Clarithromycin 250 Mg/500 Mg Film-Coated Tablets

CLARITHROMYCIN 250 mg AUSTELL tablets and CLARITHROMYCIN 500 mg AUSTELL tablets 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 caused by S. pneumonia, M. pneumonia, M. catarrhalis, or H. influenzae.
• Upper respiratory tract infections such as pharyngitis and sinusitis due to S. pyogenes.
• Mild to moderately severe acute otitis media due to S. pneumoniae, M. catarrhalis and H. influenza.
• Skin and soft tissue infections such as folliculitis, cellulitis or erysipelas due to S. aureus.
• Eradication of Helicobacter pylori when used in combination with a proton pump inhibitor and another antibiotic to decrease recurrence of duodenal ulcer.

Posology

DOSAGE AND DIRECTIONS FOR USE

Adults and children older than 12 years: 250 mg twice daily. In more severe infections, the dosage may be increased to 500 mg twice daily.

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 CLARITHROMYCIN AUSTELL tablets in combination with proton - pump inhibitors other than omeprazole has not been established.

Concomitant use of ritonavir: The metabolism of CLARITHROMYCIN AUSTELL is inhibited. No dosage reduction of CLARITHROMYCIN AUSTELL is needed in patients with normal renal function. Patients with renal function impairment require a reduction in the dosage of CLARITHROMYCIN AUSTELL as follows:

• Creatinine clearance 30 to 60 mL/min u2013 Reduce dose by 50 %
• Creatinine clearance < 30 mL/min u2013 Reduce dose by 75 %.

Do not exceed a dose of 1 g/day during concurrent administration of CLARITHROMYCIN AUSTELL with ritonavir. It has been suggested that other HIV - protease inhibitors and non - nucleotide reverse transcriptase inhibitors may have a similar effect on CLARITHROMYCIN AUSTELL.

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 CLARITHROMYCIN AUSTELL tablets for more than 12 weeks. CLARITHROMYCIN AUSTELL tablets should be used in conjunction with other antimycobacterial agents. CLARITHROMYCIN AUSTELL tablets may be taken with or without meals.

Special populations

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

Paediatric population: The safety and efficacy in infants under 6 months have not been established. This formulation is not suitable for use in children less than 12 years of age.

Method of administration: CLARITHROMYCIN AUSTELL tablets is for oral use.

• Hypersensitivity to clarithromycin, other macrolide antibiotics or to any of the excipients listed in section 6.1.
• Concomitant administration of CLARITHROMYCIN AUSTELL tablets with astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation and cardiac dysrhythmias including ventricular tachycardia, fibrillation and torsades de pointes (see section 4.5).
• Clarithromycin should not be given to patients with a history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).
• Porphyria.
• Pregnancy (see section 4.6)
• Concomitant administration of CLARITHROMYCIN AUSTELL tablets with ergotamine or dihydroergotamine as this may result in ergot toxicity characterised by vasospasm and ischaemia of the extremities and central nervous system resulting in permanent tissue damage.
• HMG - CoA reductase inhibitors (statins) such as lovastatin or simvastatin taken with clarithromycin may increase the risk of rhabdomyolysis. Treatment with statins should be discontinued during CLARITHROMYCIN AUSTELL treatment (see section 4.4 and 4.5).
• Colchicine is contraindicated in patients on CLARITHROMYCIN AUSTELL with renal or hepatic impairment who are taking P - glycoprotein inhibitors or a strong CYP34A inhibitor (see section 4.4 and 4.5).
• Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5).
• Concomitant administration of clarithromycin and lomitapide is contraindicated (see section 4.5).
• Concomitant administration with ticagrelor or ranolazine is contraindicated.
• Clarithromycin should not be given to patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval).
• Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
• Concomitant administration with atypical antipsychotics that are predominantly metabolised through the CYP3A4 pathway, for example quetiapine, cariprazine and aripiprazole is contraindicated (see section 4.5).

Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug - resistant organisms. The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6).

Liver function impairment: Clarithromycin is principally metabolised by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function. No dosage adjustment is required in patients with hepatic function impairment unless there is also concurrent severe renal function impairment. Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. 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. Isolated cases of increased serum creatinine have been reported but an association with CLARITHROMYCIN AUSTELL tablets has not been established. Treatment with CLARITHROMYCIN AUSTELL tablets should be discontinued if any signs of hepatic dysfunction develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Renal function impairment: Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment (see section 4.2). The elimination of CLARITHROMYCIN 250 mg AUSTELL tablets and CLARITHROMYCIN 500 mg AUSTELL tablets is reduced in patients with renal function impairment, especially those with a creatinine clearance of < 30 mL/min.

Clostridioides difficile - associated diarrhoea (CDAD): Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life - threatening. Clostridioides difficile - associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents 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 agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed, and adequate treatment initiated. Medicines inhibiting peristalsis should be avoided.

Colchicine: There have been post - marketing reports of colchicine toxicity with concomitant use of clarithromycin 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).

Triazolobenzodiazepines: Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5). Concomitant administration of clarithromycin and oral midazolam is contraindicated.

Cardiovascular Events: Prolongation of the QT interval, reflecting effects on cardiac repolarisation imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including clarithromycin (see section 4.8). Due to increased risk of QT prolongation and ventricular arrhythmias (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 arrhythmia (see section 4.3). Carefully consider the balance of benefits and risks before prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).

Furthermore, clarithromycin 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 medicinal products 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 arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing clarithromycin.

