Consumer medicine information

Clarithromycin Sandoz

Clarithromycin

BRAND INFORMATION

Brand name

Clarithromycin Sandoz

Active ingredient

Clarithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Clarithromycin Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Clarithromycin Sandoz. 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 risk of you taking Clarithromycin Sandoz against the benefits it is expected to 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 CLARITHROMYCIN SANDOZ IS USED FOR

Clarithromycin Sandoz is used to treat certain bacterial infections, including the following:

  • respiratory tract infections (throat, airways and lungs)
  • ear infections
  • skin infections
  • peptic ulcer

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

Clarithromycin Sandoz 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. It contains the active ingredient clarithromycin.

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

Clarithromycin Sandoz will not work against infections caused by viruses, such as colds or flu.

Clarithromycin Sandoz 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 Sandoz (clarithromycin), another appropriate antibiotic and stomach acid control treatments.

However, the best combination of tablets to treat H. 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 Sandoz may no longer be effective in treating the H. pylori infection and a different antibiotic may be needed.

There is no evidence that Clarithromycin Sandoz is addictive. Clarithromycin Sandoz is only available with a doctor's prescription.

BEFORE YOU TAKE CLARITHROMYCIN SANDOZ

When you must not take it

Do not take Clarithromycin Sandoz if you have an allergy to:

  • medicines containing clarithromycin, the active ingredient or to any of the other ingredients mentioned at the end of this leaflet under Product Description.
  • other antibiotics from the macrolide family, such as, erythromycin, roxithromycin or azithromycin.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty in breathing or swallowing.

Do not take Clarithromycin Sandoz if you have any of the following medical conditions:

  • severe liver problems
  • poor kidney function
  • cardiac arrhythmia (irregular heartbeat)
  • heart condition called long QT syndrome (or QT prolongation)
  • hypokalaemia (low potassium levels in blood).

Do not take Clarithromycin Sandoz if you are currently also taking the medicines:

  • astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines may be available without a prescription)
  • cisapride (used to relieve certain stomach problems)
  • domperidone (used for nausea)
  • pimozide (used to treat schizophrenia)
  • ergotamine or dihydroergotamine (used to treat headaches)
  • lovastatin or simvastatin (used to treat high cholesterol)
  • ticagrelor or ranolazine (used to prevent blood clotting)
  • colchicine (used to treat gout)
  • midazolam tablets or syrup (used to treat sleeplessness and anxiety).

Taking Clarithromycin Sandoz with any of the above medicines may cause serious side effects.

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, especially if they are in the same drug class as Clarithromycin Sandoz
  • any other substances, including foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor will discuss the risks and benefits of taking Clarithromycin Sandoz when pregnant.

Tell your doctor if you are breastfeeding or wish to breastfeed. Your doctor will discuss the risks and benefits of taking Clarithromycin Sandoz when breastfeeding.

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

  • heart problems, including slow heart rate
  • liver problems
  • poor kidney function
  • myasthenia gravis, a condition which the muscles become weak and tire easily
  • intolerance to sugars
  • low magnesium or any other electrolyte imbalances.

Your doctor may want to take special care if you have any of these conditions.

If you have not told your doctor or pharmacist about any of the above, tell him/her before you start taking Clarithromycin Sandoz.

Taking other medicines

Tell your doctor or pharmacist 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 and Clarithromycin Sandoz may interfere with each other. These include the medicines already listed under "When you must not take Clarithromycin Sandoz" (see above) and the following medicines

