Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection

Active : Clarithromycin 500mg/vial

Lyophilised powder for reconstitution to give a solution for IV administration.

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection is indicated whenever parenteral therapy is required for treatment of infections caused by susceptible organisms in the following conditions;

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

- Upper respiratory tract infections for example, sinusitis and pharyngitis.

- Skin and soft tissue infections.

For intravenous administration only.

Intravenous therapy may be given for 2 to 5 days and should be changed to oral clarithromycin therapy when appropriate.

Adults: The recommended dosage of Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection is 1.0 gram daily, divided into two 500mg doses, appropriately diluted as described below.

Children: At present, there are insufficient data to recommend a dosage regimen for routine use in children.

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.

Recommended administration:

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection 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. Clarithromycin should not be given as a bolus or an intramuscular injection.

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs.

Clarithromycin and ergot derivatives should not be co-administered (see section 4.5).

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide and terfenadine. Elevated cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these drugs and clarithromycin concomitantly. This may result in 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 is principally excreted by the liver and kidney. Caution should be exercised in administering this antibiotic to patients with impaired hepatic and renal function.

Prolonged or repeated use of clarithromycin may result in an overgrowth of non-susceptible bacteria or fungi. If super-infection occurs, clarithromycin should be discontinued and appropriate therapy instituted.

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).

Clarithromycin has been shown not to interact with oral contraceptives.

As with other macrolide antibiotics the use of clarithromycin in patients concurrently taking drugs metabolised by the cytochrome p450 system (e.g. cilostazol, methylprednisolone, oral anticoagulants (eg warfarin), quinidine, sildenafil, ergot alkaloids, alprazolam, triazolam, midazolam, disopyramide, lovastatin, rifabutin, phenytoin, cyclosporin, vinblastine, valproate and tacrolimus) may be associated with elevations in serum levels of these other drugs. Rhabdomyolysis, co-incident with the co-administration of clarithromycin, and HMG-CoA reductase inhibitors, such as lovastatin and simvastatin has been reported.

The administration of Clarithromycin to patients who are receiving theophylline has been associated with increased serum theophylline levels and potential theophylline toxicity.

The use of Clarithromycin in patients receiving warfarin may result in a potentiation of the effects of warfarin. Prothrombin time should be frequently monitored in these patients. The effects of digoxin may be potentiated with concomitant administration of Clarithromycin. Monitoring of serum digoxin levels should be considered.

Clarithromycin may potentiate the effects of carbamazepine due to a reduction in the rate of excretion.

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected adults may result in decreased steady-state zidovudine concentrations. Since this interaction in adults is thought to be due to interference of clarithromycin with simultaneously administered oral zidovudine, this interaction should not be a problem when clarithromycin is administered intravenously. With oral clarithromycin, the interaction can be largely avoided by staggering the doses; see Summary of Product Characteristics for Clarithromycin tablets for further information. No similar reaction has been reported in children.

Ritonavir increases the area under the curve (AUC), C_max and C_min of clarithromycin when administered concurrently. 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 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 coadministered with ritonavir.

There have been post-marketed reports of Torsade de Pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Levels of these medications should be monitored during clarithromycin therapy.

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

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 (see section 4.3 Contraindications).

The safety of Clarithromycin during pregnancy and breast feeding of infants has not been established. Clarithromycin should thus not be used during pregnancy or lactation unless the benefit is considered to outweigh the risk. Some animal studies have suggested an embryotoxic effect but only at dose levels which are clearly toxic to mothers. Clarithromycin has been found in the milk of lactating animals and in human breast milk.

None reported.

The most frequently reported infusion-related adverse events in clinical studies were injection-site inflammation, tenderness, phlebitis and pain. The most common non-infusion related adverse event reported was taste perversion.

During clinical studies with oral Clarithromycin, the drug was generally well tolerated. Side-effects included nausea, vomiting, diarrhoea, dyspepsia and abdominal pain and paraesthesia. Stomatitis, glossitis and oral monilia have been reported. Other side-effects include headache, tooth and tongue discolouration, arthralgia, myalgia and allergic reactions ranging from urticaria, mild skin eruptions and angioedema to anaphylaxis have been reported. There have been reports of Stevens-Johnson syndrome/ toxic epidermal necrolysis with orally administered clarithromycin.

Reports of alteration of the sense of smell, usually in conjunction with taste perversion have also been received. There have been reports of transient central nervous system side-effects including dizziness, vertigo, anxiety, insomnia, bad dreams, tinnitus, confusion, disorientation, hallucinations, psychosis, and depersonalisation. There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy.

Pseudomembranous colitis has been reported rarely with clarithromycin, and may range in severity from mild to life threatening.

There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin.

There have been very rare reports of uveitis mainly in patients treated with concomitant rifabutin, most of these were reversible.

Isolated cases of leukopenia and thrombocytopenia have been reported.

As with other macrolides, hepatic dysfunction (which is usually reversible) including altered liver function tests, hepatitis and cholestasis with or without jaundice, has been reported. Dysfunction may be severe and very rarely fatal hepatic failure has been reported.

Cases of increased serum creatinine, interstitial nephritis, renal failure, pancreatitis and convulsions have been reported rarely.

As with other macrolides, QT prolongation, ventricular tachycardia and Torsade de Pointes have been rarely reported with clarithromcyin.

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 sections 4.4 and 4.5).

There is no experience of overdosage after IV administration of clarithromycin. However, reports indicate that the ingestion of large amounts of clarithromycin orally can be expected to produce gastro-intestinal symptoms. Adverse reactions accompanying overdosage should be treated by gastric lavage and supportive measures.

As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia.

Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. Clarithromycin demonstrates excellent in vitro activity against standard strains of clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram positive and negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

The 14-(R)-hydroxy metabolite of clarithromycin, formed in man by first pass metabolism also has anti-microbial activity. The MICs of this metabolite are equal to or two-fold higher than the MICs of the parent compound except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection is usually active against the following organisms in vitro:

Gram-positive Bacteria:Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococcus (viridans group); Streptococcus (Diplococcus) pneumoniae; 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 has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Morazella (Brahamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter spp.

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

The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism as indicated by lower biovailability of the metabolite following IV administration. Following IV administration the blood levels of clarithromycin achieved are well in excess of the MIC ₉₀s for the common pathogens and the levels of 14-hydroxyclarithromycin exceed the necessary concentrations for important pathogens, e.g. H. influenzae.

The pharmacokinetics of clarithromycin and the 14-hydroxy metabolite are non-linear; steady state is achieved by day 3 of IV dosing. Following a single 500mg IV dose over 60 minutes, about 33% clarithromycin and 11% 14-hydroxyclarithromycin is excreted in the urine at 24 hours.

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection does not contain tartrazine or other azo dyes, lactose or gluten.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Lactobionic acid and Sodium Hydroxide EP.

None known. However, Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection should only be diluted with the diluents recommended.

36 months unopened.

24 hours (at 5ºC - 25ºC) once reconstituted in 10ml water for injections.

6 hours (at 25ºC) or 24 hours at (5ºC) once diluted in 250ml of appropriate diluent.

Do not store above 30° C. Store in the original container.

15ml Ph.Eur. Type I flint glass tubing vial with a 20mm grey halobutyl siliconised lyophilisation stopper with a flip-off cap. Vials are packed in units of 1, 4 and 6. Pack size 500mg.

Klaricid IV or Clarithromycin 500 mg/vial Powder for Solution for Injection 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. Clarithromycin should not be given as a bolus or an intramuscular injection.

Abbott Laboratories Limited

Queenborough

Kent

ME11 5EL.

PL 00037 / 0251

22/09/93

07 July 2009