral midazolam. The concomitant use of CLARIBAX and oral midazolam is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see 4.3) as these Statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking CLARIBAX concomitantly with these statins. If treatment with CLARIBAX cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing CLARIBAX with statins. In s situations where the concomitant use of CLARIBAX with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (such as fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Effects of other medicines on CLARIBAX

CYP3A inducing medicines: Medicines that are inducers of CYP3A (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St Johnu2019s wort) may induce the metabolism of CLARIBAX. This may result in sub-therapeutic levels of CLARIBAX leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by CLARIBAX (see also the relevant product information for the CYP3A4 inducer administered). There are reports of an increase in rifabutin, and decrease in CLARIBAX serum levels, together with an increased risk of uveitis following the co-administration of CLARIBAX and rifabutin.

Medicines affecting circulating concentrations of CLARIBAX

The following medicines are known or suspected to affect circulating concentrations of CLARIBAX (dosage adjustment of CLARIBAX or consideration of alternative treatments may be required): Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine: Strong inducers of the cytochrome P450 metabolism system, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of CLARIBAX and thus lower the plasma levels of CLARIBAX, while increasing those of 14-hydroxyclarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-hydroxyclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of CLARIBAX and enzyme inducers.

Etravirine: There have been reports of a decrease in exposure of CLARIBAX following the co-administration with etravirine, while the concentrations of the active metabolite, 14-hydroxyclarithromycin increased. 14-hydroxyclarithromycin has reduced activity against Mycobacterium avium complex (MAC) and overall activity against this pathogen may be altered. Alternative therapies for the treatment of MAC should be considered.

Fluconazole: Following the co-administration of CLARIBAX 500 mg twice daily and fluconazole 200 mg daily, studies reported an increase in the mean steady- state minimum CLARIBAX concentration (C min ) and area under the curve (AUC). Steady-state concentrations of the active metabolite 14- hydroxyclarithromycin are not significantly affected. No CLARIBAX dose adjustment is required.

Ritonavir: A pharmacokinetic study has reported a marked inhibition of CLARIBAX metabolism following the concomitant use of CLARIBAX and ritonavir 200 mg, resulting in increased CLARIBAX C max , C min and AUC. The formation of 14-hydroxyclarithromycin is essentially completely inhibited. Due to the large therapeutic window for CLARIBAX, no dosage reduction is required in patients with normal renal function. The following dosage adjustments must be considered for patients with renal impairment: For patients with a creatinine clearance of 30 u2013 60 mL/min, a dose reduction of 50 % CLARIBAX is required. For patients with a creatinine clearance of 1 g/day of CLARIBAX should not be used.

Women of childbearing potential / Contraception in males and females

Concurrent use of CLARIBAX and oral contraceptives decreases the efficacy of the oral contraceptive. Patients should be strongly advised to use an alternative or additional method of contraception while taking this medicine (see section 4.5).

Pregnancy

The safety of CLARIBAX during pregnancy has not been established and the use of CLARIBAX during pregnancy is therefore not advised. Based on various animal studies, including mice, rats, rabbits and monkeys, the possibility of embryofoetal development cannot be excluded.

Breastfeeding

CLARIBAX is excreted into breast milk and should not be used during breastfeeding.

Fertility

No data are available on the effects of CLARIBAX on human fertility.

Side effects such as dizziness, vertigo, confusion and disorientation may occur and impair the ability to drive or operate machines. Caution is advised before driving a vehicle or operating machinery until the effects of CLARIBAX are known.

Summary of safety profile

The most frequent adverse reactions reported are abdominal pain, diarrhoea, nausea, vomiting, and taste perversion. These adverse reactions are generally mild to moderate in severity and are consistant with the known safety profile of macrolide antibiotics. Clinical trials have reported no significant difference in the incidence of these gastrointestinal effects between patients with or without preexisting mycobacterial infections.

The following adverse reactions were reported during clinical trials and post-marketing experience:

System Organ Class Frequency Adverse reaction

Infections and infestations Less frequent Frequency unknown Candidiasis, gastroenteritis, vaginal infection Pseudomembranous colitis, erysipelas

Blood and lymphatic system disorders Less frequent Frequency unknown Leukopenia,neutropenia, eosinophilia Agranulocytosis, thrombocytopenia

Immune system disorders Less frequent Frequency unknown Hypersensitivity Anaphylactic reaction, angioedoema

Metabolism and nutrition disorders Less frequent Anorexia, decreased

Psychiatric disorders Frequent Less frequent Frequency unknown Insomnia Anxiety, nervousness Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania

Nervous system Frequent Dysgeusia, headache,

disorders Less frequent Frequency unknown Somnolence, dizziness, tremor Convulsion, ageusia, parosmia, anosmia, paraesthesia

Ear and labyrinth disorders Less frequent Frequency unknown Vertigo, hearing impairment, tinnitus Deafness

Cardiac disorders Less frequent Frequency unknown Electrocardiogram QT prolongation, palpitations Torsades de Pointes, ventricular tachycardia, ventricular fibrillation

Vascular disorders Frequency unknown Haemorrhage

Respiratory, thoracic and mediastinal disorder Less frequent Epistaxis

Gastrointestinal disorders Frequent Less frequent Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain Gastritis, gastroesophageal reflux disease, proctalgia, stomatitis, glossitis, abdominal distension, constipation, dry mouth, eructation, flatulence

Frequency unknown Acute pancreatitis, tongue discolouration, tooth discolouration

Hepato - biliary disorders Frequent Less frequent Frequency unknown Abnormal liver function test Cholestasis, hepatitis, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyl transferase Hepatic failure, jaundice hepatocellular

Skin and subcutaneous tissue disorders Frequent Less frequent Frequency unknown Rash, hyperhidrosis Urticaria, pruritis, rash maculo - papular Severe cutaneous adverse reactions (SCAR); such as acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis, medicine rash with eosinophilia and systemic symptoms (DRESS), acne

Musculoskeletal and connective tissue disorders Less frequent Frequency unknown Muscle spasms, myalgia Rhabdomyolysis, myopathy

Renal and urinary disorders Frequency unknown Renal failure, nephritis interstitial

General disorders and administration site conditions Less frequent Malaise, pyrexia, asthenia, chest pain, chills, fatigue

Investigations Less frequent Frequency unknown Increased blood alkaline phosphatase, increased blood lactate dehydrogenase Increased international normalised ratio, abnormal prothrombin time prolonged, abnormal urine colour

Description of selected adverse events

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Other special populations

Immunocompromised patients: When studying treatment in AIDS and other immunocompromised patients treated with higher doses over long periods of time for mycobacterial infections, it is often difficult to distinguish adverse events possibly associated with CLARIBAX administration from underlying signs of human immunodeficiency virus (HIV) disease or intercurrent illness.

In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1 000 mg and 2 000 mg were nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) elevations. Additional events, such as dyspnoea, insomnia and dry mouth occurred at a low frequency. The incidences were comparable for patients treated with 1 000 mg and 2 000 mg, but were generally about 3 u2013 4 times as frequent for those patients who received total daily doses of 4 000 mg.

Evaluations of laboratory values were made by analysing values outside the seriously abnormal level (the extreme high or low limit) for the specified test. Based on these criteria, an estimated 2 % u2013 3 % of those patients who received 1 000 mg or 2 000 mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. Elevated blood urea nitrogen levels were also observed in a lower percentage of patients in these two dosage groups.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of CLARIBAX is important. It allows continued monitoring of the benefit/risk balance of CLARIBAX. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms of overdose

Following ingestion of large amounts of CLARIBAX, it is anticipated that gastrointestinal symptoms may occur. The consumption of 8 g clarithromycin in a patient with a history of bipolar disorder resulted in altered mental status, paranoid behaviour, hypokalaemia and hypoxemia.

Management of overdose

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures. CLARIBAX serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.