Mycifor XL 500mg Prolonged Release Tablets

Summary of Product Characteristics Updated 14-Jan-2015 | Forum Products Ltd

1. Name of the medicinal product

Mycifor XL 500mg Prolonged Release Tablets

2. Qualitative and quantitative composition

Each film-coated prolonged release tablet contains 500mg clarithromycin as clarithromycin citrate.

Each tablet contains 293mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged release tablet

Yellow, oblong-shaped, biconvex film-coated tablet

4. Clinical particulars
4.1 Therapeutic indications

Mycifor XL 500mg Prolonged Release Tablets are indicated for treatment of

Lower respiratory tract infections, for example acute and chronic bronchitis and pneumonia

Upper respiratory tract infections, for example sinusitis and pharyngitis

Skin and soft tissue infections (mild to moderate severity), for example folliculitis, cellulitis and erysipelas

Consideration should be given to official guidance on appropriate use of antibacterial agents.

4.2 Posology and method of administration

Adults: The usual recommended dosage is one 500mg prolonged release tablet daily to be taken with food.

In more severe infections, the dosage can be increased to two 500mg prolonged release tablets taken as one dose daily.

The usual duration of treatment is 7 to 14 days.

Children older than 12 years: as for adults.

Children younger than 12 years: Mycifor XL is not suitable for children younger than 12 years. An alternative formulation of clarithromycin suitable for children should be used in this patient population.

Mycifor XL 500mg Prolonged Release Tablets should not be used in patients with renal impairment (creatinine clearance less than 30 ml/min). Clarithromycin immediate release tablets should be used in this patient population. (See 4.3 Contra-indications).

Patients with hepatic impairment: Caution should be exercised when administering Mycifor XL in patients with hepatic impairment (see section 4.4).

4.3 Contraindications

Clarithromycin is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs or any of the excipients.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine (see section 4.5).

Clarithromycin should not be given to patients with a history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CP3A4, (lovastatin or simvastatin), due to the risk of myopathy, including rhabdomyolysis. Treatment with these agents should be discontinued during clarithromycin treatment (see section 4.4).

Colchicine is contraindicated in patients with renal or hepatic impairment who are taking P-glycoprotein or a strong CYP3A4 inhibitor.

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

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

As the dose cannot be reduced from 500mg daily, Mycifor XL 500mg Prolonged Release Tablets are contraindicated in patients with creatinine clearance less than 30 mL/min.

4.4 Special warnings and precautions for use

Clarithromycin is principally excreted by the liver and kidney. Caution should be exercised in administering this antibiotic to patients with impaired hepatic function and moderate to severe renal impairment (see also section 4.3).

Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. 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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Clostridium 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. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Prolonged or repeated use of clarithromycin may result in an overgrowth of non-susceptible bacteria or fungi. If super-infection occurs, clarithromycin should be discontinued and appropriate therapy instituted. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy (see section 4.8).

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). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.3).

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

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesaemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with QT prolongation (see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).

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-lactam 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 (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, DRESS and Henoch-Schonlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

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

HMG-CoA reductase inhibitors: Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 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. Caution should be exercised when prescribing clarithromycin with statins. 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.

Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents and/or insulin can result in significant hypoglycaemia. With certain hypoglycaemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.

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

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

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

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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

Cisapride, pimozide, astemizole and terfenadine

Clarithromycin has been reported to elevate plasma levels of cisapride when taken concomitantly. Increased levels of these drugs may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concurrently (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.

Ergotamine/dihydroergotamine

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3 and section 4.4).

Effect of other medicinal products on clarithromycin

Products that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. Furthermore it might be necessary to monitor the plasma levels of the CYP3A4 inducer, which could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin 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 clarithromycin 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 clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200mg daily and clarithromycin 500mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14(R)-hydroxyclarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200mg every eight hours and clarithromycin 500mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin 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. For patients with moderate renal function (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation, such as clarithromycin immediate release tablets, or clarithromycin sachet, or clarithromycin paediatric suspensions (not all presentations may be marketed).

Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors (see section 4.2).

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, bidirectional pharmacokinetic interactions).

Effects of clarithromycin on other medicinal products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme.

Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been post-marketing reports of torsade de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum concentrations of these medications should also be monitored during clarithromycin therapy.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin. Dose reduction may need to be considered.

Oral anticoagulants (e.g., warfarin, acenocoumarol)

In isolated cases, patients receiving combination therapy with clarithromycin and oral anticoagulants may experience increased pharmacologic effects and even toxic effects of these drugs. International normalized ratio (INR) or Prothrombin times should be carefully monitored while patients are simultaneously receiving clarithromycin and oral anticoagulants.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when coadministered with clarithromycin.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metaboliser population.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolised by CYP3A (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.

There have been post-marketing reports of drug 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.