  • digoxin, quinidine, disopyramide (used to treat heart failure)
  • warfarin and other anticoagulants (used to prevent blood clotting)
  • phenytoin, carbamazepine, phenobarbital (phenobarbitone), sodium valproate (used to treat epilepsy)
  • theophylline (used to treat asthma)
  • triazolam, alprazolam, midazolam (used to treat sleeplessness and anxiety)
  • cilostazol (use to treat poor circulation)
  • statins such as rosuvastatin, atorvastatin (used to treat high cholesterol)
  • methylprednisolone (a corticosteroid)
  • vinblastine (used to treat cancer)
  • sildenafil, tadalafil or vardenafil (used to treat erectile dysfunction in adult males)
  • ciclosporin, tacrolimus (medicines affecting the immune system)
  • medicines used to treat HIV infection
  • rifabutin, rifapentine, rifampicin (used to treat some infections)
  • repaglinide, nateglinide, pioglitazone, rosiglitazone (used to treat diabetes)
  • insulin (used to treat diabetes)
  • calcium channel blockers such as verapamil, amlodipine, diltiazem (used to treat high blood pressure)
  • fluoxetine (used to treat depression)
  • omeprazole (used to treat stomach problems)
  • aminoglycosides (used to treat infections)
  • fluconazole and itraconazole (used to treat fungal infections)
  • tolterodine (used to treat bladder symptoms)
  • herbal medicines such as St John's Wort
  • quetiapine (used in psychotic disorders)
  • ibrutinib (used in cancer therapy)

These medicines may be affected by Clarithromycin Sandoz, or may affect how well it works. You may need to use different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE CLARITHROMYCIN SANDOZ

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

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

How much to take

The dose of Clarithromycin Sandoz will depend on the infection to be treated.

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

For more severe infections, the dose can be increased to two Clarithromycin Sandoz 250mg tablets 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.

How to take it

Clarithromycin Sandoz tablets should be swallowed whole with a glass of water.

If you need to break Clarithromycin Sandoz, hold tablet with both hands and snap along break line.

When to take it

Take Clarithromycin Sandoz at about the same time each day.

This will allow your medicine to have the best effect and help you remember to take it.

How long to take it

Keep taking Clarithromycin Sandoz until you finish the pack or for as long as your doctor tells you. If you are being treated for an infection, Clarithromycin Sandoz is usually taken for one or two weeks.

Do not stop taking Clarithromycin Sandoz, 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 Sandoz.

If you forget to take your dose

Take your dose as soon as you remember, and continue to take it as you would normally.

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

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

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

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

If you take too much

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

Symptoms of an overdose may include severe gastrointestinal symptoms, liver problems, or allergic reactions.

WHILE YOU ARE USING CLARITHROMYCIN SANDOZ

Things you must do

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking Clarithromycin Sandoz.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Clarithromycin Sandoz.

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

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

Tell your doctor immediately if you experience any heart palpitations, changes in heartbeat, dizziness or fainting while taking Clarithromycin Sandoz. If you have to take any urine tests, tell your doctor you are taking Clarithromycin Sandoz as it may affect the results of some laboratory tests.

Things you must not do

Do not stop taking Clarithromycin Sandoz without your doctor's permission.

Do not use Clarithromycin Sandoz to treat any other complaints unless your doctor says so.

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

Things to be careful of

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

SIDE EFFECTS

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

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

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.

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

  • stomach cramps and pains
  • nausea, vomiting and severe diarrhoea
  • oral thrush (sore white mouth or tongue) or vaginal thrush (vaginal itching or discharge)
  • change in taste sensation
  • headache
  • asthma, shortness of breath
  • muscle weakness, pain or spasms
  • conjunctivitis
  • chills
  • fatigue
  • eructation
  • stomach distension
  • flatulence

These are the more common side effects of Clarithromycin Sandoz. Mostly, these are mild and short-lived.

Tell your doctor immediately 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
  • fainting, irregular heart beat
  • any type of skin rash, itching, hives
  • severe diarrhoea, especially if bloody
  • severe upper stomach pain, with nausea and vomiting (pancreatitis)

This above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking Clarithromycin Sandoz and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth, throat or neck which may cause difficulty in swallowing or breathing or sudden collapse. These are symptoms of an allergic reaction.

This above list includes very serious side effects. You may need urgent medical attention or hospitalisation. All of these side effects are very rare.

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

Other side effects not listed above may also occur in some people.

After you have finished taking Clarithromycin Sandoz

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

  • severe stomach or abdominal cramps
  • watery and severe diarrhoea, which may also be bloody (this may occur several weeks after you stop taking Clarithromycin Sandoz)
  • 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.

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 Sandoz even if it is not on this list.

AFTER TAKING CLARITHROMYCIN SANDOZ

Storage

Keep your medicine in the original container. If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Clarithromycin Sandoz 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 that is left over.

PRODUCT DESCRIPTION

What Clarithromycin Sandoz looks like

Clarithromycin Sandoz 250 mg film-coated tablet: white, oblong, convex tablet scored on both faces.

Available in blister packs of 14 tablets.

Ingredients

Active Ingredient:

Each Clarithromycin Sandoz 250 mg tablet contains 250 mg clarithromycin.

Inactive Ingredients:

Each Clarithromycin Sandoz tablet also contains:

  • microcrystalline cellulose
  • magnesium stearate
  • croscarmellose sodium
  • powdered cellulose
  • colloidal anhydrous silica
  • lactose monohydrate
  • hypromellose
  • macrogol 4000
  • titanium dioxide

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in April 2019.

Australian Register Numbers

Clarithromycin Sandoz 250 mg tablet: AUST R 101265 (blisters)

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Clarithromycin Sandoz

Active ingredient

Clarithromycin

Schedule

S4

 

1 Name of Medicine

Clarithromycin.

6.7 Physicochemical Properties

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.
The chemical name of clarithromycin is (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 (other names is 6-O-methylerythromycin A). Its chemical formula is C38H69NO13 (MW: 748 g/mol).

Chemical structure.

Its chemical structure is:

CAS number.

81103-11-9.

2 Qualitative and Quantitative Composition

Each Clarithromycin Sandoz 250 mg contains 250 mg clarithromycin.
Each Clarithromycin Sandoz 500 mg contains 500 mg clarithromycin.
Not all strengths may be marketed in Australia.

Excipient with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Clarithromycin Sandoz 250 mg film-coated tablets are white, oblong, convex tablets, scored on both faces.
Clarithromycin Sandoz 500 mg film-coated tablets are white, oblong, convex tablets scored on both faces.

5 Pharmacological Properties

Clarithromycin is a semi-synthetic macrolide antibiotic.

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.

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 anti-secretory 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.

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 2.
The principal metabolite of clarithromycin in man is a microbiologically active metabolite, 14-OH-clarithromycin. This metabolite is as active or one to two fold 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 tests.

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.

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. In a study, the mean Cmax and AUC values after a single oral dose of 500 mg clarithromycin (fasting state) was 2.37 ± 0.63 microgram/mL and 16.9 ± 4.44 microgram.h/mL, respectively.
In studies of fasting healthy adults, peak serum concentrations were attained within 1.8 hours after oral dosing. Steady-state peak serum clarithromycin concentrations were attained in two to three 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 three to four hours with 250 mg administered every 12 hours but increased to five to seven hours with 500 mg administered every 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 and 500 mg administered every 12 hours but is quite marked at higher doses. With a dosing of 250 mg every 12 hours, 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 five to six hours. With a dosing of 500 mg every 12 hours, the peak steady-state concentration of 14-OH-clarithromycin is slightly higher (up to 1 microgram/mL) and its elimination half-life is about seven hours. With either dose, the steady-state concentration of this metabolite is generally attained within two to three days.

Distribution.

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 3). 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 (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-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 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% to 15% of either a 250 mg or 500 mg dose administered every 12 hours.

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-OH-clarithromycin concentrations were lower in the hepatically impaired patients. The decreased formation of 14-OH-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-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.)

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 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 nonlinearity of clarithromycin pharmacokinetics.

5.3 Preclinical Safety Data

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 proposed doses. The clinical significance of these observations is not known.

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.

Carcinogenicity.

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

4 Clinical Particulars

4.1 Therapeutic Indications

Clarithromycin Sandoz (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 micro-organisms in the conditions listed below.
1. Acute streptococcal pharyngitis.
2. Community acquired pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila and Streptococcus pneumoniae (see Section 4.4 Special Warnings and Precautions for Use regarding sensitivity testing).
3. Uncomplicated skin and skin structure infections due to Staphylococcus aureus or Streptococcus pyogenes (see Section 4.4 Special Warnings and Precautions for Use regarding sensitivity testing).
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 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.
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 Sandoz (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 Sandoz 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

Clarithromycin Sandoz 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, domperidone, pimozide, as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
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).
Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).
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 in patients who suffer from severe hepatic failure in combination with renal impairment.
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).
Concomitant administration with ticagrelor or ranolazine is contraindicated.

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 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.

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.
Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication.
Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.

Prophylaxis of Mycobacterium avium complex infection.

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

Patients with duodenal ulcers.

Patients with bleeding duodenal ulcers should be maintained on anti-secretory 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). 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, and intravenous or oromucosal midazolam (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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.

Pneumonia.

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

Skin and soft tissue infections of mild to moderate severity.

These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reaction (SCAR) (e.g. acute generalized exanthematous pustulosis (AGEP)), Stevens-Johnson syndrome, and 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).
Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

Oral hypoglycaemic agents/insulin.

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

Oral anticoagulants.

There is a risk of serious haemorrhage and significant elevations in international normalized ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

HMG-CoA reductase inhibitors (statins).

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Section 4.3 Contraindications). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should be considered.
As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors. Patients should be monitored for signs and symptoms of myopathy.

Use in hepatic impairment.

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 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.

Use in renal impairment.

In the presence of significant renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate. Caution is advised in patients with moderate to severe renal insufficiency (see Section 4.2 Dose and Method of Administration).
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 the elderly.

Dosage adjustments are recommended in those patients with possible severe renal impairment (see Section 4.2 Dose and Method of Administration).

Paediatric use.

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

Effects on laboratory tests.

Clarithromycin does not affect laboratory tests.

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.

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 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 and astemizole.

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). Similar effects have been observed with concomitant administration of astemizole and other macrolides.

HMG-CoA reductase inhibitors (statins).

Concomitant use of clarithromycin with lovastatin or simvastatin is contradicted (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 received for patients taking clarithromycin with atorvastatin or rosuvastatin, they 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 medical 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 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

Efavirenz, nevirapine, rifampicin, rifapentine and rifabutin.

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifapentine 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-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 CrCl 30-60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CrCl < 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, Bi-directional 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.

Effects of clarithromycin on other medicinal products.

Antiarrhythmics.

There have been post-marketing 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 post-marketing 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.

Oral hypoglycaemic agents/insulin.

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.

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 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, atypical antipsychotics (e.g. quetiapine), ergot alkaloids, ibrutinib, domperidone, methylprednisolone, quinidine, triazolam, sodium valproate, vinblastine, midazolam, disopyramide, phenytoin, digoxin, tacrolimus, ciclosporin, 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 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 250 mg or 500 mg every 12 hours 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 metabolizer population.

Triazolobenzodiazepine (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 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 post-marketing reports of drug interactions and CNS effects (e.g. somnolence and confusion) with the concomitant 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 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.

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.

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine.

Simultaneous oral administration of clarithromycin 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 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.

Bi-directional drug interactions.

Atazanavir.

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. 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 (CrCl 30-60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with CrCl < 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Itraconazole.

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

Saquinavir.

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. 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).

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) metabolised by CYP3A4 due to the risk of hypotension. Plasma concentrations of clarithromycin as well as CCBs 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 (86%). At this time there is 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 (3 with oral doses and one with intravenous doses 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 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 yet been established. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk particularly during the first three months of pregnancy.
Clarithromycin and other macrolides are excreted in human breast milk. The safety of clarithromycin for use during breastfeeding of infants has not been established.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Nonmycobacterial 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-2000 mg of clarithromycin are reported in Table 1. The incidence is generally 3-4 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.

Post-marketing experience.

Adverse events have been reported during post-approval 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.

Very rare (< 0.01%). Anaphylaxis, abdominal pain, asthenia, hypersensitivity, allergic reaction, fever, headache, angioedema, chills, fatigue.

Skin and skin structure.

Very rare (< 0.01%). Severe cutaneous adverse reactions (SCAR) (e.g. acute generalised exanthematous pustulosis (AGEP)), Stevens-Johnson syndrome, urticaria, rash, hyperhidrosis, pruritus, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, Henoch-Schonlein purpura.

Central nervous system.

Very rare (< 0.01%). Anxiety, insomnia*, hallucinations, confusion, psychosis, vertigo, dizziness, dream abnormality, tinnitus, disorientation, depersonalisation, confusion, nervousness, hyperkinesia, depression, paraesthesia, mania.
Unknown. Dream abnormality.
There have been rare reports of convulsions.

Haematopoietic and lymphatic system.

Very rare (< 0.01%). Decreased white blood cell counts, decreased platelet counts, thrombocytopenia, leukopenia, agranulocytosis.

Metabolic and nutritional.

Very rare (< 0.01%). Increased serum creatinine, increased gamma-glutaryl transferase (GGT), hypoglycaemia, anorexia, decreased appetite.
There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin.

Special senses.

Very rare (< 0.01%). Hearing disturbances, dysgeusia, taste perversion, smell perversion, ageusia, anosmia, otitis media, deafness.

Digestive system.

Very rare (< 0.01%). Dry mouth, tongue discolouration, glossitis, moniliasis oral, stomatitis, diarrhoea, nausea, vomiting, liver abnormalities, tooth discolouration, dyspepsia, enteritis, abdominal distension, eructation, flatulence.
There have been rare reports of pancreatitis.

Respiratory system.

Very rare (< 0.01%). Dyspnoea.

Urogenital system.

Very rare (< 0.01%). 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.

Torsades de pointes, electrocardiogram QT prolonged, ventricular tachycardia, ventricular fibrillation, palpitations.
As with other macrolides, QT prolongation, ventricular tachycardia and torsades de pointes have rarely been reported with clarithromycin.

Hepatobiliary system.

Very rare (< 0.01%). Hepatic failure, hepatitis, cholestatic hepatitis, cholestatic jaundice, hepatocellular jaundice, abnormal hepatic function.
In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

Musculoskeletal and connective tissue disorders.

Very rare (< 0.01%). Myalgia, rhabdomyolysis, myopathy, muscle spasms.
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with other drugs known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol).

Infections and infestations.

Pseudomembranous colitis, erysipelas, erythrasma, candidiasis, vaginal infection.

Vascular disorders.

Haemorrhage.

Investigations.

International normalised ratio (INR) increased, prothrombin time prolonged, urine colour abnormal.
A special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis (see Section 4.4 Special Warnings and Precautions for Use).
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening (see Section 4.4 Special Warnings and Precautions for Use).
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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.

4.2 Dose and Method of Administration

Patients with non-mycobacterial 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.

Renal impairment.

In patients with renal impairment with creatinine clearance (CrCl) 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.

Note.

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

Patients with peptic ulcers.

In patients with peptic ulcer due to H. pylori infection, clarithromycin can be administered in a dose of 500 mg twice daily in combination with other appropriate antimicrobial treatments and a proton pump inhibitor for 7-14 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.

A. Treatment of mycobacterial infections.

The recommended dosage for adults and children 12 years and older with disseminated or localised mycobacterial infections is 500 mg twice daily.
This may be increased to 1000 mg twice daily if no clinical or bacteriological response is seen after 3-4 weeks of therapy.
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.

Use in the elderly.

Experience in patients older than 65 years is limited. The recommended starting dose for elderly patients with calculated CrCl of greater than 30 mL/min is 500 mg twice a day. 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)).

B. Prophylaxis of mycobacterial infections.

Use in adults.

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 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.

Paediatric use.

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

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. General supportive measures and the use of activated charcoal (where physicochemically appropriate) have generally been seen as acceptable recommendations. 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Clarithromycin Sandoz tablets contain microcrystalline cellulose, magnesium stearate, croscarmellose sodium, powdered cellulose, colloidal anhydrous silica, lactose monohydrate, hypromellose, macrogol 4000 and titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 25°C.

6.5 Nature and Contents of Container

Clarithromycin Sandoz 250 mg are available in blister packs (PVC/Al) of 14 and 100 tablets.
Clarithromycin Sandoz 500 mg are available in blister packs (PVC/Al) of 14, 42 and 100 tablets.
Not all strengths or presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes