Clarithromycin 500 mg Powder for Concentrate for Solution for Infusion

Summary of Product Characteristics Updated 14-May-2020 | Tillomed Laboratories Ltd

1. Name of the medicinal product

Clarithromycin 500 mg Powder for Concentrate for Solution for Infusion

2. Qualitative and quantitative composition

Each vial contains 500 mg clarithromycin (as clarithromycin lactobionate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

powder for concentrate for solution for infusion

White to off white lyophilized powder

4. Clinical particulars
4.1 Therapeutic indications

Clarithromycin is indicated for the treatment of adults and adolescents (from 12 years of age) with moderate to severe infections caused by clarithromycin-sensitive organisms or when oral therapy is not applicable; in patients with known penicillin hypersensitivity or when penicillin is not appropriate for other reasons (see sections 4.4 and 5.1):

• moderate to severe community acquired pneumonia (see sections 4.4 and 5.1 regarding sensitivity testing)

• Acute exacerbation of chronic bronchitis (adequately diagnosed)

• Bacterial pharyngitis

• acute bacterial sinusitis (adequately diagnosed)

• moderate to severe skin and soft tissue infections (e.g. folliculitis, cellulitis, erysipelas) (see sections 4.4 and 5.1 regarding sensitivity testing).

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

4.2 Posology and method of administration

Posology

Intravenous therapy may be given for 2 to 5 days in the very ill patient and should be changed to oral clarithromycin therapy whenever possible as determined by the physician. After the symptoms have subsided, treatment with oral clarithromycin should be continued for at least 2 days.

Adults: The recommended dosage of Clarithromycin 500 mg is 1 g daily, divided into two 500 mg doses, appropriately diluted as described below.

Adolescents older than 12 years: As for adults.

The usual duration of treatment is 6 to 14 days.

Children under 12 years: Use of Clarithromycin 500 mg is not recommended for children younger than 12 years. Use Clarithromycin Paediatric Suspension.

Elderly: As for adults.

Renal Impairment: In patients with renal impairment who have creatinine clearance less than 30ml/min, the dosage of clarithromycin should be reduced to one half of the normal recommended dose.

Method of administration

For intravenous infusion after dilution only.

For instructions on reconstitution/dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance, macrolide antibiotics or to any of the excipients listed in section 6.1.

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

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

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

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

Concomitant administration with ticagrelor or ranolazine is contraindicated.

Clarithromycin must not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).

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

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

Clarithromycin must 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).

Clarithromycin is principally metabolised by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function.

Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment (see section 4.2).

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 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. Medicinal products inhibiting peristalsis should be avoided.

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). Concomitant administration of clarithromycin and colchicine is contraindicated (see section 4.3).

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

Cardiovascular Events:

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including clarithromycin (see section 4.8). Therefore, as the following situations may lead to an increased risk for ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the following patients;

• Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia

• Patients with electrolyte disturbances such as hypomagnesaemia. Clarithromycin must not be given to patients with hypokalaemia (see section 4.3).

• Patients concomitantly taking other medicinal products associated with QT prolongation (see section 4.5).

• Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section 4.3).

• Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).

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–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the medicinal product of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS)), clarithromycin therapy 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 (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy.

In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. (See section 4.5).

Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see section 4.5).

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.

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

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

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per 1 vial, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

The use of the following medicinal products is strictly contraindicated due to the potential for severe medicinal product interaction effects:

Cisapride, domperidone, 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 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Ergot alkaloids:

Post-marketing reports indicate that 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 ergot alkaloids is contraindicated (see section 4.3).

Oral Midazolam

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin 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.

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. Patients should be monitored for signs and symptoms of myopathy.

Effects of Other Medicinal Products on Clarithromycin

Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

The following medicinal products 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 200 mg daily and clarithromycin 500 mg 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-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 200 mg every eight hours and clarithromycin 500 mg 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. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g /day should not be co-administered with ritonavir.

Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional medicinal product interactions).

Effect of Clarithromycin on Other Medicinal Products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a medicinal product primarily metabolised by CYP3A may be associated with elevations in medicinal product concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant medicinal product. Clarithromycin should be used with caution in patients receiving treatment with other medicinal products 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 medicinal products primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following medicinal products or medicinal product classes are known or suspected to be metabolised by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, domperidone, ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, see 4.4), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine but this list is not exhaustive. Medicinal products interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been post-marketed reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these medicinal products. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.

There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Oral hypoglycemic agents/Insulin

With certain hypoglycemic medicinal products such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg 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), 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 medicinal products are co-administered with clarithromycin.

Theophylline, carbamazepine

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

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. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Medicinal product delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the medicinal product, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

There have been post-marketing reports of medicinal product 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 medicinal products 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. (see section 4.3 and 4.4).

Digoxin

Digoxin is thought to be 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

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 medicinal products not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these medicinal products when administered concomitantly with clarithromycin. Increased serum levels have been reported.

Bi-directional medicinal product interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional medicinal product interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg 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 1000 mg per day should not be co-administered with protease inhibitors.

Calcium Channel Blockers

Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional medicinal product 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 medicinal product interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and 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 medicinal products are co-administered for a limited time at the doses/formulations studied. Observations from medicinal product interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from medicinal product 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 (see section 4.5: Ritonavir).

4.6 Fertility, pregnancy and lactation

Pregnancy

Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear evidence of teratogenic effects, or of adverse effects on the health of the neonate. Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of abortions. To date no other relevant epidemiological data are available.

Data from animal studies have shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should only be used during pregnancy after a careful benefit/risk assessment.

Breast-feeding

Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be considered. The benefit of treatment of the mother should be weighed against the potential risk for the infant.

Fertility:

There is no data available on the effect of clarithromycin on fertility in humans. In rats, the limited data available do not indicate any effects on fertility.

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 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 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)

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

Frequency category

Very common

(≥1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥1/1,000 to < 1/100)

Not Known*

(cannot be estimated from the available data)

Infections and infestations

Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection

Pseudomembranous colitis, erysipelas

Blood and lymphatic system

Leukopenia, neutropenia4, thrombocythaemia3, eosinophilia4

Agranulocytosis, thrombocytopenia

Immune system disorders

Anaphylactoid reaction1, hypersensitivity

Anaphylactic reaction, angioedema

Metabolism and nutrition disorders

Anorexia, decreased appetite

Psychiatric disorders

Insomnia

Anxiety, nervousness3

Psychotic disorder, confusional state5, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania

Nervous system disorders

Dysgeusia, headache

Loss of consciousness1, dyskinesia1, dizziness, somnolence5, tremor

Convulsion, ageusia, parosmia, anosmia, paraesthesia

Ear and labyrinth disorders

Vertigo, hearing impaired, tinnitus

Deafness

Cardiac disorders

Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged, extrasystoles1, palpitations

Torsades de pointes, ventricular tachycardia, ventricular fibrillation

Vascular disorders

Vasodilation1

Haemorrhage

Respiratory, thoracic and mediastinal disorder

Asthma1, epistaxis2, pulmonary embolism1

Gastrointestinal disorders

Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain

Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence,

Pancreatitis acute, tongue discolouration, tooth discolouration

Hepatobiliary disorders

Liver function test abnormal

Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4

Hepatic failure, jaundice hepatocellular

Skin and subcutaneous tissue disorders

Rash, hyperhidrosis

Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3

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 spasms3, musculoskeletal stiffness1, myalgia2

Rhabdomyolysis2,6, myopathy

Renal and urinary disorders

Blood creatinine increased1, blood urea increased1

Renal failure, nephritis interstitial

General disorders and administration site conditions

Injection site phlebitis1

Injection site pain1, injection site inflammation1

Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4

Investigations

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

International normalised ratio increased, prothrombin time prolonged, urine colour abnormal

1 ADRs reported only for the Powder for Concentrate for Solution for Infusion formulation

2ADRs 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 drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.

c. Description of selected adverse reactions

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

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 medicinal product interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).

There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.

Special population: Adverse Reactions in Immunocompromised Patients (see section 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.

