SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500mg of clarithromycin

3    PHARMACEUTICAL FORM

A white or almost white, Lyophilisate for Solution for Infusion

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is indicated for the parenteral treatment of infections caused by susceptible organisms in the following conditions:

-    Lower respiratory tract infections, such as pneumonia and acute and chronic bronchitis

-    Upper respiratory tract infections, such as pharyngitis and sinusitis

-    Skin and soft tissue infections

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

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is indicated in adults and children 12 years and older.

4.2 Posology and method of administration

For intravenous use only. Clarithromycin should not be given as a bolus or as an intramuscular injection.

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion should be administered as an IV infusion over 60 minutes into one of the larger proximal veins using a solution concentration of approximately 2mg/ml when reconstituted and diluted as recommended. Intravenous therapy may be given for 2 to 5 days after which time the patient should be changed to oral clarithromycin as appropriate. For instructions on appropriate dilution of the product before administration see section 6.6.

Recommended doses are:

Adults:

1.0 gram daily, divided into two 500mg doses diluted as described in Section 6.6.

Children younger than 12 years:

Use of Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is not recommended for children younger than 12 years. Use clarithromycin paediatric suspension.

Children older than 12 years:

As for adults

Elderly:

The dosing regimen for the elderly does not differ to that recommended for adults.

Renal impairment

In patients with renal impairment with creatinine clearance less than 30ml/minute the dose of clarithromycin should be reduced by one half of the normal adult recommended dose i.e. 250mg once daily or 250mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.

4.3 Contraindications

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is contraindicated in patients with a known hypersensitivity to clarithromycin, to other macrolide antibiotic drugs, or to any of the other ingredients.

Concomitant administration of clarithromycin with any ergot derivatives (e.g. ergotamine or dihydroergotamine) must be avoided as this may result in ergot toxicity (see section 4.5).

Concomitant administration of cisapride, pimozide and terfenadine is contraindicated with clarithromycin. Elevated plasma levels of cisapride, pimozide, and terfenadine have been reported in patients when these drugs are taken concomitantly with clarithromycin. This may lead to QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

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

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

Clarithromycin must not be used concomitantly with HMG-CoA reductase inhibitors (statins), simvastatin or lovastatin due to the risk of rhabdomyolysis. Treatment with any of these agents should be discontinued during clarithromycin treatment.

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

4.4 Special warnings and precautions for use

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).

Caution is advised in patients with severe renal insufficiency (see section 4.2)

Clarithromycin is primarily excreted by the liver therefore caution should be exercised when administering to patients with impaired hepatic function.

Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

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, pruritis, or tender abdomen.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, particularly in elderly patients, some of which occurred in patients with renal insufficiency. Deaths have been reported in some of these cases (see section 4.5). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, 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. 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. Drugs inhibiting peristalsis should be avoided.

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy.

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

An overgrowth of non-susceptible bacteria or fungi can result following prolonged or repetitive use of clarithromycin. If a super-infection occurs, clarithromycin should be discontinued and appropriate therapy commenced. Attention also should be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

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 a risk of QT prolongation, clarithromycin should be used with caution in patients with a coronary vessel disease, severe cardiac insufficiency, non-compensated hypokalemia and/or hypomagnesemia, bradycardia (<50bpm), or when co-administered with other medicinal products with a QT-prolonging effect. Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation or a history of ventricular arrhythmia.

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 events 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.

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 with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (see section 4.5). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. When used with clarithromycin, atorvastatin or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should 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 hemorrhage and significant elevations in International Normalised 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.

4.5 Interaction with other medicinal products and other forms of interaction

Clarithromycin does not interact with oral contraceptives.

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

Cisapride, pimozide, astemizole 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 torsades 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 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. Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein P-glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence, clarithromycin should not be used during treatment with other medicinal products that are substrated for CYP3A4, unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate can be closely monitored. A dose reduction may be necessary for medicinal products that are substrates for CYP3A4 if coadministered with clarithromycin. Alternatively, treatment with these products may be interrupted during clarithromycin treatement.

Ergot vasoconstrictors (ergotamine/dihydroergotamine)

Co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity. This has been characterised by vasospasm and ischemia of the extremities and other tissues including the central nervous system (see section 4.3). Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).

Effects of other medicinal products on clarithromycin

Drugs 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. When clarithromycin is clearly indicated it might be necessary to increase the dose of clarithromycin and monitor the efficacy and safety of clarithromycin carefully. 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.

Fluconazole

Concomitant administration of fluconazole 200mg daily and clarithromycin 500mg twice daily to 21 health volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the cuve (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 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 C_max increased by 31%, C _min increased 182% and area under the curve (AUC) increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted.

However, due to the large therapeutic window of clarithromycin, dose reduction should not be necessary in patients with normal renal function. For renally impaired patients however, the following dose adjustments should be considered:

For patients with CL_cr 30 to 60ml/min the dose of clarithromycin should be decreased by 50%

For patients with CL_cr < 30ml/min the dose of clarithromycin should be decreased by 75%

Doses of clarithromycin greater than 1g/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, Bidirectional drug interactions).

Effect of clarithromycin on other medicinal products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolised 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 metabolised by this enzyme.

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

The following drugs or drug classes are known or suspected to be metabolised 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.

Clarithromycin may potentiate the effects of warfarin when administered concomitantly. Prothrombin time should be frequently monitored in these patients.

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during coadministration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.

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 (C_max, AUC_0-24, and t_1/2 increased by 30%, 89% and 34% respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolised, 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 these drugs are co-administered with clarithromycin.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin. There is the potential for theophylline toxicity. Dose reduction may need to be considered.

The use of clarithromycin in patients receiving carbamazepine may cause potentiation of the effects of carbamazepine due to a reduction in the rate of excretion.

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 (250mg b.i.d.) 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 metazolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolised by CYP3A (temazepam, nitrazepam, lorazepam) a clinically important 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.

Other drug interactions

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter P-glycoprotein (Pgp), both of which are inhibited by clarithromycin and other macrolides. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to an increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. The concentration of digoxin may be increased when co-administered with clarithromycin. 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 levels should be monitored in patients receiving both clarithromycin and digoxin.

Zidovudine

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and Valproate

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

Bi-directional drug 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-OH-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. Doses of clarithromycin greater than 1000mg per day should not be co-administered with protease inhibitors.

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 bi-directional drug interaction. Concomitant administration of clarithromycin (500mg twice daily) and saquinavir (soft gelatine capsules, 1200mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and C_max values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and C_max 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 gelatine capsule formulation may not be representative of the effects seen using the saquinavir hard gelatine capsule. Observations from drug interaction studies performed with saquinavir alone 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.

Verapamil

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

HMG-CoA reductase inhibitors

Rhabdomyolysis has been reported following co-incident co-administration of clarithromycin and HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin).

4.6 Pregnancy and lactation

Clarithromycin should not be used during pregnancy or lactation unless the benefit is considered to outweigh the risk since the safety of clarithromycin during pregnancy and breast feeding has not been established. Clarithromycin has been found in the milk of lactating animals and in human breast milk.

Although some animal studies have shown clarithromycin to have an embryotoxic effect, this was only observed at doses which were clearly toxic to the mothers. 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 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.

4.8 Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse effects in clinical studies included injection site reactions. More specifically, inflammation, tenderness, phlebitis and pain have all been reported at the site of injection.

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 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, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000), 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 (>1/1,000, <1/100)	Rare (>1/10,000, <1/1,000)	Very Rare (<1/10,000)	Not Known (cannot be estimated from the available data)
Infections and infestations		Oral candidiasis	Cellulitis1, candidiasis, • • 2 gastroenteritis , infection3, vaginal infection			Pseudomembranous colitis (severity may range from mild to life-threatening), Erysipelas, erythrasma
Blood and lymphatic system			Leukopenia, neutropenia4, thrombocythemia3, eosinophilia4			Agranulocytosis Thrombocytopenia
Immune system disorders5			Anaphylactoid reaction1, hypersensitivity			Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis
Metabolism and nutrition disorders			Anorexia, decreased appetite			Hypoglycaemia6
Psychiatric disorders		Insomnia	Anxiety, 3 nervousness , 3 screaming			Psychotic disorder, confusional state, depersonalisation, depression disorientation, hallucinations, nightmares, abnormal dreams
Nervous system disorders		Dysgeusia, headache, taste perversion e.g.	Loss of consciousness1, dyskinesia1, dizziness,		Paresthesia (oral clarithromycin only)	Convulsions, ageusia, parosmia, anosmia

		metallic or bitter taste	somnolence , tremor
Eye disorders				Uveitis (mainly in patients treated with concomitant rifabutin)
Ear and labyrinth disorders			Vertigo, hearing impairment, tinnitus,			Deafness (usually reversible following discontinuation of therapy)
Cardiac disorders			Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged8, extrasystole1, palpitations			Torsades de Pointes8 Ventricular tachycardia8
Vascular disorders		Vaso-dilation1				Hemorrhage9
Respiratory, thoracic and mediastinal disorders			Asthma1, epistaxis2, pulmonary embolism1
Gastrointestin al disorders		Diarrhoea10, vomiting, dyspepsia, nausea, abdominal pain	Oesophagitis1, gastro-oesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence			Pancreatitis acute, reversible tooth and tongue discolouration
Hepato-biliary disorders		Abnormal liver function tests	Hepatic dysfunction (which is usually transient and reversible but may be severe), hepatitis4, cholestasis (with or without jaundice)4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4			Fatal hepatic failure has been reported particularly in patients with preexisting liver disease or taking other hepatotoxic medicinal products.11 Jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyper-hidrosis	Bullous dermatitis1, pruritis, urticaria, maculo-papular rash3			Stevens-Johnson syndrome5, toxic epidermal necrolysis5, Angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), acne
Musculoskeletal and connective			Muscle spasms3, arthralgia1, myalgia2			Rhabdomyo lysis2,12, myopathy

tissue disorders
Renal and urinary disorders			Blood creatinine increased1, blood urea increased2			Renal failure, interstitial nephritis
General disorders and administration site conditions	Injection site phlebitis1	Injection site pain2, injection site inflammation1 or tenderness	Malaise3, pyrexia4, asthenia, chest pain3, chills5, fatigue6
Investi-gations			Abnormal Albumin globulin ratio7, increased blood alkaline phosphatise8, increased blood lactate dehydrogenase3, elevated serum creatinine, altered liver function tests (increased transaminase levels).			International normalised ratio increased9, prolongation of prothrombin time9, abnormal urine colour. Hypoglycaemia has been observed especially after concomitant administration with antidiabetic medicinal products and insulin

There have been reports of colchicine toxicity following concomitant administration of clarithromycin. This has occurred particularly in the elderly some of whom had renal insufficiency. Some such reports have been fatal (See sections 4.4 and 4.5) 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 report 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 the 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 hemorrhage 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).

d.    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.

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 1000mg and 2000mg 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 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg 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 1000mg or 2000mg 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 4000mg daily for all parameters except White Blood Cell.

4.9 Overdose

Reports indicate the ingestion of large amounts of clarithromycin 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.

There is no experience of overdose with Clarithromycin by the intravenous route. Consequently symptoms accompanying overdose should be treated by prompt elimination of unabsorbed drug and supportive measures. As with other macrolides the serum levels of clarithromycin are not expected to be significantly altered by haemodialysis or peritoneal dialysis.

In the case of overdosage, clarithromycin for solution for infusion should be discontinued and all other appropriate supportive measures should be instituted.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Macrolide antibacterial for systemic use: ATC J01FA09

Clarithromycin is a semi-synthetic derivative of erythromycin A.

Clarithromycin exerts antibacterial action by binding to the 50s ribosomal subunit thereby inhibiting protein synthesis in susceptible bacteria. Clarithromycin is highly potent against a wide range of aerobic and anaerobic gram-positive and gramnegative organisms and shows excellent in vitro activity against standard strains of clinical isolates. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than those of erythromycin from which it is derived.

14-(R)-hydroxyclarithromycin, the first pass metabolite of clarithromycin, has antimicrobial activity with MICs equal to or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-(R)-hydroxy metabolite is two-fold more active than the parent clarithromycin.

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is active against the following micro-organisms in vitro:

GRAM-POSITIVE BACTERIA

Staphylococcus aureus (methicillin susceptible); Streptococcus (Diplococcus) pneumoniae; Streptococcus pyogenes (Group A beta-haemolytic streptococci); Alpha-haemolytic streptococcus (viridans group); Streptococcus agalactiae; Listeria monocytogenes;

GRAM-NEGATIVE BACTERIA

Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni

MYCOPLASMA

Mycoplasma pneumoniae; Ureaplasma urealyticum OTHER ORGANISMS

Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae

ANAEROBES

Macrolide susceptible Bacteriodes fragilis; Clostridium perfringens; Peptococcus species, Peptostreptococcus species, Propionibacterium acnes.

Clarithromycin also has bactericidal activity against several bacterial strains including; H influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and campylobacter species.

The activity of clarithromycin against Helicobacter pylori is greater at neutral pH than at acid pH.

5.2 Pharmacokinetic properties

14-hydroxyclarithromycin, the microbiologically active metabolite of clarithromycin, is formed by first pass metabolism as indicated by lower availability of the metabolite following intravenous administration. Blood levels of clarithromycin following IV administration reach in excess of the MIC₉₀s for the common pathogens and the levels of 14-hydroxyclarithromycin exceed the required concentrations for key pathogens (e.g. H. influenzae).

Following a single intravenous dose of 500mg over 60 minutes about 33% clarithromycin and 11% of the 14-hydroxyclarithromycin metabolite is excreted in the urine at 24 hours.

The pharmacokinetics of clarithromycin and the 14-hydroxyclarithromycin metabolite are non-linear, with steady state being achieved by day 3 of intravenous dosing.

5.3 Preclinical safety data

There are no relevant preclinical data which are additional to that already in other sections of the SPC

6.1    List of excipients

Lactobionic acid

Sodium Hydroxide (for pH adjustment)

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3    Shelf life

The unopened shelf-life of Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion is 36 months.

Once reconstituted chemical and physical in-use stability has been demonstrated for 24 hours (at 5°C to 25°C) when reconstituted in 10ml of water for injections and for 6 hours (at 25°C) or 24 hours (at 5°C) once diluted in 250ml of an appropriate infusion solution.

From a microbiological point of view the product should be used immediately. If not used immediately the in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8° C unless the reconstitution and dilution has taken place in controlled and validated aseptic conditions.

6.4    Special    precautions for storage

No special precautions for storage

6.5    Nature    and contents of container

The product is supplied in a 15ml clear Type 1 glass vial sealed with a 20mm grey bromobutyl Type 1 lyophilisation stopper and protected by a 20mm cap that is silver in colour with a red ring on the top surface that incorporates a transparent flip-off plastic top. The product is supplied in packs of 1 vial.

6.6    Special    precautions for disposal

Special precautions for handling

Clarithromycin should not be given as a bolus or as an intramuscular injection.

Clarithromycin 500mg/vial Lyophilisate for Solution for Infusion should be administered into one of the larger proximal veins as an IV infusion over 60 minutes using a solution concentration of about 2mg/ml.

An approximately 2mg/ml solution may be obtained by reconstituting the product in 10ml of water for injections. Once dissolution is complete, the 10ml solution must be added to 250ml of a suitable infusion solution/diluent (see below) in order to obtain an approximately 2mg/ml solution.

Recommended infusion solutions/diluents are;

•    5% Dextrose in Lactated Ringers solution

•    5% Dextrose

•    Lactated Ringers solution

•    5% Dextrose in 0.3% Sodium chloride

•    Normosol-M in 5% Dextrose

•    Normosol-R in 5% dextrose

•    5% Dextrose in 0.45% Sodium chloride

•    0.9% Sodium chloride.

Compatibility with other intravenous additives has not been established.

Diluents containing preservatives or inorganic salts should not be used.

Special precautions for disposal

For single use only. Any unused solution and the vial should be adequately disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Britannia Pharmaceuticals Limited

Park View House

65 London Road

Newbury

Berkshire

RG14 1JN

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04483/0063

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

December 2008

14/03/2012

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 Immediate-Release Tablets formulation

4

ADRs reported only for the Granules for Oral Suspension formulation

5

   ^10,11,12 See section a)

^{6,7 8 9} See section c)

c. Description of selected adverse reactions

6

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

7

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).

8

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).

9

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Sydrome and toxic epidermal necrolysis, clarithromycin