Consumer medicine information

APO-Clarithromycin

Clarithromycin

BRAND INFORMATION

Brand name

APO-Clarithromycin

Active ingredient

Clarithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Clarithromycin.

What is in this leaflet

This leaflet answers some common questions about clarithromycin. It does not contain all 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 using this medicine 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 want to read it again.

What this medicine is used for

Clarithromycin belongs to a group of medicines called macrolide antibiotics.

Clarithromycin is used to treat certain bacterial infections, such as:

  • respiratory tract infections
  • skin infections
  • peptic ulcers

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

How it works

Clarithromycin works by killing or stopping the growth of bacteria which causes infections.

This medicine will not work against infection caused by viruses, such as cold or flu.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

These tablets are not recommended for children under 12 years of age.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • clarithromycin
  • other macrolide antibiotics (e.g. erythromycin, roxithromycin, azithromycin)
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you have or have had any of the following medical conditions:

  • irregular heartbeat, including Torsades de pointes
  • severe liver and kidney problems
  • liver or kidney problems, and taking a p-glycoprotein inhibitor or a strong CYP3A4 inhibitor
  • hypokalaemia (low potassium).

Do not take this medicine if you are taking any of the following medicines:

  • astemizole or terfenadine, used to treat allergy symptoms
  • cisapride, used to treat stomach problems
  • pimozide, used to treat psychotic disorders
  • ergotamine or dihydroergotamine, used to treat migraines
  • lovastatin or simvastatin, used to treat high cholesterol
  • midazolam
  • ticagrelor or ranolazine

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver, kidney or heart problems
  • low potassium or magnesium
  • myasthenia gravis
  • pneumonia
  • skin and soft tissue infections.

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

Taking other medicines

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

Some medicines may interact with clarithromycin. These include:

  • medicines used to prevent blood clotting (e.g. warfarin, cilostazol)
  • some medicines used for epilepsy (e.g. phenytoin, valproate, carbamazepine, hexobarbital)
  • theophylline, used to treat asthma
  • some medicines used to treat heart complaints (e.g. digoxin, quinidine, disopyramide, verapamil, amlodipine, diltiazem)
  • medicines used to treat sleeplessness such as triazolam
  • alprazolam, used to treat anxiety
  • anti-viral medicines (e.g. zidovudine, ritonavir, indinavir, atazanavir, saquinavir, efavirenz, nevirapine, etravirine)
  • some antibiotics (e.g. rifampicin, rifabutin, aminoglycosides)
  • itraconazole and ketoconazole, used to treat fungal infections
  • fluoxetine, used for treating depression
  • colchicine, used to treat gout
  • some medicines used to treat erection problems (e.g. sildenafil, tadalafil, vardenafil)
  • vinblastine, used to treat certain cancers
  • some medicines used to suppress the immune system (e.g. cyclosporin, tacrolimus, methylprednisolone)
  • atorvastatin and rosuvastatin, used for lowering cholesterol
  • omeprazole, used in treating stomach ulcers
  • tolterodine, used to treat urinary incontinence
  • medicines used to treat diabetes, (e.g. insulin, repaglinide, nateglinide, pioglitazone, rosiglitazone)
  • herbal medicines (e.g. St John's Wort)

If you are taking any of these, you may need a different dose, or you may need to take different medicines.

Other medicines not listed above may also interact with clarithromycin.

How to take this medicine

Follow all directions given to you by your doctor and pharmacist carefully. They may differ to the information contained in this leaflet.

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

How much to take

Your doctor will tell you how much of this medicine you should take, depending on your condition and if you are taking any other medicines.

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

For more severe infections, the dose may be increased.

For respiratory tract infections, the usual dose for children is 7.5mg/kg twice a day.

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

How to take it

Swallow the tablet whole with a full glass of water.

When to take it

Take your medicine at about the same time each day. Taking your medicine at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take it with or without food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

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

Do not stop taking clarithromycin, 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.