Omeprazole

Clarithromycin (500mg every 8 hours) was given in combination with omeprazole (40mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89% and 34% respectively, when administered concomitantly with clarithromycin for H. pylori eradication; however the change in the mean 24-hour gastric pH value from 5.2 (omeprazole alone) to 5.7 (omeprazole + clarithromycin) is not considered clinically significant.

Other Interactions

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. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).

Digoxin

Digoxin is a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine

Due to reduced gastrointestinal absorption of zidovudine in the presence of clarithromycin, reduced serum levels of zidovudine were observed in adults during concomitant therapy with clarithromycin and zidovudine. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, patients should observe a 4-hour interval between taking these two drugs. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and valproate

There have been spontaneous or published reports of interactions with CYP3A inhibitors, including clarithromycin, and drugs not thought to be metabolized by CYP3A, including phenytoin and valproate. Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased concentrations have been reported.

Bidirectional pharmacokinetic interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500mg twice daily) with atazanavir (400mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14(R)-hydroxy-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation, such as clarithromycin immediate release tablets, or clarithromycin sachet, or clarithromycin paediatric suspensions (not all presentations may be marketed).

Doses of clarithromycin greater than 1000mg per day should not be co-administered with protease inhibitors (see also section 4.2).

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction: clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state area under the curve (AUC) and maximum concentration (Cmax) values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule (see section 4.5: Ritonavir).

Observations from drug interaction studies done with unboosted saquinavir may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see section above, effect of other medicinal products on clarithromycin).

Verapamil

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.

4.6 Fertility, pregnancy and lactation

Pregnancy and lactation

The safety of clarithromycin during pregnancy and breast feeding of infants has not been established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk. Clarithromycin is excreted into human breast milk.

4.7 Effects on ability to drive and use machines

There are no data on the effect of this product on the driving ability. When driving or using machines, one should take into account that dizziness, vertigo, confusion and disorientation may occur.

4.8 Undesirable effects

a. Summary of the safety profile

The most frequent and common adverse reactions related to clarithromycin for both adult and paediatric populations are abdominal pain, 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 pre-existing mycobacterial infections.

b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended- release tablets and modified-release tablets.

The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.

System Organ Class

Very common (≥1/10)

Common (≥ 1/100, <1/10)

Uncommon (≥1/1000, <1/100)

Not known (cannot be estimated from the available data)

Infections and infestations

cellulitis1, gastroenteritis2, candidiasis, infection3, vaginal infection

pseudomembranous colitis, erysipelas, erythrasma

Blood and the lymphatic system disorders

leukopenia, neutropenia4, eosinophilia4, thrombocythaemia

agranulocytosis, thrombocytopenia

Immune system disorders

anaphylactoid reaction1, hypersensitivity

anaphylactic reaction

Psychiatric disorders

insomnia

Anxiety, nervousness3, screaming

psychiatric disorder, confusional state, depression, hallucination, disorientation, depersonalisation, abnormal dreams and confusion

Metabolism and nutrition disorders

anorexia, decreased appetite

hypoglycaemia6

Vascular disorders

vasodilation

heamorrhage9

Respiratory, thoracic and mediastinal disorders

asthma1, epitaxis2, pulmonary embolism1

General disorders and administration site conditions

Injection site phlebitis1

injection site pain1, injection site inflammation1

pyrexia3, asthenia, chest pain4, chills4, malaise4, fatigue, thirst

Nervous system disorders

dysguesia, headache, taste perversion

loss of consciousness1, dyskinesia1, tremor, dizziness, somnolence

convulsions, aguesia, parosmia, anosmia

Ear and labyrinth disorders

vertigo, hearing impaired, tinnitus

deafness

Cardiac disorders

cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged8, extrasystoles1, palpitations

ventricular tachycardia8, torsade de pointes8

Gastrointestinal disorders

nausea, diarrhoea10, vomiting, abdominal pain, dyspepsia

esophagitis1, gastrooseophageal reflux disease2, gastritis, proctalgia, stomatitis, glossitis, abdominal distention4, constipation, dry mouth, eructation, flatulence, gastrointestinal haemorrhage

pancreatitis acute; tongue discolouration, tooth discolouration

Hepato-biliary disorders

liver function test abnormal

hepatitis4, cholestasis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4

fatal hepatic failure has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic drugs

Skin and subcutaneous tissue disorders

rash, hyperhidrosis

dermatitis bullous1, dry skin, pruritus, urticaria, rash maculopapular3

Stevens-Johnson syndrome5, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne

Musculoskeletal, connective tissue and bone disorders

muscle spams3, musculoskeletal stiffness1, myalgia2

Rhabdomyolysis2, 12, myopathy, exacerbation of symptoms of myasthenia gravis (see section 4.4)

Renal and urinary disorders

blood creatinine increased1, blood urea increased1

Investigations

albumin globulin ratio abnormal1, alkaline phosphatase increased4, blood lactate dehydrogenase increased4

international normalised ration increased9, increased prothrombin time9, urine colour abnormal

1 ADRs reported only for the Powder for Solution for Injection 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, 8, 10, 11, 12 See section a) above

6, 7, 9 See section c) below

c. Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).

