Consumer medicine information

Clarithromycin AN Tablets

Clarithromycin

BRAND INFORMATION

Brand name

Clarithromycin AN Tablets

Active ingredient

Clarithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clarithromycin AN Tablets.

What is in this leaflet

This leaflet answers some common questions about Clarithromycin AN tablets.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CLARITHROMYCIN AN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What CLARITHROMYCIN AN is used for

CLARITHROMYCIN AN is used to treat certain bacterial infections, including the following:

  • respiratory tract infections
  • skin infections
  • peptic ulcer

CLARITHROMYCIN AN is also used to prevent a specific bacterial infection associated with HIV infection.

Your doctor, however, may have prescribed CLARITHROMYCIN AN for another purpose. Ask your doctor if you have any questions about why CLARITHROMYCIN AN has been prescribed for you.

CLARITHROMYCIN AN is an antibiotic that belongs to the group of medicines called macrolides. These medicines work by killing or stopping the growth of bacteria which cause infections.

CLARITHROMYCIN AN will not work against infections caused by viruses, such as colds or flu.

CLARITHROMYCIN AN is available only with a doctor’s prescription.

CLARITHROMYCIN AN to treat peptic ulcer
Peptic ulcers are associated with an infection in the intestine and stomach by a bacteria called Helicobacter pylori (H. pylori). Nearly all patients with peptic ulcers are infected with this bacteria.

The H. pylori infection can be treated with a combination of CLARITHROMYCIN AN (clarithromycin), another antibiotic (amoxycillin) and another medicine called omeprazole (used to control the acidity of the stomach).

However, the best combination of tablets to treat Helicobacter pylori infection is yet to be determined. Your doctor will determine the best combination for you.

If your symptoms return, consult your doctor. It is possible that CLARITHROMYCIN AN may no longer be effective in killing the Helicobacter pylori infection and a different antibiotic may be needed.

Before You Take CLARITHROMYCIN AN

When you must not take it

Do not take CLARITHROMYCIN AN if:

  1. You have ever had an allergic reaction to medicines containing clarithromycin or to other antibiotics from the macrolide family. These may include:
    - erythromycin (EES, Erythrocin, Eryc, Emycin, EMU-V)
    - roxithromycin (Rulide, Biaxsig)
    - azithromycin (Zithromax)
  2. You are allergic to any of the ingredients listed at the end of this leaflet.
  3. If you have an allergic reaction to CLARITHROMYCIN AN you may have some of the following symptoms:
    - rash
    - itching or hives
    - swelling of the face, lips, tongue or other parts of the body
    - shortness of breath, wheezing or difficulty in breathing
  4. You have severe liver problems or poor kidney function.
  5. You have an irregular heart beat.
  6. The packaging is torn or shows any signs of tampering.
  7. The use by date (Exp.) printed on the pack has passed.
    If it has expired or is damaged return it to your pharmacist for disposal.

Do not take CLARITHROMYCIN AN if you are taking the following medicines:

  • astemizole or terfenadine (commonly used to treat allergy symptoms - these medicines may be available without prescription)
  • cisapride (used to relieve certain stomach problems)
  • pimozide (used to treat schizophrenia)
  • ergotamine or dihydroergotamine (used to treat headaches)
  • lovastatin or simvastatin (used to treat high cholesterol)

Before you start to take it

Tell your doctor if:

  1. You are pregnant or plan to become pregnant. Your doctor will discuss the risks and benefits of taking CLARITHROMYCIN AN when pregnant.
  2. You are breastfeeding or wish to breastfeed. Your doctor will discuss the risks and benefits of taking CLARITHROMYCIN AN when breastfeeding.
  3. You have, or have ever had, any other health problems or medical conditions, including liver problems or poor kidney function.
  4. You are allergic to any other medicines, foods, dyes or preservatives.
  5. You have myasthenia gravis, a condition in which the muscles become weak and tire easily.

If you have not told your doctor about any of the above, tell them before you start taking or are given CLARITHROMYCIN AN.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect the way CLARITHROMYCIN AN works. These include the following medicines:

  • digoxin, quinidine, disopyramide (used to treat heart failure)
  • warfarin (used to prevent blood clotting)
  • phenytoin, carbamazepine, hexobarbital, sodium valproate (used to treat epilepsy)
  • theophylline (used to treat asthma)
  • triazolam, midazolam, alprazolam (used to treat sleeplessness and anxiety)
  • cilostazol (used to treat poor circulation)
  • rosuvastatin, atorvastatin (used to treat high cholesterol)
  • methylprednisolone (a corticosteroid)
  • vinblastine (used to treat cancer)
  • sildenafil, tadalafil, vardenafil (used to treat erectile dysfunction in adult males)
  • cyclosporin, tacrolimus (medicines affecting the immune system)
  • medicines used to treat HIV infection
  • rifabutin, rifampicin (used to treat some infections)
  • repaglinide, nateglinide, pioglitazone, and rosiglitazone (used to treat diabetes)
  • insulin (used to treat diabetes)
  • colchicine (used to treat gout)
  • verapamil (used to treat high blood pressure)
  • fluoxetine (used to treat depression)
  • omeprazole (used to treat stomach problems)
  • tolterodine (used to treat bladder problems)
  • herbal medicines such as St John’s Wort

These medicines may be affected by CLARITHROMYCIN AN or may affect how well CLARITHROMYCIN AN works. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while taking CLARITHROMYCIN AN.