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community - acquired pneumonia. In hospital - acquired pneumonia, clarithromycin 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 beta u2013 lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the medicine 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, and toxic epidermal necrolysis and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), treatment with clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Atypical antipsychotics: Concomitant administration of clarithromycin and atypical antipsychotics that are metabolised through the CYP3A4 pathway, for example quetiapine, cariprazine and aripiprazole are contraindicated (see section 4.3 and 4.5).

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

• Astemizole, cisapride, pimozide, domperidone 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 arrhythmia, ventricular tachycardia, ventricular fibrillation and torsade de pointes. Fatalities have occurred. The most likely cause is the inhibition of metabolism of these medicines by CLARITHROMYCIN AUSTELL tablets.
• 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 torsades de pointes (see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two - to - three - 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 co - administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these ergot alkaloids is contraindicated (see section 4.3).
• Oral midazolam: When midazolam was co - administered together with clarithromycin tablets (500 mg twice per day), the AUC of midazolam increased 7 - fold following the administration of oral midazolam. The concomitant administration of clarithromycin 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 clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
• Atypical antipsychotics: Concomitant administration of clarithromycin 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.
• Lomitapide: Concomitant administration of clarithromycin with lomitapide is contraindicated due the potential for markedly increased transaminases (see section 4.3).
• Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P - glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine (see section 4.3 and 4.4).

Pregnancy: Safety and efficacy in pregnancy has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations with use of macrolides including clarithromycin during pregnancy provide conflicting results. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks.

Breastfeeding: Safety and efficacy in lactation has not been established. CLARITHROMYCIN AUSTELL tablets is excreted in the breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7 % of the maternal weight - adjusted dose of clarithromycin.

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

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

a) Summary of the safety profile: The most frequent and common adverse reactions related to clarithromycin therapy for both adult and paediatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8). There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

b) Tabulated list of adverse reactions: The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with clarithromycin.

System Organ Class Frequency Frequent Less Frequent Not known Infections and infestations Cellulitis 1, candidiasis, gastroenteritis 2, infection 3, vaginal infection Pseudomembranous colitis, erysipelas Blood and lymphatic system disorders Leukopenia, neutropenia 4, thrombocythemia 3, eosinophilia 4 Agranulocytosis, thrombocytopenia Immune system disorders Anaphylactoid reaction 1, Hypersensitivity Anaphylactic reaction, angioedema Metabolism and nutrition disorders Anorexia, decreased appetite, hypoglycaemia Psychiatric disorders Insomnia Anxiety, nervousness 3 Psychotic disorder, confusional state 5, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania Nervous system disorders Dysgeusia, headache, taste perversion Loss of consciousness 1, dyskinesia 1, dizziness, somnolence 5, tremor, convulsions. Convulsion, ageusia, parosmia, anosmia, paraesthesia Ear and labyrinth disorders Vertigo, hearing loss, tinnitus Deafness Cardiac disorders Cardiac arrest 1, atrial fibrillation 1, electrocardiogram QT prolongation, extrasystoles 1, palpitations Torsades de pointes, ventricular tachycardia, ventricular fibrillation Vascular disorders Vasodilation 1 Haemorrhage Respiratory, thoracic and mediastinal disorders Asthma 1, epistaxis 2, pulmonary embolism 1 Gastrointestinal disorders Nausea, vomiting, abdominal pain, abnormal taste, diarrhoea, dyspepsia Oesophagitis 1, gastrooesophageal reflux disease 2, gastritis, proctalgia 2, glossitis, stomatitis, oral candidiasis, pseudomembranous colitis (abdominal cramps or pain, tenderness, severe, watery diarrhoea which may also be bloody, fever), constipation, dry mouth, eructation, flatulence Pancreatitis acute, tongue discolouration, tooth discolouration Hepatobiliary disorders Liver function test abnormal Cholestasis 4, hepatitis 4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma - glutamyl transferase increased 4, increase in liver enzymes Hepatitis (with or without jaundice), hepatocellular and/or cholestatic, pancreatitis Skin and subcutaneous tissue disorders Rash, hyperhidrosis Dermatitis bullous 1, pruritus, urticaria, rashmaculo - papular 3 Severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens - Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS)), acne Musculoskeletal and connective tissue disorders Muscle spasms 3, musculoskeletal stiffness 1, myalgia 2 Rhabdomyolysis 2,6, myopathy Renal and urinary disorders Blood creatinine increased 1, blood urea increased 1 Renal failure, nephritis interstitial General disorders and administration site conditions Injection sitephlebitis 1, injection site pain 1, injection site inflammation 1 Malaise 4, pyrexia 3, asthenia, chest pain 4, chills 4, fatigue 4 Investigations Albumin globulin ratio abnormal 1, blood alkaline phosphatase increased 4, blood lactate dehydrogenase increased 4 International normalised ratio increased, prothrombin time prolonged, urine colour abnormal Other Allergic reactions, anaphylaxis 1 ADRs reported only for the Concentrate for Solution for Infusion formulation 2 ADRs reported only for the Extended - Release Tablets formulation 3 ADRs reported only for the Granules for Oral Suspension formulation 4 ADRs reported only for the Immediate - Release Tablets formulation 5, 6 See section c) * Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to medicine exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.

Symptoms of overdose: Ingestion of large amounts of CLARITHROMYCIN AUSTELL tablets can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia. Allergic reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed medicine and supportive measures.

Treatment of overdosage: Treatment is symptomatic and supportive. CLARITHROMYCIN AUSTELL tablets is not expected to be appreciably affected by haemodialysis or dialysis.