A special attention to diarrhoea should be paid as Clostridium 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 (see section 4.4).

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).

As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).

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 colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome (see sections 4.4 and 4.5).

There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin (see section 4.4 and 4.5).

There have been post-marketing reports of drug 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 is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co- administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 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 e).

d. Paediatric populations

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. There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.

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

e. 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 1,000mg and 2,000mg of clarithromycin 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 low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1,000mg and 2,000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4,000mg of clarithromycin.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1,000mg or 2,000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4,000mg daily for all parameters except White Blood Cell.

4.9 Overdose

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal 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. Adverse reactions accompanying overdosage should be treated by gastric lavage and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacological-therapeutical group: Macrolides

ATC Code: J01FA09

Clarithromycin is a semi-synthetic derivative of erythromycin. It exerts its antibacterial action by inhibiting the intracellular protein synthesis of susceptible bacteria. It selectively binds to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for Haemophilus influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

Clarithromycin is usually active against the following organisms in vitro:

Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenza; Haemophilus parainfluenza; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Mycobacterium kansasii; Mycobacterium chelonae; Mycobacterium fortuitum; Mycobacterium intracellularis; Chlamydia pneumoniae.

Anaerobes: Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae and Campylobacter spp.

5.2 Pharmacokinetic properties

The kinetics of orally administered modified-release clarithromycin have been studied in adult humans and compared with clarithromycin 250mg and 500mg immediate release tablets. The extent of absorption was found to be equivalent when equal total daily doses were administered. The absolute bioavailability is approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Based upon the finding of equivalent absorption the following in vitro and in vivo data are applicable to the modified-release formulation.

In vitro: Results of in vitro studies showed that the protein binding of clarithromycin in human plasma averaged about 70 % at concentrations of 0.45 - 4.5μg/mL. A decrease in binding to 41% at 45.0μg/mL suggested that the binding sites might become saturated, but this only occurred at concentrations far in excess of therapeutic drug levels.

In vivo: Clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were found in the liver and lung tissue, where the tissue to plasma ratios reached 10 to 20.

The pharmacokinetic behaviour of clarithromycin is non-linear. In fed patients given 500mg clarithromycin modified-release daily, the peak steady state plasma concentration of clarithromycin and 14 hydroxy clarithromycin were 1.3 and 0.48μg/mL, respectively. When the dosage was increased to 1000mg daily, these steady-state values were 2.4μg/mL and 0.67μg/mL respectively. Elimination half-lives of the parent drug and metabolite were approximately 5.3 and 7.7 hours respectively. The apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at higher doses.

Urinary excretion accounted for approximately 40% of the clarithromycin dose. Faecal elimination accounts for approximately 30%.

5.3 Preclinical safety data

In repeated dose studies, clarithromycin toxicity was related to dose and duration of treatment. The liver was the primary target organ in all species with hepatic lesions seen after 14 days in dogs and monkeys. Systemic exposure levels associated with this toxicity are not known but toxic mg/kg doses were higher than the dose recommended for patient treatment.

Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and in monkeys embryonic loss was seen but only at dose levels which were clearly toxic to the mothers.

No other toxicological findings considered to be of relevance to the dose level recommended for patient treatment have been reported.

6. Pharmaceutical particulars
6.1 List of excipients

Core:

Lactose Monohydrate

Hypromellose

Hypromellose phthalate

Magnesium stearate

Talc

Film-coat:

Lactose monohydrate

Hypromellose

Titanium dioxide E171

Macrogol 4000

Macrogol 400

Talc

Quinoline Yellow Aluminium Lake E104b

6.2 Incompatibilities

None known

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The blisters are constructed of a rigid colourless 250µm PVC film, coated with PVDC and are heat sealed with 25µ aluminium foil. Each blister strip contains 7 tablets. The blister strips are packaged in a cardboard carton of 7 and 14 (2x7) tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

There are no special requirements for disposal. Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Quantum Generics

Crown House

2-8 Station Road

Redhill

Surrey

RH1 1FH

United Kingdom

8. Marketing authorisation number(s)

PL 15894/0005

9. Date of first authorisation/renewal of the authorisation

08/05/2012

10. Date of revision of the text

September 2014

Company Contact Details
Forum Products Ltd
Address

Crown House, 2-8 Gloucester Road, Redhill, Surrey, RH1 1FH

Telephone

+44(0)1737 857700