How to take CLARITHROMYCIN AN

Your doctor will tell you how much to take and when to take it. Take CLARITHROMYCIN AN exactly as directed by your doctor.

This may differ from the information contained in this leaflet.

How much to take

The dose of CLARITHROMYCIN AN will depend on the infection to be treated.

For respiratory tract infections and skin infections, the usual adult dose is one CLARITHROMYCIN AN 250 mg tablet twice a day.

For more severe infections, the dose can be increased to two CLARITHROMYCIN AN 250 mg tablet twice a day.

Your doctor will adjust the amount or frequency of your doses according to the infection being treated and the severity of your condition.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

CLARITHROMYCIN AN tablets should be swallowed whole with a glass of water.

How long to take it

Keep taking CLARITHROMYCIN AN until you finish the pack or for as long as your doctor tells you.

If you are being treated for an infection, CLARITHROMYCIN AN is usually taken for one or two weeks.

Do not stop taking CLARITHROMYCIN AN, even if you feel better after a few days, unless advised by your doctor.

Your infection may not clear completely if you stop taking your medicine too soon.

Check with your doctor if you are not sure how long you should be taking CLARITHROMYCIN AN.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you miss more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much CLARITHROMYCIN AN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. Keep telephone numbers for these places/services handy.

If you take too much CLARITHROMYCIN AN, you may develop severe gastrointestinal symptoms, liver problems, or allergic reactions.

While you are taking CLARITHROMYCIN AN

Things you must do

If you are taking CLARITHROMYCIN AN for an infection and your symptoms do not improve within a few days, or if they become worse, tell your doctor.

If you become pregnant while taking CLARITHROMYCIN AN, tell your doctor.

If you get severe diarrhoea, tell your doctor or pharmacist immediately. Do this even if it occurs several weeks after stopping CLARITHROMYCIN AN.

Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any medicine to stop your diarrhoea without first checking with your doctor.

If you have to have any urine tests, tell your doctor you are taking CLARITHROMYCIN AN as it may affect the results of some laboratory tests.

If you are about to start taking a new medicine, tell your doctor or pharmacist that you are taking CLARITHROMYCIN AN.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking CLARITHROMYCIN AN.

Things you must not do

Do not use CLARITHROMYCIN AN to treat any other complaints unless your doctor says so.

Do not give CLARITHROMYCIN AN to anyone else, even if their symptoms seem similar to yours.

Things to be careful of

Be careful driving or operating machinery until you know how CLARITHROMYCIN AN affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CLARITHROMYCIN AN.

CLARITHROMYCIN AN treats infections in most people, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

While you are taking Clarithromycin AN

Tell your doctor if you experience any of the following and they worry you:

  • stomach cramps and pains
  • nausea, vomiting and severe diarrhoea
  • oral thrush or vaginal thrush
  • change in taste sensation
  • headache

Tell your doctor immediately if you notice any of the following, as you may need urgent medical care:

  • yellowing of the eyes or skin (jaundice)
  • feeling generally unwell and having poor appetite
  • hearing disturbances
  • chest pain
  • dizziness, confusion, hallucinations, convulsions
  • any type of skin rash, itching, hives
  • severe diarrhoea, especially if bloody
  • severe upper stomach pain, with nausea and vomiting (pancreatitis)

Stop taking CLARITHROMYCIN AN and tell your doctor immediately or go to casualty at your nearest hospital if any of the following happen:

  • swelling of the face, lips, mouth, throat or neck which may cause difficulty in swallowing or breathing or sudden collapse

After you have finished taking Clarithromycin AN

Tell your doctor immediately if you notice any of the following side effects, even if they occur several weeks after stopping treatment with CLARITHROMYCIN AN:

  • severe stomach or abdominal cramps
  • watery and severe diarrhoea, which may also be bloody
  • fever, in combination with one or both of the above.

These are rare but serious side effects. You may have a serious condition affecting your bowel and you may need urgent medical care.

Do not take any diarrhoea medicine without first checking with your doctor.

Other side effects not listed above may also occur in some patients. Ask your doctor or pharmacist for more information about side effects, as they have a more complete list of side effects. Inform your doctor promptly about these or any other symptoms. If the condition persists or worsens, seek medical attention. Do not be alarmed by this list of possible side effects. They do not occur often and you are unlikely to experience any of them.

Tell your doctor if you notice anything that is making you feel unwell while you are taking, or soon after you have finished taking CLARITHROMYCIN AN, even if it is not on this list.

After taking CLARITHROMYCIN AN

Storage

Keep your medicine where children cannot reach them.

A locked cupboard at least 1.5 metres above the ground is a good place to store medicines.

Keep the pack away from sources of heat.

Keep CLARITHROMYCIN AN tablets in a cool dry place, protected from light, where the temperature stays below 30°C.

Do not keep CLARITHROMYCIN AN or any other medicine in the bathroom or near a sink. Do not leave CLARITHROMYCIN AN in the car or on window sills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking CLARITHROMYCIN AN, or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

CLARITHROMYCIN AN 250 mg tablets (AUST R 184263) are bright yellow, capsule shaped tablets with ‘CLA’ engraved on one side and ‘250’ engraved on the other side.

Ingredients

Active Ingredient:
The active ingredient in CLARITHROMYCIN AN tablets is clarithromycin. Each tablet contains 250 mg of clarithromycin.

Other Ingredients:

  • croscarmellose sodium,
  • pregelatinised maize starch,
  • microcrystalline cellulose,
  • povidone,
  • stearic acid,
  • magnesium stearate,
  • colloidal anhydrous silica,
  • quinoline yellow,
  • Opadry White Y-1-7000 hypromellose,
  • quinoline yellow,
  • aluminium lake,
  • vanillin flavour.

CLARITHROMYCIN AN tablets do not contain lactose or gluten.

Name and Address of the Sponsor

Scentia Pharmaceuticals Pty Ltd
8 - 12 Ordish Road
Dandenong South,
VIC - 3175
Australia

Date of Preparation

January 2014

Doc ID: 51.AN.M.1.0

BRAND INFORMATION

Brand name

Clarithromycin AN Tablets

Active ingredient

Clarithromycin

Schedule

S4

 

Name of the medicine

Clarithromycin.

Excipients.

Microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, povidone, stearic acid, magnesium stearate, anhydrous colloidal silica, quinoline yellow, Opadry White Y-1-7000 (containing hypromellose, titanium dioxide and macrogol 400), quinoline yellow aluminium lake, hypromellose and vanillin.

Description

Chemical name: (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-C- methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]oxacyclotetradecane-2,10-dione (6-O-methylerythromycin A). Molecular formula: C38H69NO13. MW: 747.97. CAS: 81103-11-9. Clarithromycin is a semisynthetic macrolide antibiotic. Clarithromycin is a white to off white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol and acetonitrile, and practically insoluble in water.

Pharmacology

Hepatotoxicity, atrophy of lymphatic tissues (lymph, thymus) and adverse reproductive toxicity were seen in several species at exposures less than those which might be expected clinically at the proposed doses. The clinical significance of these observations is not known. There are no data from long-term animal carcinogenicity studies.

Clinical pharmacokinetics.

Clarithromycin is absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg tablets is approximately 50%.
Food intake half an hour before tablet dosing increased both the rate and extent of clarithromycin absorption. In a study on the 250 mg tablets, the mean Cmax and AUC values were 0.72 ± 0.27 microgram/mL and 4.3 ± 1.5 microgram.h/mL (fasting) and 0.84 ± 0.38 microgram/mL and 4.7 ± 1.7 microgram.h/mL (nonfasting), respectively. The consequences for clinical efficacy of the increase in bioavailability caused by food are not known.
In studies of fasting healthy adults, peak serum concentrations were attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations were attained in 2 to 3 days and were approximately 1 microgram/mL with a 250 mg dose administered every 12 hours and 2 to 3 microgram/mL with a 500 mg dose administered every 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 12 hours but is quite marked at higher doses. With a 250 mg every 12 hours dosing, the principal metabolite, 14-hydroxy-clarithromycin attains a peak steady-state concentration of about 0.6 microgram/mL and has an elimination half-life of 5 to 6 hours. With a dose of 500 mg every 12 hours, the peak steady-state concentrations of 14-hydroxy-clarithromycin are slightly higher (up to 1 microgram/mL) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2 to 3 days.
Clarithromycin and the 14-hydroxy-clarithromycin metabolite distribute readily into body tissues and fluids. In vitro studies showed that protein binding of clarithromycin in human plasma averaged about 70% at clinically relevant concentrations of 0.45 to 4.5 mg/mL. Because of high intracellular concentrations, tissue concentrations may be higher than serum concentrations (see Table 1). Animal studies indicate that clarithromycin penetration into the CNS is poor.
Information was obtained regarding the penetration of clarithromycin in middle ear fluid in paediatric patients with otitis media. Approximately 2.5 hours after receiving the fifth dose (7.5 mg/kg twice daily) the mean concentration of clarithromycin was 2.53 microgram/g fluid in the middle ear, and for the 14-OH metabolite was 1.27 microgram/g. The concentrations of parent drug and 14-OH metabolite were variable, with two-thirds of patients having levels greater than the corresponding concentration in serum and one-third of patients having levels similar or lower. The mean ratio was 2.48 ± 3.57.
Approximately 20% of a 250 mg oral dose given every 12 hours is excreted in the urine as unchanged clarithromycin. After a dose of 500 mg every 12 hours, urinary excretion of unchanged parent drug is approximately 30%. The renal clearance of clarithromycin is however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-hydroxy-clarithromycin which accounts for an additional 10% to 15% of either a 250 mg or 500 mg dose administered every 12 hours.
A number of drugs are metabolised by specific forms (isoforms) of the cytochrome P450 enzyme system. If two drugs are metabolised by the same isoform, the propensity for an interaction between the two drugs is magnified.
Studies demonstrate that clarithromycin undergoes cytochrome P450 dependent N-demethylation and 14-(R)-hydroxylation in the presence of human liver microsomes. Available data indicate that N-demethylation and 14-(R)-hydroxylation of clarithromycin are mediated principally by members of the CYP3A subfamily, most likely CYP3A4, and that CYP2C19, CYP2D6, CYP2E1, CYP1A2, CYP2C9 and CYP2A6 play relatively minor roles.