Make sure you have enough to last over weekends and holidays.

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 it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much clarithromycin, you may develop severe stomach problems, liver problems or experience an allergic reaction.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

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

Tell your doctor immediately if you get severe diarrhoea. Do this even if it occurs several weeks after stopping clarithromycin. 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 get a sore white mouth or tongue while taking or soon after stopping clarithromycin, tell your doctor. Also tell your doctor if you get vaginal itching or discharge. This may mean you have a fungal infection called thrush. Sometimes the use of this medicine allows fungi to grow and the above symptoms to occur.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor. Your infection may not clear completely if you stop taking your medicine too soon.

Things to be careful of

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

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking clarithromycin.

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

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist if you notice any of the following:

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

Tell your doctor as soon as possible if you notice any of the following:

  • 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)
  • unexpected muscle pain, tenderness or weakness not caused by exercise.

These may be serious side effects and you may need medical attention.

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

  • 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 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 occur in some patients.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Allergic reactions

If you think you are having an allergic reaction to clarithromycin, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take the tablets out of their pack, they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

250 mg tablets:
Pale yellow, oval, film-coated tablets engraved "CLA250" on one side, "APO" on the other side.

Available in blister packs of 2, 14, 28 and 100 tablets. AUST R 134850

Available in bottles of 14, 28 and 100 tablets. AUST R 134865

500 mg tablets:
Pale yellow, capsule-shaped, film-coated tablets engraved "CLA500" on one side, "APO" on the other side.

Available in blister packs of 3, 14, 20, 28, 42 and 100 tablets. AUST R 134856

Available in bottles of 14, 20, 28, 42 and 100 tablets. AUST R 134883

* Not all strengths, pack sizes and/or pack types may be available.

Ingredients

Each tablet contains 250 mg or 500 mg of clarithromycin as the active ingredient.

It also contains the following:

  • microcrystalline cellulose
  • croscarmellose sodium
  • magnesium stearate
  • colloidal anhydrous silica
  • hypromellose
  • iron oxide yellow E172
  • titanium dioxide E171
  • macrogol 8000

This medicine does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in March 2019.

Published by MIMS May 2019

BRAND INFORMATION

Brand name

APO-Clarithromycin

Active ingredient

Clarithromycin

Schedule

S4

 

1 Name of Medicine

Clarithromycin.

6.7 Physicochemical Properties

Clarithromycin is a semi-synthetic 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.
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.
Molecular Weight: 747.97.

Chemical structure.


CAS number.

81103-11-9.

2 Qualitative and Quantitative Composition

Each tablet contains 250 mg or 500 mg of clarithromycin as the active ingredient.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

250 mg tablets.

Pale yellow, oval, film-coated tablets engraved "CLA250" on one side, "APO" on the other side.

500 mg tablets.

Pale yellow, capsule-shaped, film-coated tablets engraved "CLA500" on one side, "APO" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 in Table 3.

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.

Helicobacter pylori.

Helicobacter pylori is strongly associated with peptic ulcer disease. 90 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.

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 (twice daily), amoxycillin 1000 mg bid and omeprazole 20 mg daily for 10 days or dual therapy with clarithromycin 500 mg tid (three times daily) 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 56-68% (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.

5.2 Pharmacokinetic Properties

Absorption.

Clarithromycin is absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg tablets is approximately 50%. Two 250 mg tablets have been shown to be bioequivalent to one 500 mg tablet. The 250 mg/5 mL powder for oral liquid has been demonstrated to be bioequivalent to the 250 mg clarithromycin tablet.
Food intake half an hour before tablet dosing increased both the rate and extent of clarithromycin absorption, the effects being greater with the 500 mg tablet than with the 250 mg tablet. 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 (non-fasting), respectively. In a study of the 500 mg tablets, the mean Cmax and AUC values were 1.6 ± 0.6 microgram/mL and 12.6 ± 4.0 microgram.h/mL (fasting) and 2.5 ± 0.8 microgram/mL and 15.7 ± 4.9 microgram.h/mL (non-fasting) respectively. The consequences for the clinical efficacy of the increase in bioavailability caused by food are not known.

