Klarizon 250 or 500 mg FC tablets.

KLARIZON is indicated for the treatment of the following mild to moderate severe infections caused by susceptible organisms:

• Lower respiratory tract infections such as bronchitis and pneumonia.
• Upper respiratory tract infections such as pharyngitis and sinusitis.
• Mild to moderately severe acute otitis media due to S. pneumoniae, M. catarrhalis and H. influenzae.
• Skin and soft tissue infections such as folliculitis, cellulitis or erysipelas.
• Eradication of Helicobacter pylori when used in combination with a proton pump inhibitor and another antibiotic to decrease recurrence of duodenal ulcer.

Posology

Adults: 250 mg twice daily. In more severe infections, the dosage may be increased to 500 mg twice daily.

Renal impairment

Creatinine clearance (< 30 mL/min): Reduce dose by half i.e., 250 mg once daily or 250 twice daily for severe infections. Limit the duration of treatment to 14 days.

Eradication of H.pylori

Adults: 500 mg twice daily, in combination with an appropriate antibiotic and an acid lowering agent, for 7 to 10 days. The safety and efficacy of KLARIZON in combination with proton-pump inhibitors other than omeprazole has not been established.

Atypical mycobacterial infections (MAC) in HIV patients

Adults: 500 mg twice daily. Treatment of disseminated MAC infections in AIDS patients should continue as long as clinical and microbiological benefit is demonstrated. A decrease in efficacy has been noted in patients taking KLARIZON for more than 12 weeks. KLARIZON should be used in conjunction with other antimycobacterial medicines.

Method of administration

For oral administration. KLARIZON may be taken with or without meals.

• Hypersensitivity to clarithromycin or the macrolide antibiotics or to any of the excipients of KLARIZON listed in section 6.1.
• Concomitant administration of KLARIZON with astemizole, cisapride, pimozide, domperidone and terfenadine as this may result in QT prolongation and cardiac dysrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.4 and 4.5).
• Concomitant administration of KLARIZON and ergot alkaloids (e.g., ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see sections 4.4 and 4.5).
• Concomitant administration of KLARIZON and oral midazolam is contraindicated (see section 4.5).
• KLARIZON should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac dysrhythmia, including torsades de pointes. (See section 4.4 and 4.5).
• Concomitant administration with ticagrelor or ranolazine is contraindicated.
• KLARIZON should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).
• Concomitant administration of clarithromycin (e.g., KLARIZON) and atypical antipsychotics that are predominantly metabolised through the CYP3A4 pathway, for example quetiapine, cariprazine, and aripiprazole may result in an increase in plasma levels of these antipsychotics as a result of inhibition which may present a potential for serious adverse reactions (see section 4.5).
• As with other strong CYP3A4 inhibitors, KLARIZON should not be used in patients taking colchicine (see sections 4.4 and 4.5).
• KLARIZON should not be given to patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval).
• KLARIZON should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
• Porphyria.
• Safety and efficacy in infants less than 6 months of age have not been established.

KLARIZON should be used with caution in:

• Clarithromycin as contained in KLARIZON is principally metabolised by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function.
• Caution should also be exercised when administering KLARIZON to patients with moderate to severe renal impairment (see section 4.2).
• Renal function impairment (severe) - The elimination of KLARIZON is reduced in patients with renal function impairment, especially those with a creatinine clearance of < 30 mL/min. The dose of KLARIZON should be halved or the dosing interval doubled in patients with a creatinine clearance of < 30 mL/min.
• Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. Treatment with KLARIZON should be discontinued if any signs of hepatic dysfunction develop. Hepatic dysfunction is usually reversible but may be severe. In rare instances, hepatic failure with fatal outcome has been reported, usually associated with other serious underlying diseases and/or concomitant medicines. 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. Cases of increased serum creatinine have been reported but an association with KLARIZON has not been established.
• Rhabdomyolysis has been reported with concomitant use of KLARIZON and the HMGCoA reductase inhibitors e.g., simvastatin and lovastatin (see section 4.3 and 4.5).
• Rifabutin and rifampicin - May decrease serum concentration of KLARIZON by > 50 %. Co-administration has been reported to cause a higher incidence of uveitis compared to rifabutin alone (see section 4.5).
• Theophylline u2013 The area under the plasma concentration-time curve is increased. Monitoring of theophylline serum concentrations is recommended (see section 4.5).
• Cross-resistance between KLARIZON and other macrolides, lincomycin and clindamycin have been reported.
• Pseudomembranous colitis has been reported with KLARIZON and it may range in severity from mild to life-threatening. Clostridioides difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial medicines including KLARIZON 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 KLARIZON 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 with concomitant use of KLARIZON and colchicine have been reported during post-marketing experience, especially in the elderly, some of which occurred in patients with renal insufficiency. Fatalities have been reported in such patients (see section 4.5). Concomitant administration of KLARIZON and colchicine is contraindicated (see section 4.3).
• Caution is advised regarding concomitant administration of KLARIZON and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5). Concomitant administration of KLARIZON and midazolam is contraindicated (see section 4.3).

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 KLARIZON (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 electrolyte disturbances such as hypomagnesaemia or hypokalaemia; and in patients with a history of QT prolongation or ventricular cardiac dysrhythmia (see section 4.3).
• Furthermore, KLARIZON should be used with caution in the following: Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia. Patients concomitantly taking other medicines associated with QT prolongation other than those which are contraindicated. 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 dysrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin as contained in KLARIZON. Consideration of these findings should be balanced with treatment benefits when prescribing KLARIZON.

Pneumonia

• In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing KLARIZON for community-acquired pneumonia. In hospital-acquired pneumonia, KLARIZON should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity

• These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where betau2013lactam antibiotics cannot be used (e.g., allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

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)), clarithromycin therapy e.g., KLARIZON should be discontinued immediately and appropriate treatment should be urgently initiated.

KLARIZON 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 KLARIZON with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing KLARIZON with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy.
• In situations where the concomitant use of KLARIZON 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).

Concomitant use of KLARIZON with:

• Astemizole, cisapride, domperidone, pimozide and terfenadine: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see section 4.3). Have resulted in cardiac dysrhythmias, including QTc-interval prolongation, ventricular dysrhythmia, ventricular tachycardia, ventricular fibrillation and torsades de pointes. Fatalities have occurred. The most likely cause is the inhibition of metabolism of these medicines by KLARIZON. Concurrent use is contraindicated. See section 4.3.
• Macrolides such as KLARIZON have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac dysrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in 2- to 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: Post-marketing reports indicate that concomitant use of KLARIZON with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Permanent tissue damage may result.
• Oral Midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and KLARIZON is contraindicated (see section 4.3).

HMG-CoA Reductase Inhibitors (statins): Concomitant use of KLARIZON with lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively metabolised by CYP3A4 and concomitant treatment with KLARIZON increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin e.g., KLARIZON concomitantly with these statins. If treatment with KLARIZON cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Caution should be exercised when prescribing KLARIZON with statins. In situations where the concomitant use of KLARIZON 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.

Effects of other medicines on KLARIZON: Medicines that are inducers of CYP3A (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin 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 clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and KLARIZON resulted in an increase in rifabutin and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following medicines are known or suspected to affect circulating concentrations of clarithromycin; KLARIZON dosage adjustment 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 clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH- clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of KLARIZON and enzyme inducers.
• Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH- clarithromycin, were increased. Because 14-OH- clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore, alternatives to KLARIZON should be considered for the treatment of MAC.
• Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (C min) and area under the curve (AUC) of 33 % and 18 % respectively. Steady state concentrations of the active metabolite 14-OH- clarithromycin were not significantly affected by concomitant administration of fluconazole. No KLARIZON dose adjustment is necessary.
• Ritonavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin C max increased by 31 %, C min increased 182 % and AUC increased by 77 % with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50 %. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75 %. Doses of KLARIZON greater than 1 g/day should not be co-administered with ritonavir. Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions).

Pregnancy

Safety and efficacy in pregnancy has not been established.

Breastfeeding

Safety and efficacy for using during breastfeeding of infants has not been established. KLARIZON is excreted into human breast milk in small amounts.

Fertility

In the rat, fertility studies have not shown any evidence of harmful effects.

KLARIZON could have a minor influence on the patientu2019s ability to drive and use machines and the effect on the individual should be established before driving or using machinery.

Tabulated list of adverse reactions

Blood and lymphatic system disorders

• Less frequent: Leukopenia, neutropenia, eosinophilia.
• Frequency unknown: Agranulocytosis, thrombocytopenia.

Infections and infestations

• Less frequent: Candidiasis, gastroenteritis, infection (fever and chills, cough or hoarseness, lower back or side pain, painful or difficult urination), vaginal infection.
• Frequency unknown: Pseudomembranous colitis (abdominal cramps or pain, tenderness, severe, watery diarrhoea which may also be bloody, fever), erysipelas, oral candidiasis.

Immune system disorders

• Less frequent: Hypersensitivity reactions, anaphylaxis.
• Frequency unknown: Anaphylactic reaction, angioedema.

Metabolism and nutrition disorders

• Less frequent: Anorexia, decreased appetite.

Psychiatric disorders

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

Nervous system disorders

• Frequent: Headache, dysgeusia.
• Less frequent: Dizziness, somnolence, tremor.
• Frequency unknown: Convulsions, ageusia, parosmia, anosmia, paraesthesia.

Ear and labyrinth disorders

• Less frequent: Vertigo, tinnitus, impaired hearing.
• Frequency unknown: Deafness.

Eye disorders

• Frequency unknown: Visual impairment, blurred vision.

Cardiac disorders

• Less frequent: QT prolongation, palpitations.
• Frequency unknown: Torsades de pointes, ventricular tachycardia, ventricular fibrillation and dysrhythmias.

Vascular disorders

• Frequency unknown: Haemorrhage.

Endocrine disorders

• Frequency unknown: Hypoglycaemia.

Respiratory, thoracic and mediastinal disorders

• Less frequent: Epistaxis.

Gastrointestinal disorders

• Frequent: Nausea, vomiting, abdominal pain, diarrhoea, dyspepsia.
• Less frequent: Abnormal taste sensation, flatulence, gastrointestinal disturbances, gastroesophageal reflux disease, gastritis, proctalgia, glossitis, stomatitis, abdominal distension, constipation, dry mouth, eructation.
• Frequency unknown: Tongue discolouration, tooth discolouration, pancreatitis acute.

Hepato-biliary disorders

• Frequent: Abnormal liver function test.
• Less frequent: Cholestasis, hepatitis, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma glutamyltransferase.
• Frequency unknown: Hepatic failure, jaundice hepatocellular.

Skin and subcutaneous tissue disorders

• Frequent: Rash, hyperhidrosis.
• Less frequent: Pruritus, rash maculo-papular, urticaria.
• Frequency unknown: Mild skin eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis, severe cutaneous adverse reactions (SCAR) (e.g., acute generalised exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), acne.

Musculoskeletal and connective tissue disorders

• Less frequent: Muscle spasms, myalgia.
• Frequency unknown: Rhabdomyolysis, myopathy.

Renal and urinary disorders

• Frequency unknown: Nephritis interstitial, renal failure.

General disorders and administration site conditions

• Less frequent: Malaise, asthenia, chest pain, chills, fatigue.

Investigations

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

Description of selected adverse reactions

In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4). There have been post-marketing reports of medicine interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5). There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g., suspension) or another antibiotic.

Special population: Adverse Reactions in immunocompromised patients (see section Other special populations).

Paediatric population: Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Other special populations: Immunocompromised patients: In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin 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 of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, hearing disturbance, AST and ALT elevations, elevated BUN levels and abnormally low white blood cell and platelet counts. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1 000 mg and 2 000 mg but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4 000 mg of clarithromycin.

(See section 4.4)

Symptoms of overdose

Ingestion of large amounts of KLARIZON can be expected to produce gastrointestinal symptoms. Allergic reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures.

Treatment of overdose

Treatment is symptomatic and supportive. KLARIZON serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.