Impaired hepatic function.

The steady-state concentrations of clarithromycin in patients with impaired hepatic function did not differ from those of normal patients; however, the 14-hydroxy-clarithromycin concentrations were lower in hepatically impaired patients. The decreased formation of 14-hydroxy-clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the patients with impaired hepatic function when compared to healthy patients.

Impaired renal function.

The pharmacokinetics of clarithromycin were also altered in patients with impaired renal function who received multiple 500 mg doses. The plasma levels, half life, Cmax, Cmin for both clarithromycin and its 14-hydroxy metabolite were higher and the AUC was larger in patients with renal impairment than in normal patients. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference. Plasma levels and elimination half-life start increasing at creatinine clearance values of less than 30 mL/min. The need for dosage adjustment should be considered in such cases (see Dosage and Administration).

Helicobacter pylori infection with concomitant omeprazole administration.

A pharmacokinetic study was conducted with clarithromycin 500 mg three times a day and omeprazole 40 mg daily. When clarithromycin was given alone at 500 mg every eight hours, the mean steady-state Cmax value was approximately 3.8 microgram/mL and the mean Cmin value was approximately 1.8 microgram/mL. The mean AUC0-8 for clarithromycin was 22.9 microgram.hr/mL. The Tmax and half-life were 2.1 hr and 5.3 hr, respectively, when clarithromycin was dosed at 500 mg three times a day.
In the same study when clarithromycin 500 mg three times a day was administered with omeprazole 40 mg daily, increases in omeprazole half-life and AUC0-24 were observed. For all subjects combined, the mean omeprazole AUC0-24 was 89% greater and the harmonic mean for omeprazole t1/2 was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state Cmax, Cmin, and AUC0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively, over values achieved when clarithromycin was administered with placebo.
At steady state, clarithromycin gastric mucus concentrations 6 hours postdosing were approximately 25-fold higher in the clarithromycin-omeprazole group compared with the clarithromycin alone group. Six hours postdosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.

Mycobacterial infection.

The steady-state concentrations of clarithromycin and 14-hydroxy-clarithromycin in adults with HIV infection did not differ from those in non-HIV infected patients. However, at the higher doses which may be required to treat mycobacterial infections, clarithromycin concentrations were much higher than those observed at the usual doses.
In adult HIV infected patients taking 1000 mg/day in two divided doses, steady state clarithromycin Cmax values ranged from 5 to 10 microgram/mL. Elimination half-lives appeared to be lengthened at these higher doses as compared to that seen with usual doses in non-HIV infected patients. The higher plasma concentrations and longer elimination half lives observed at these doses are consistent with the known nonlinearity of clarithromycin pharmacokinetics.

Clinical pharmacology.

Helicobacter pylori is strongly associated with peptic ulcer disease. Ninety to 100% of patients with peptic ulcers are infected with this pathogen. Eradication of H. pylori is associated with a reduction in the rate of duodenal ulcer recurrence, thereby reducing the need for maintenance antisecretory therapy.
The development of antimicrobial resistance may have an adverse effect on eradication regimens. The clinical impact of clarithromycin resistance on H. pylori eradication has not been studied.
The optimal treatment regimen for the eradication of H. pylori is yet to be determined.

Microbiology.

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunits of susceptible organisms and inhibiting protein synthesis. The minimum inhibitory concentrations (MIC) of clarithromycin are generally one log2 dilution more potent than the MICs of erythromycin. However, clarithromycin is much more potent than erythromycin against atypical mycobacteria.
Clarithromycin is active in vitro and in vivo against the organisms listed below.

Usually sensitive bacteria.

Chlamydia pneumoniae (TWAR), Haemophilus influenzae, Haemophilus parainfluenzae, Helicobacter pylori, Legionella pneumophila, Moraxella (Branhamella) catarrhalis, Mycobacterium avium, Mycobacterium chelonae, Mycobacterium intracellulare, Mycoplasma pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, alpha-haemolytic Streptococci (viridans group).

Nonsensitive bacteria.

Enterobacteriaceae, Pseudomonas species.

Note.

1. Most strains of methicillin resistant and oxacillin resistant staphylococci are resistant to clarithromycin.
2. Clarithromycin is not active in vitro against M. tuberculosis.
The principal metabolite of clarithromycin in man is a microbiologically active metabolite, 14-hydroxy-clarithromycin. This metabolite is as active or one to twofold less active than the parent compound for most organisms, except against H. influenzae where it is twice as active.
Clarithromycin was found to be 2 to 10 times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse subcutaneous abscess and mouse respiratory tract infections caused by S. pneumoniae, S. aureus, S. pyogenes and H. influenzae. In guinea pigs with Legionella infection, this effect is more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50 mg/kg/day of erythromycin.

Susceptibility testing of bacteria other than atypical mycobacteria.

Dilution or diffusion techniques, either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of ‘susceptible’ indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of ‘intermediate’ indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of ‘resistant’ indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Note.

The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.

Susceptibility testing of atypical mycobacteria.

No standard reference method for susceptibility testing of atypical mycobacteria currently exists, nor has a correlation between the results of in vitro susceptibility testing and clinical efficacy been clearly established. Clinical isolates of M. avium and M. intracellulare resistant to clarithromycin have been reported. Susceptibility testing of atypical mycobacteria requires specialised techniques and media, and should be referred to a mycobacterial reference laboratory.

Clinical Trials

In a well controlled, double blind study, H. pylori infected duodenal ulcer patients received triple therapy with clarithromycin 500 mg bid, amoxycillin 1000 mg bid and omeprazole 20 mg daily for 10 days or dual therapy with clarithromycin 500 mg tid and omeprazole 40 mg daily for 14 days. H. pylori was eradicated in 88% of the patients (intent to treat analysis) receiving triple therapy and in 55% of the patients (intent to treat analysis) receiving dual therapy.
In well controlled, double blind studies, H. pylori infected duodenal ulcer patients received eradication therapy with clarithromycin 500 mg tid and omeprazole 40 mg daily for 14 days, followed by omeprazole 40 mg (study A) or omeprazole 20 mg (study B, C, D) daily for an additional 14 days. Patients in each control group received omeprazole alone for 28 days. In study A, H. pylori was eradicated in 81% of patients (intent to treat analysis), who received clarithromycin and omeprazole and in only 1% in patients receiving omeprazole alone. In studies B, C, and D, the combined eradication rate was from 56 to 68% (intent to treat analysis), in patients receiving clarithromycin and omeprazole and less than 1% in patients receiving omeprazole alone. The rate of ulcer recurrence at 6 months was statistically lower in the clarithromycin and omeprazole treated patients when compared to patients receiving omeprazole alone.
The development of antimicrobial resistance may have an adverse effect on eradication regimens. The clinical impact of clarithromycin resistance on H. pylori eradication has not been studied.
The optimal treatment regimen for the eradication of H. pylori is yet to be determined.
In a randomised, double blind study of the safety and efficacy of clarithromycin for the prevention of disseminated Mycobacterium avium complex (MAC) infection in HIV infected patients with CD4 counts ≤ 100 cells/mm3, 113 (33.9%) clarithromycin patients and 155 (46.4%) placebo patients either died or developed a MAC infection. This represents a statistically significant (p < 0.001) reduction of 37% in the combined risk of developing MAC or dying for the clarithromycin group compared to the placebo group. Figure 1 summarises the analysis of MAC free survival.

Indications

Clarithromycin AN is indicated for use in adults and children older than 12 years for the treatment of mild to moderately severe infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
1. Acute streptococcal pharyngitis.
2. Community acquired pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophilia and Streptococcus pneumoniae.
3. Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes.
4. Disseminated or localised mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare and skin and skin structure infections due to Mycobacterium chelonae. Clarithromycin should be used in combination with other antimycobacterial agents.
5. Prevention of disseminated Mycobacterium avium complex infection in HIV infected adults with CD4 lymphocyte counts < 75 cells/mm3 (see Precautions). Disseminated infection due to Mycobacterium avium complex should be excluded by a negative blood culture prior to commencement of prophylaxis.
6. Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
7. Combination therapy for the treatment of peptic ulcer disease associated with Helicobacter pylori infection.
Clarithromycin AN (clarithromycin) is indicated for use in children for the treatment of mild to moderately severe infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
1. Acute streptococcal pharyngitis and tonsillitis caused by Streptococcus pyogenes.
2. Community acquired pneumonia including infections due to Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila.
3. Skin and skin structure infections (e.g. impetigo).
4. Disseminated or localised infections due to Mycobacterium avium or Mycobacterium intracellulare in immunocompromised children, including those with HIV infection or AIDS.
5. Acute otitis media.

Note.

1. Penicillins are the drug of first choice in the treatment of acute otitis media.
2. Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections including prophylaxis of rheumatic fever. Clarithromycin appears to be as effective as phenoxymethylpenicillin in the eradication of Streptococci from the nasopharynx, however substantial data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not available at present.
3. There is insufficient evidence of efficacy to support the use of clarithromycin in acute bronchitis in young children.
4. The data presented on infections of skin and skin structure were confined largely to mild to moderate infections such as impetigo.

Contraindications

Clarithromycin is contraindicated in patients with known hypersensitivity to macrolide antibiotic drugs or any of its excipients.
Concurrent administration of clarithromycin and any of the following drugs is contraindicated: astemizole, terfenadine, cisapride, pimozide, as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity. Concomitant administration of clarithromycin with lovastatin or simvastatin is also contraindicated (see Precautions).
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes (see Precautions).
Colchicine is contraindicated in patients with renal or hepatic impairment who are taking a p-glycoprotein inhibitor or a strong CYP3A4 inhibitor.

Precautions

General.

Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of significant renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate (see Dosage and Administration). Caution is advised in patients with severe renal insufficiency.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.
In vitro studies have demonstrated cross resistance between clarithromycin, erythromycin, azithromycin and other macrolides, as well as lincomycin and clindamycin. Attention should be paid to this possibility when considering the use of clarithromycin. Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug resistant organisms.
Long-term use may, as with other antibiotics, result in colonisation with increased numbers of nonsusceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Due to the risk for QT prolongation clarithromycin should be used with caution in patients with a medical condition associated with an increased tendency toward QT prolongation and torsades de pointes.

Myasthenia gravis.

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

Pseudomembranous colitis.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including macrolides. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range 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.
It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against C.difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil), may prolong and/or worsen the condition and should not be used.

Prophylaxis of Mycobacterium avium complex infection.

The majority of cases of disseminated Mycobacterium avium complex infection occur in patients with CD4 cell counts below 50 cells/mm3. Some authorities recommend delay of initiation of prophylaxis until the cell count has fallen to 50 cells/mm3.

Patients with duodenal ulcers.

Patients with bleeding duodenal ulcers should be maintained on antisecretory therapy.

Colchicine.

There have been postmarketing 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 Interactions with Other Medicines, Colchicine.)

Triazolobenzodiazepines.

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam (see Interactions with Other Medicines, Triazolobenzodiazepines).

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 and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, and Henoch-Schonlein purpura clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see Interactions with Other Medicines).

Oral hypoglycemic agents/ insulin.

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

Oral anticoagulants.

There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is coadministered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

HMG-CoA reductase inhibitors.

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated and treatment with these agents should be discontinued during clarithromycin treatment (see Contraindications). As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors. 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.

Use in pregnancy.

(Category B3)
Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking this drug, the patient should be appraised of the potential hazard to the foetus. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryofoetal development in monkeys, rats, mice and rabbits at doses that produced plasma levels 2 to 17 times the serum levels achieved in humans treated at the maximum recommended doses.
Four teratogenicity studies in rats (3 with oral doses and one with intravenous dose up to 160 mg/kg/day administered during the period of organogenesis) and two in rabbits (an oral dose up to 125 mg/kg/day or an intravenous dose of 160 mg/kg/day administered during gestation days 6 to 18) failed to demonstrate any teratogenicity due to clarithromycin. Two other studies in rats under similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15. Plasma AUC values after administration of 150 mg/kg/day to rats were approximately comparable with AUC values in humans given 500 mg clarithromycin twice daily. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day dose in mice resulted in AUC values 9 times the AUC values in humans given 500 mg clarithromycin twice a day. Abortions were observed in monkeys receiving 150 mg/kg/day on days 20 to 50 of pregnancy. AUC values in monkeys receiving this dose were about 2.5-fold higher than AUC values in humans given 500 mg clarithromycin twice daily.
The safety of clarithromycin for use in pregnancy has not been established. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.

Use in lactation.

Clarithromycin and other macrolides are excreted in human breast milk. The safety of clarithromycin for use during breastfeeding of infants has not been established.

Use in the elderly.

Dosage adjustments are recommended in those patients with possible severe renal impairment (see Dosage and Administration).

Paediatric patients.

The use of Clarithromycin AN tablets has not been studied in children less than 12 years of age.

Carcinogenicity.

Long-term studies in animals have not been performed to assess carcinogenic potential.

Genotoxicity.

Clarithromycin gave negative results in a battery of mutagenicity studies with the exception of a positive result in an in vitro chromosome aberration assay.

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.

Interactions

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

Cisapride and pimozide.

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 Contraindicatons).

Ergotamine/ dihydroergotamine.

Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischaemia of the extremities and other tissues, including the central nervous system.
Concomitant administration of clarithromycin and these medicinal products is contraindicated (see Contraindications).

Terfenadine.

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 Contraindications).

Effects of other medicinal products on clarithromycin.

Drugs 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 subtherapeutic 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 inhibitor 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.

Efavirenz, nevirapine, rifampicin and rifabutin.

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin and rifabutin 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 adult volunteers led to increases in the mean steady-state of clarithromycin concentration (Cmin) and AUC of 33% and 18%, respectively. Steady-state concentrations of 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 q 8 hours and clarithromycin 500 mg q 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 (99.8% decrease) 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 coadministered 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). Conversely, clarithromycin increases ritonavir AUC by 12%; no dosage adjustment of ritonavir is recommended.

Fluoxetine.

Fluoxetine is partially metabolised by the 2D6 isoform of P450. It is a weak inhibitor of CYP3A; theoretically, this inhibition could result in possible elevation of clarithromycin levels.

Effect of clarithromycin on other medicinal products.

Antiarrhythmics.

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

CYP3A based interactions.

Coadministration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme.
Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
As with other macrolide antibiotics, the use of clarithromycin in patients concurrently taking drugs metabolised by the cytochrome P450 system (e.g. alprazolam, cilostazol, oral anticoagulants such as warfarin, ergot alkaloids, methylprednisolone, quinidine, triazolam, valproate, vinblastine, midazolam, disopyramide, phenytoin, digoxin, tacrolimus, cyclosporine, rifabutin and sildenafil) may be associated with elevations in serum levels of these other drugs.

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 coadministered 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. Coadministration 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 coadministered with clarithromycin.

Theophylline.

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 mg or 500 mg q 12 h clarithromycin), the steady-state levels of Cmax, Cmin and the area under the serum concentration time curve (AUC) increased about 20%. Theophylline dosage may need to be reduced.

Carbamazepine.

Single dose administration of clarithromycin has been shown to result in increased concentrations of carbamazepine. Blood level monitoring of carbamazepine may 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. triazolam and alprazolam) and related benzodiazepines (e.g. midazolam).

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus may increase the pharmacologic effect of these benzodiazepines. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is coadministered with clarithromycin, the patient must be closely monitored to allow dose adjustment.
The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines, which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely. There have been postmarketing reports of drug interactions and 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.

Repaglinide.

Clarithromycin may enhance and/or prolong the hypoglycaemic effect of repaglinide. In an interaction study in healthy volunteers, coadministration of 250 mg clarithromycin, a mechanism based inhibitor of CYP3A4, increased the repaglinide AUC by 40% and Cmax by 67%, and increased the mean incremental AUC of serum insulin by 51% and the maximum concentration by 61%. The exact mechanism of this interaction is not clear.

Other drug Interactions.

Colchicine.

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

Digoxin.

When clarithromycin and digoxin are administered together, inhibition of P-glycoprotein (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 postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentration should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine.

Simultaneous oral administration of clarithromycin and zidovudine in 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 largely be avoided by staggering the doses of clarithromycin and zidovudine by at least two hours. This interaction does not appear to occur in paediatric HIV infected patients taking clarithromycin suspensions with zidovudine or didanosine.

Phenytoin and valproate.

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolized 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.

Bidirectional drug interactions.

Atazanavir.

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction. 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 coadministered 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 bidirectional drug interaction. When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Precautions, Drug interactions).

Verapamil.

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

Interaction that has been investigated, for which outcome was negative.

Didanosine.

Simultaneous administration of clarithromycin tablets and didanosine in 12 HIV infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.

Indinavir.

The potential pharmacokinetic interaction between indinavir and clarithromycin was assessed in a 3 period, randomised, crossover, multiple dose study. Plasma concentration profiles of indinavir were consistently slightly higher in the presence of clarithromycin, although Cmax changed minimally. Thus, clarithromycin has a modest inhibitory effect on indinavir metabolism. Results suggest that indinavir competitively inhibits the oxidative metabolism of clarithromycin. The magnitude of the changes in the pharmacokinetics of clarithromycin and indinavir were not considered to be clinically significant, and coadministration of the drugs does not require dose adjustment.

Ketoconazole.

Ketoconazole appreciably inhibits the N-demethylation of erythromycin. At this time there is no data regarding concomitant administration of ketoconazole and clarithromycin.

Adverse Effects

Clinical trial experience.

Nonmycobacterial infections.

At the recommended doses for nonmycobacterial infections, clarithromycin was generally well tolerated in the reported clinical trials. The incidence of adverse reactions considered to be remotely, possibly or probably related to treatment was comparable in nature to that with other macrolide antibiotics. Most reactions were described as mild to moderately severe; less than 1% were described as severe. Fewer than 3% of patients discontinued therapy because of drug related side effects. The following side effects have been reported as common (1-10%) and uncommon (0.1-1%) (see Table 2).

Hepatic system.

As with other macrolides, hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with and without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances (0.03%) hepatic failure with fatal outcomes has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
The following adverse events have not been reported in clinical trials with clarithromycin but have rarely been associated with erythromycin products, ventricular arrhythmias, including ventricular tachycardia and torsades de pointes in individuals with prolonged QT intervals.

Immunocompromised and HIV/ AIDS 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 HIV disease or intercurrent illness.
In adult patients, the most frequently reported adverse events by patients treated with total daily doses of 1000 mg and 2000 mg of clarithromycin were reported in the table above. The incidence is generally about 3 to 4 times more frequent for those patients treated with total daily doses of 4000 mg of clarithromycin.
Approximately 2% to 3% of these patients who received 1000 mg or 2000 mg of clarithromycin daily had seriously abnormal elevated levels (greater than three times upper limit of normal) of aspartate transaminase (AST) and alanine transaminase (ALT) and abnormally low white blood cell (less than 2 x 109/L) or platelet (less than 75 x 109/L) counts. A lower percentage of patients in these two dosage groups also had elevated blood urea levels. Slightly higher incidences of abnormal laboratory values were also noted with these patients for all parameters except for white blood cell count (WBC).

Elderly patients.

Limited data is available in elderly patients with Mycobacterium avium complex infections. In a clinical study, 11/13 patients on doses of clarithromycin between 1000 mg and 2000 mg per day discontinued therapy due to adverse events.

Other reported side effects.

In addition to hepatic dysfunction, side effects such as pseudomembranous colitis, pancreatitis, thrombocytopenia, and a reduction in prothrombin time have also been reported with the use of clarithromycin.

Postmarketing experience.

Adverse events have been reported during postapproval use of clarithromycin. Because these events 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 clarithromycin exposure.

Body as a whole.

Anaphylaxis, abdominal pain, asthenia, allergic reaction, fever, headache.

Skin and skin structure.

Steven-Johnson syndrome, urticaria, rash, pruritus, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, Henoch-Schonlein purpura.

Central nervous system.

Anxiety, insomnia*, hallucinations, confusion, psychosis, vertigo, dizziness, dream abnormality, tinnitus, disorientation, depersonalisation, nervousness, hyperkinesia, depression. There have been rare reports of convulsions.

Haematopoietic and lymphatic system.

Decreased white blood cell counts, decreased platelet counts, thrombocytopenia, leukopenia, agranulocytosis.

Metabolic and nutritional.

Increased serum creatinine, increased gamma glutaryl transferase (GGT), hypoglycaemia1.

Special senses.

Hearing disturbances, taste perversion, smell perversion, ageusia, anosmia, otitis media.

Digestive system.

Dry mouth, tongue discolouration, glossitis, moniliasis, oral stomatitis, diarrhoea, nausea, vomiting, liver abnormalities, tooth discolouration, dyspepsia, enteritis. There have been rare reports of pancreatitis.

Respiratory system.

Dyspnoea.

Urogenital system.

Dysuria, renal failure, isolated cases of increased serum creatinine have been reported but an association has not been established. There have been reports of interstitial nephritis coincident with clarithromycin use.

Cardiac system.2

Torsades de pointes, electrocardiogram, QT prolonged, ventricular tachycardia.

Hepatobiliary system.3

Hepatic failure, hepatitis, hepatitis cholestatic, jaundice cholestatic, jaundice hepatocellular, hepatic function abnormal.

Musculoskeletal and connective tissue disorders.4

Myalgia, rabdomyolysis, myopathy.

Infections and infestations.

Pseudomembranous colitis, erysipelas, erythrasma.

Vascular disorders.

Haemorrhage.

Investigations.

International normalised ratio (INR) increased, prothrombin time prolonged, urine colour abnormal.
1There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin.
2As with other macrolides, QT prolongation, ventricular tachycardia and torsades de pointes have rarely been reported with clarithromycin.
3In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
4In some reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol.
There have been postmarketing 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 Interactions with Other Medicines, Colchicine and Precautions.)
*See Immunocompromised and HIV/AIDS patients.

Dosage and Administration

Patients with nonmycobacterial infections.

The usual recommended dosage of clarithromycin is 250 mg twice daily. In more severe infections, the dosage can be increased to 500 mg (as 2 x 250 mg tablets) twice daily. The usual duration of therapy is 7 to 14 days.
For the treatment of Legionella pneumophilia infection, a dose of 500 mg (as 2 x 250 mg tablets) twice daily for 4 weeks is appropriate.
In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of clarithromycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

Note.

In the treatment of haemolytic streptococcal infections, a therapeutic regimen should be administered for at least 10 days.

Patients with peptic ulcers.

For the eradication of H. pylori, the recommended dosage regimen is clarithromycin 500 mg (as 2 x 250 mg tablets) bid in conjunction with amoxycillin 1000 mg bid and omeprazole 20 mg daily for 7-10 days.
Patients should be retreated if there is a return of symptoms and H. pylori infection. However, in this situation, possible resistance of the organism to the antimicrobial agents should be considered.
The optimal treatment regimen for the eradication of H. pylori is yet to be determined.

Patients with mycobacterial infections.

A. Treatment of mycobacterial infections.

The recommended dosage for adults and children older than 12 years with disseminated or localised mycobacterial infections is 500 mg (as 2 x 250 mg tablets) twice daily. This may be increased to 1000 mg (as 4 x 250 mg tablets) twice daily if no clinical or bacteriological response is seen after 3-4 weeks of therapy.
Experience in patients older than 65 years is limited. The recommended starting dose for elderly patients with calculated creatinine clearance of greater than 30 mL/min is 500 mg (as 2 x 250 mg tablets) twice a day. A further reduction of the initial dose and dose titration is recommended in those patients with possible severe renal impairment (see Precautions, Adverse Effects).
Clarithromycin should be used in conjunction with other antimycobacterial agents; the optimal regimen for treating patients with mycobacterial infections is yet to be determined.
Treatment with clarithromycin should continue as long as clinical benefit is demonstrated.

B. Prophylaxis of mycobacterial infections.

The recommended dosage of clarithromycin in HIV infected adults with CD4 lymphocyte counts < 75 cells/mm3 for prophylaxis of disseminated Mycobacterium avium complex infections is 500 mg (as 2 x 250 mg tablets) twice daily. Disseminated disease due to Mycobacterium avium complex should be excluded by a negative blood culture prior to commencement of prophylaxis, and concurrent medication reviewed to avoid the possibility of drug interaction. Should prophylaxis fail, at least two other nonmacrolide agents with good antimycobacterial activity should be chosen empirically, as the isolate of Mycobacterium avium complex may be highly resistant to clarithromycin and other macrolides.
Clarithromycin has not been studied as a prophylactic agent in mycobacterial infections in other immunocompromised groups or in HIV infected children. Also, clarithromycin has no useful activity against Mycobacterium tuberculosis.

Overdosage

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce pronounced gastrointestinal symptoms. Severe liver toxicity, including cholestatic jaundice may occur.
There is no known antidote. Treatment consists of prompt elimination of the unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.
For advice on the management of overdose please contact the Poisons Information Centre in Australia please call 131 126.

Presentation

Tablets, 250 mg (bright yellow, capsule shaped, marked CLA, 250 on reverse): 2's*, 10's*, 14's, 100's* (PVC/PVDC/ aluminium blister pack, AUST R 184263).
*Not currently marketed in Australia.

Storage

Store below 30°C.

Poison Schedule

S4.