Distribution.

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 2-3 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 non-linearity 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-OH 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-OH 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-OH 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 4). Animal studies indicate that clarithromycin penetration into the central nervous system (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 (dosage was 7.5 mg/kg twice a day) the mean concentration of clarithromycin was 2.53 microgram/g fluid in the middle ear, and for the 14-hydroxy 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.

Metabolism.

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.

Excretion.

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-OH clarithromycin which accounts for an additional 10-15% of either a 250 mg or 500 mg dose administered every 12 hours.

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 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 post-dosing were approximately 25-fold higher in the clarithromycin/ omeprazole group compared with the clarithromycin alone group. Six hours post-dosing, 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-OH 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 non linearity of clarithromycin pharmacokinetics.

5.3 Preclinical Safety Data

Genotoxicity.

Adverse reproductive toxicity was seen in several species at exposures less than those which might be expected clinically at proposed doses. The clinical significance of these observations is not known. Clarithromycin gave negative results in a battery of mutagenicity studies with the exception of a positive result in an in vitro chromosome aberration assay.

Carcinogenicity.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Clarithromycin 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.
Acute streptococcal pharyngitis.
Community acquired pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila and Streptococcus pneumoniae; see Section 4.4 Special Warnings and Precautions for Use.
Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes, see Section 4.4 Special Warnings and Precautions for Use.
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.
Prevention of disseminated Mycobacterium avium complex infection in HIV infected adults with CD4 lymphocyte counts < 75 cells/mm3 (see Section 4.4 Special Warnings and Precautions for Use). Disseminated infection due to Mycobacterium avium complex should be excluded by a negative blood culture prior to commencement of prophylaxis.
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Combination therapy for the treatment of peptic ulcer disease associated with Helicobacter pylori infection.
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.
Acute streptococcal pharyngitis and tonsillitis caused by Streptococcus pyogenes.
Community acquired pneumonia including infections due to Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila;
Skin and skin structure infections (e.g. impetigo).
Disseminated or localised infections due to Mycobacterium avium or Mycobacterium intracellulare in immunocompromised children, including those with HIV Infection or AIDS.
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.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.3 Contraindications

Hypersensitivity to macrolide antibiotic drugs or any of its excipients.
Clarithromycin should 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concurrent administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide, terfenadine, domperidone, as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
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 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (lovastatin or simvastatin) due to the increased risk of myopathy, including rhabdomyolysis (see Section 4.4 Special Warnings and Precautions for Use).
Clarithromycin (and other strong CYP3A4 inhibitors) should not be used concomitantly with colchicine (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clarithromycin is contraindicated in patients with hypokalaemia (risk of prolongation of QT-time).
Concomitant administration with ticagrelor or ranolazine is contraindicated.
Clarithromycin is contraindicated in patients who suffer from severe hepatic failure in combination with renal impairment.

4.4 Special Warnings and Precautions for Use

General.

In-vitro studies have demonstrated cross-resistance between clarithromycin, erythromycin, azithromycin and other macrolides, as well as lincomycin and clindamycin. Attention should also 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 non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

Cardiovascular events.

Prolonged cardiac repolarization 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 Adverse Effects (Undesirable Effects)). 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 Contraindications).
Patients concomitantly taking other medicinal products associated with QT prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant administration of clarithromycin with astemizole, cisapride, domperidone, pimozide and terfenadine is contraindicated (see Section 4.3 Contraindications).
Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see Section 4.3 Contraindications).
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.
Atrophy of lymphatic tissues (lymph, thymus) were seen in several species at exposures less than those which might be expected clinically at proposed doses. The clinical significance of these observations is not known.