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 1000 mg 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 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 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Reports indicate that the ingestion of large amounts of clarithromycin orally 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 the prompt elimination of unabsorbed medicinal product and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

In the case of overdose, Clarithromycin should be discontinued and all other appropriate supportive measures should be instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use; Macrolides

ATC code: J01FA09.

Mechanism of Action:

Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activated amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria.

The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has anti-microbial activity. The metabolite is less active than the parent compound for most organisms, including mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD relationship

Recent in-vitro and in-vivo studies have shown that the bactericidal activity of clarithromycin is primarily concentration-dependent. Clarithromycin becomes active and accumulates in high concentrations in phagocytes. The post-antibiotic effect is 2 to 3 times stronger in vivo than with erythromycin.

Mechanism of resistance:

Resistance to clarithromycin can be based on the following mechanisms:

• Efflux: Resistance can be caused by increasing the number of efflux pumps in the cytoplasmic membrane, which only affect 14- and 15-membered macrolides (so-called M phenotype)

• Change in the target structure: Methylation of the 23S rRNA reduces the affinity for the ribosomal binding sites, which leads to resistance to macrolides (M), lincosamides (L) and streptogramins of group B (SB) (so-called MLSB phenotype)

• The enzymatic inactivation of macrolides is only of minor clinical importance.

The M phenotype shows complete cross-resistance between clarithromycin and azithromycin, erythromycin and roxithromycin. The MLSB phenotype also has cross resistance with clindamycin and streptogramin B. There is partial cross resistance with the 16-membered macrolide spiramycin.

Breakpoints:

Clarithromycin is tested using the standard dilution series. The following minimum inhibitory concentrations for sensitive and resistant germs were determined:

EUCAST (European Committee on Antimicrobial Susceptibility Testing), version 10.0, valid 2020-01-01.

Breakpoints

Microorganism

Susceptible

Resistant

Staphylococcus spp.1

≤ 1 mg/L

>2 mg/L

Streptococcus spp 1

(Groups A, B, C and G)

≤ 0.25 mg/L

>0.5 mg/L

Streptococcus pneumoniae1

≤ 0.25 mg/L

>0.5 mg/L

Moraxella catarrhalis1

≤ 0.25 mg/L

>0.5 mg/L

Helicobacter pylori2

≤ 0.25 mg/L1

>0.5 mg/L

1 Erythromycin can be used as a test substance to demonstrate sensitivity to clarithromycin.

2 The breakpoint values are based on the epidemiological cut-off values (ECOFFs), which allow a differentiation between wild-type isolates and those with reduced sensitivity.

Prevalence of acquired resistance in Germany

The prevalence of acquired resistance of individual species can vary locally and over time. Therefore, local information about the resistance situation is required - especially for the adequate treatment of severe infections. If the effectiveness of clarithromycin is questioned due to the local resistance situation, therapy advice from experts should be sought. Microbiological diagnosis with detection of the pathogen and its sensitivity to clarithromycin is particularly desirable in the case of serious infections or treatment failure. However, it has not been definitively proven that in vitro resistance leads to clinical ineffectiveness in mild to moderate, community-acquired respiratory infections.

Prevalence of acquired resistance in Germany based on data from the past 5 years from national resistance monitoring projects and studies (as of February 2018):

Commonly susceptible species

Aerobic Gram-positive Microorganisms

Streptococcus pyogenes

Aerobic Gram-negative Microorganisms

Haemophilus influenzae$

Legionella pneumophila°

Moraxella catarrhalis

Other microorganisms

Chlamydophila pneumoniae°

Mycobacterium avium°

Mycobacterium chelonae°

Mycobacterium intrazellulare°

Mycobacterium kansasii°

Mycoplasma pneumoniae°

Species for which acquired resistance may be a problem

Aerobic Gram-negative Microorganisms

Helicobacter pylori1

Aerobic Gram-positive Microorganisms

Staphylococcus aureus (Methicillin-susceptible)

Staphylococcus aureus (Methicillin-resistent)+

Streptococcus pneumoniae Ω

Other microorganisms

Mycobacterium fortuitum

Naturally resistant species

Aerobic Gram-negative Microorganisms

Escherichia coli

Klebsiella spp.

Pseudomonas aeruginosa

° No current data were available when the tables were published. Sensitivity is assumed in the primary literature, in standard works and in therapy recommendations.

$ The natural sensitivity of most isolates is in the intermediate range.

+ In at least one region, the resistance rate is over 50%.

1 Resistance rate already in one-time pretreated patients ≥ 50%.

Ω The resistance rate for isolates from invasive diseases is below 10%.

5.2 Pharmacokinetic properties

The single intravenous application of clarithromycin lactobionate over a period of 30 minutes resulted in the following values after measurement of clarithromycin in plasma:

Clarithromycin dose (mg)

Cmax (µg/ml)

tmax (h)

T1/2 (h)

AUC (h.µg/ml)

75

1.23

0.5

2.1

2.29

125

1.87

0.5

2.3

3.61

250

4.75

0.5

2.6

11.44

In steady state, the following values were found in a study with 39 healthy volunteers after intravenous administration of clarithromycin lactobionate twice a day after clarithromycin was measured in plasma:

Clarithromycin dose (mg)

Infusion time (min)

Cmax (µg/ml)

T1/2 (h)

125

30

2.1

2.8

250

30

3.2

3.4

500

60

5.5

6.3

Distribution

With a clarithromycin concentration in the plasma of 0.45 to 4.5 μg per ml, the binding to plasma proteins is 72%. The degree of binding decreases with increasing concentration in the plasma.

Experimental studies and those on humans prove the excellent tissue mobility of the active ingredient. Except in the central nervous system (or in the cerebrospinal fluid), concentrations are reached in all other examined tissues that are several times higher than the concentrations in plasma and up to 10 times higher than the corresponding concentrations of erythromycin in the tissue.

Concentrations of clarithromycin in the tissue (mg / kg) at steady state after oral administration of 2 times 250 mg or 2 times 500 mg * Clarithromycin:

1 Hour

4 Hours

12 Hours

Lung

Not specified

17.5

3.8

Nasal mucosa

4.2

8.3

2.8

Tonsils

1.8

6.7

2.6

Metabolism / Elimination

Clarithromycin is extensively metabolized, especially via N-demethylation or oxidation in position 14 of the molecule. The hydroxylation at position C-14 is stereospecific. The main metabolite in plasma is the 14-hydroxy (R) epimer of clarithromycin with peak concentrations of 0.6 μg / ml after oral administration of 2 times 250 mg clarithromycin. The half-life of the metabolite is 5 to 6 hours. Small amounts of descladinosyl clarithromycin were observed in plasma only after the high oral dose of 1200 mg clarithromycin.

In healthy adults, the plasma half-life of clarithromycin after oral administration of 1000 mg daily, divided into 2 single doses, was 4.5 to 4.8 hours and correspondingly 6.9 to 8.7 hours for 14-hydroxy-clarithromycin.

The non-linear, pharmacokinetic behavior of clarithromycin, coupled with the relative decrease in 14-hydroxylation and N-demethylation at higher doses, indicates that clarithromycin metabolism saturates at high doses.

Measurements with radioactively labeled substances show that the elimination of the active substance takes place predominantly (70 - 80%) with the faeces. 20 - 30% are excreted unchanged via the kidney.

Elderly patients

In elderly patients (65 to 81 years), higher concentrations of clarithromycin in plasma were observed after oral administration of clarithromycin 500 mg twice daily compared to younger patients (21 to 29 years). After administration of the 5th dose, a Cmax of 2.4 μg / ml was determined in the group of younger patients and a Cmax of 3.28 μg / ml in older patients. The elimination half-life was 4.9 and 7.7 hours, respectively. The same applies to the 14-hydroxy metabolite. These differences could be related to the physiological decrease in renal function in the elderly.

Impaired kidney function

When orally administered clarithromycin 500 mg twice daily to patients with impaired renal function (creatinine clearance 10 to 122 ml / min), the parameters Cmax, Cmin, t1 / 2 and AUC were higher. After 5 days of use, a Cmax of 8.3 μg / ml was measured in patients with severe renal insufficiency (creatinine clearance 10 to 29 ml / min). Similar changes were noted for the kinetics of the 14-hydroxy metabolite. Most pharmacokinetic parameters have a clear correlation with creatinine clearance.

Impaired liver function

No changes in the pharmacokinetic data of clarithromycin and the 14-hydroxy metabolite were observed in patients with alcohol-related mild liver damage. Studies with severely impaired liver function are not available.

5.3 Preclinical safety data

In 4-week-studies in animals, toxicity of clarithromycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses (300 mg/kg/day) were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

In vitro and in vivo studies showed that clarithromycin did not have genotoxic potential.

Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical dose in rabbit (IV) and 10x the clinical dose in monkey (po) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was generally noted in rat studies. However, cardiovascular malformations were observed in two studies in rats treated with doses of 150 mg/kg/d.

In mice at doses 70x the clinical dose, cleft palate occurred at varying incidence (3-30%).

Clarithromycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Clarithromycin has not been tested for carcinogenicity.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium Hydroxide 1N (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

2 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 20°C - 25°C and for 24 hours at 2-8°C.

Reconstituted and diluted solution: Chemical and physical in-use stability has been demonstrated for 6 hours at 20°C - 25°C and for 24 hours at 2-8°C.

From a microbiological point of view, unless the method of opening/ reconstitution/ dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than the times stated above for the chemical and physical in-use stability.”

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution/dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

15 ml type-I, clear tubular glass vial stoppered with grey bromobutyl double slotted rubber stopper and sealed with baby blue aluminium seal.

Pack size: 1 vial.

6.6 Special precautions for disposal and other handling

After reconstitution the solution for infusion should be administered into one of the larger proximal veins as an intravenous infusion over 60 minutes, using a solution concentration of about 2 mg/ml. The medicinal product should not be given as a bolus or an intramuscular injection.

Preparation for Use

Reconstitution (Step 1)

Prepare the initial solution of clarithromycin 500mg by adding 10 ml of water for injections to the vial.

Shake until the vial contents have dissolved.

Use only water for injections, as other diluents may cause precipitation during reconstitution. Do not use diluents containing preservatives or inorganic salts. Each ml contains 50 mg clarithromycin.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Dilution (Step 2)

The reconstituted solution (500 mg clarithromycin in 10 ml water for injections) should be added to a minimum of 250 ml of one of the following diluents before administration: dextrose 50mg/ml (5%) in Lactated Ringer's solution, dextrose 50 mg/ml (5%) solution for infusion, Lactated Ringer's, dextrose 50 mg/ml (5%) in sodium chloride 3 mg/ml (0.3%), Normosol-M in dextrose 50 mg/ml (5%), dextrose 50mg/ml (5%) in sodium chloride 4.5 mg/ml (0.45%), and sodium chloride 9 mg/ml (0.9%) solution for infusion.

1ml of the prepared solution for infusion in this way contains 2mg clarithromycin.

For storage conditions after dilution of the medicinal product, see section 6.3.

IMPORTANT: BOTH DILUENT STEPS (1 and 2) SHOULD BE COMPLETED BEFORE USE.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Tillomed Laboratories Limited

220 Butterfield, Great Marlings,

Luton, LU2 8DL

United Kingdom

8. Marketing authorisation number(s)

PL 11311/0644

9. Date of first authorisation/renewal of the authorisation

08/04/2020

10. Date of revision of the text

08/04/2020

Company Contact Details
Tillomed Laboratories Ltd
Address

220 Butterfield, Great Marlings, Luton, LU2 8DL, UK

Telephone

+44 (0)1480 402 400

Medical Information Direct Line

+44 (0)1480 402 400

Customer Care direct line

+44 (0)1480 402431 / +44 (0)1480 402432

Stock Availability

+44 (0)1480 402431 / +44 (0)1480 402432

WWW

http://www.tillomed.com/

Fax

+44 (0)1480 402 402

Medical Information e-mail
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