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 Clostridium 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 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 Interactions with Other Medicines and Other Forms of Interactions, Colchicine). Concomitant administration of clarithromycin and colchicine is contraindicated (see Section 4.3 Contraindications).

Triazolobenzodiazepines.

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, intravenous or oromucosal midazolam (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines (such as midazolam)).

Ototoxic drugs.

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

Use in renal impairment.

The pharmacokinetics of clarithromycin was 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-OH 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 Section 4.2 Dose and Method of Administration).
Caution is advised in patients with moderate to severe renal insufficiency (see Section 4.2 Dose and Method of Administration). 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. Treatment should not be continued beyond 14 days in these patients.
Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment (see Section 4.3 Contraindications).

Use in hepatic impairment.

The steady-state concentrations of clarithromycin in patients with impaired hepatic function did not differ from those of normal patients.
The AUC for 14-OH clarithromycin is markedly reduced in hepatic impaired patients, and renal clearance of the parent drug, but not metabolite, is significantly increased.
Clarithromycin is principally excreted via the liver and kidney. Clarithromycin is principally metabolised by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function.
Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment (see Section 4.3 Contraindications).
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 disease and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen. See Use in renal impairment, above.

Pneumonia.

In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity.

These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, 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 generalized exanthematous pustulosis (AGEP), Stevens Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Paediatric use.

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

Use in the elderly.

Dosage adjustments are recommended in those patients with possible severe renal impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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

Cisapride, domperidone 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 Section 4.3 Contraindications).

Ergot alkaloids (e.g. ergotamine/ dihydroergotamine).

Post-marketing reports indicate that co-administration 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 ergot alkaloids is contraindicated (see Section 4.3 Contraindications).

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.

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 Section 4.3 Contraindications).

HMG-CoA reductase inhibitors (statins).

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Section 4.3 Contraindications) as these statins are extensively metabolised 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. Rare reports of rhabdomyolysis have also been reported in patients taking 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. Patients should be monitored for signs and symptoms of myopathy.

Effects of other medicinal products on clarithromycin.

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital [phenobarbitone], 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 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 every 8 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 (99.8% decrease) of the formation of 14-[R]-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 creatinine clearance of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%.
For patients with creatinine clearance of < 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 also 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 postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications should be monitored during clarithromycin therapy.
There have been postmarketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

CYP3A based interactions.

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolised by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolised by this enzyme. Dosage adjustments may be considered and, when possible, serum concentrations of drugs primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
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, atypical antipsychotics (e.g. quetiapine), ergot alkaloids, ibrutinib, domperidone, methylprednisolone, quinidine, triazolam, sodium valproate, vinblastine, midazolam, disopyramide, phenytoin, digoxin, tacrolimus, cyclosporin, rifabutin and sildenafil) may be associated with elevations in serum levels of these other drugs.

Oral anticoagulants.

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

Omeprazole.

Clarithromycin (500 mg every eight 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 drugs are co-administered 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 clarithromycin 250 mg or 500 mg every 12 hours), 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 (such as triazolam and alprazolam) and related benzodiazepines (such as midazolam).

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus may increase the pharmacological effect of these benzodiazepines.
Concomitant administration of oral midazolam and clarithromycin is contraindicated. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Drug delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the drug, 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 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, co-administration of clarithromycin 250 mg, 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.

Oral hypoglycemic agents/insulin.

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

Other drug interactions.

Aminoglycosides.

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides (see Section 4.4 Special Warnings and Precautions for Use).

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. Concomitant use of clarithromycin and colchicine is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

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 2 hours. This interaction does not appear to occur in paediatric HIV infected patients taking clarithromycin suspensions with zidovudine or didanosine.

Phenytoin and sodium valproate.

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolised by CYP3A (e.g. phenytoin and sodium 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 (ClCr 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with ClCr < 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg/day should not be co-administered with protease inhibitors.

Itraconazole.

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

Saquinavir.

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Ritonavir).

Calcium channel blockers.

Acute kidney injury has been reported in patients using clarithromycin and calcium channel blockers (CCBs) metabolised by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) although the causal association cannot be established. Most of these cases involved elderly patients 65 years of age or older.
Additionally, caution is advised regarding the concomitant administration of clarithromycin and CCBs metabolized by CYP3A4 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.

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 co-administration of the drugs does not require dose adjustment.

Ketoconazole.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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 embryo-foetal 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 (three with oral doses and one with intravenous dose up to 160 mg/kg/day administered during the period of organogenesis) and two in rabbits (at oral doses up to 125 mg/kg/day or intravenous doses 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 exposure in mice resulted in plasma levels 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 times higher than AUC values in humans given clarithromycin 500 mg 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 the risk.
 Clarithromycin and other macrolides are excreted in human breast milk. The safety of clarithromycin for use during breast-feeding of infants has not been established.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Non-mycobacterial infections.

At the recommended doses for non-mycobacterial 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 1.

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 drug events by patients treated with total daily doses of 1000 mg to 2000 mg of clarithromycin were reported in Table 1. The incidence is generally 3 to 4 times more frequent for those patients treated with total daily doses of 4000 mg of clarithromycin.
Approximately 2-3% 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 (< 2 x 109/L) or platelet (< 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 out of 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.

Post-marketing 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. See Table 2.
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 Interactions with Other Medicines and Other Forms of Interactions, Colchicine; Section 4.4 Special Warnings and Precautions for Use).
*See Section 4.8 Adverse Effects (Undesirable Effects), Immunocompromised and HIV/ AIDS patients.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

APO-Clarithromycin tablets are intended for oral administration.

Dosage.

Patients with nonmycobacterial infections.

The usual recommended dosage of clarithromycin in adults and children 12 years of age and older, is 250 mg twice daily. In more severe infections, the dosage can be increased to 500 mg twice daily. The usual duration of therapy is 7 to 14 days.
For the treatment of Legionella pneumophila infection, a dose of 500 mg twice daily for 4 weeks is appropriate.

Note.

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

Renal impairment.

In patients with renal impairment with creatinine clearance < 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. Treatment should not be continued beyond 14 days in these patients.

Patients with peptic ulcers.

For the eradication of H. pylori, the recommended dosage regimen is clarithromycin 500 mg twice daily in conjunction with amoxycillin 1000 mg twice daily and omeprazole 20 mg twice daily for 7-10 days in consultation with national or international guideline recommendations for H. pylori eradication.
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.

Treatment of mycobacterial infections.

The recommended dosage for adults and children older than 12 years with disseminated or localised mycobacterial infections is 500 mg twice daily.
Experience in patients older than 65 years is limited. The recommended starting dose for elderly patients with calculated creatinine clearance > 30 mL/min is 500 mg twice daily. A further reduction of the initial dose and dose titration is recommended in those patients with possible severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Clarithromycin should be used in conjunction with other anti-mycobacterial 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.

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 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 non-macrolide 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.

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.

4.9 Overdose

Symptoms.

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.

Treatment.

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 information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, hypromellose, iron oxide yellow E172, titanium dioxide E171, macrogol 8000.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in original package.

6.5 Nature and Contents of Container

APO-Clarithromycin tablets.

250 mg tablets.

Blister pack (PVC/PVDC/AL) of 2, 14, 28 and 100 tablets. AUST R 134850.
Bottles (HDPE bottle, CAP 53-400 Blue PP Lift and Peel) of 14, 28 and 100 tablets. AUST R 134865.

500 mg tablets.

Bottles (HDPE bottle, CAP 53-400 Blue PP Lift and Peel) of 14, 20, 28, 42 and 100 tablets. AUST R 134883.
Not all strengths, pack types and/or pack sizes may be available.
APO and APOTEX are the registered trademark of Apotex Inc.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes