Consumer medicine information

Klacid

Clarithromycin

BRAND INFORMATION

Brand name

Klacid

Active ingredient

Clarithromycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Klacid.

SUMMARY CMI

KLACID®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

1. Why am I taking KLACID?

KLACID contains the active ingredient clarithromycin. KLACID is used to treat certain bacterial infections including respiratory tract infections, ear infections, skin infections and peptic ulcer. KLACID is also used to prevent a specific bacterial infection associated with HIV infection. For more information, see Section 1. Why am I taking KLACID? in the full CMI.

2. What should I know before I take KLACID?

Do not take if you have ever had an allergic reaction to clarithromycin, other antibiotics from the macrolide family or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take KLACID? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KLACID and affect how it works or may be affected by KLACID.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take KLACID?

Your doctor will tell you how much to take and when to take it. Take KLACID exactly as directed by your doctor. More instructions can be found in Section 4. How do I take KLACID? in the full CMI.

5. What should I know while taking KLACID?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking KLACID.
  • Tell your doctor if you are taking KLACID for an infection and your symptoms do not improve within a few days, or they become worse, you become pregnant, you get severe diarrhoea, you experience heart palpitations, changes in heartbeat, dizziness or fainting or you are having urine tests.
Things you should not do
  • Do not take KLACID to treat any other complaints unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Driving or using machines
  • Be careful driving or operating machinery until you know how KLACID affects you.
Looking after your medicine
  • Keep KLACID tablets in a cool dry place below 25°C and protected from light.
  • Keep KLACID Powder for Oral Liquid in a cool dry place below 30°C and protected from light.
    The reconstituted suspension can be used for up to 14 days when stored below 30°C. DO NOT REFRIGERATE.

For more information, see Section 5. What should I know while taking KLACID? in the full CMI.

6. Are there any side effects?

Tell your doctor if you experience any of the following: stomach cramps and pains, nausea, vomiting and diarrhoea, oral thrush or vaginal thrush, change in taste sensation, headache, asthma, shortness of breath, muscle weakness, pain or spasms, conjunctivitis, chills, fatigue, eructation (belching), stomach distension or flatulence. Tell your doctor immediately if you notice any of the following as you may need urgent medical care: yellowing of the eyes or skin, feeling generally unwell and having poor appetite, hearing disturbances, chest pain, dizziness, confusion, hallucinations, convulsions, fainting, irregular heartbeat, any type of skin rash, itching, hives, severe diarrhoea, especially if bloody or severe upper stomach pain, with nausea and vomiting. Stop taking KLACID and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects: swelling to the face, lips, mouth, throat or neck which may cause difficulty in swallowing or breathing or sudden collapse.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

KLACID®

Active ingredient: clarithromycin


Consumer Medicine Information (CMI)

This leaflet provides important information about using KLACID. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking KLACID.

Where to find information in this leaflet:

1. Why am I taking KLACID?
2. What should I know before I take KLACID?
3. What if I am taking other medicines?
4. How do I take KLACID?
5. What should I know while taking KLACID?
6. Are there any side effects?
7. Product details

1. Why am I taking KLACID?

KLACID contains the active ingredient clarithromycin, 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. KLACID will not work against infections caused by viruses, such as colds or flu.

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

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

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

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

KLACID to treat peptic ulcer

Peptic ulcers are associated with an infection in the intestine and stomach by a type of 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 KLACID (clarithromycin) and other 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 KLACID may no longer be effective in killing the H. pylori infection and a different antibiotic may be needed.

2. What should I know before I take KLACID?

Warnings

Do not take KLACID if:

  • you are allergic to clarithromycin, other antibiotics from the macrolide family, including erythromycin, roxithromycin or azithromycin or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can take this medicine
  • you have severe liver problems and poor kidney function.
  • you have an irregular heartbeat.
  • you have ever had a heart condition called long QT syndrome (or QT prolongation).
  • you have low magnesium or potassium levels.
  • you are taking any of the following 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)
    - colchicine (used to treat gout)
    - domperidone (used for nausea)
    - ergotamine or dihydroergotamine (used to treat headaches)
    - lomitapide (used to treat high cholesterol)
    - lovastatin or simvastatin (used to treat high cholesterol)
    - midazolam tablets or syrup (used to treat sleeplessness and anxiety)
    - pimozide (used to treat schizophrenia)
    - ticagrelor or ranolazine (used to prevent blood clotting)

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

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

Do not take KLACID after the expiry date or if the packaging is torn or shows any signs of tampering.

If it has expired or is damaged return it to your pharmacist for disposal.

Check with your doctor if you have:

  • any other medical conditions or take any medicines for any other condition
  • allergies to any other medicines, foods, dyes or preservatives
  • 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
  • any 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 them before you start taking or are given KLACID.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss the risks and benefits of taking KLACID when pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Your doctor will discuss the risks and benefits of taking KLACID when breastfeeding.

3. What if I am taking other medicines?

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

Some medicines may interfere with KLACID and affect how it works or may be affected by KLACID. These include the medicines already listed under "Do not take KLACID if" (see above) and the following medicines:

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

These medicines may be affected by KLACID or may affect how well KLACID works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while taking KLACID.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect KLACID.

4. How do I take KLACID?

How much to take

  • Your doctor will tell you how much to take and when to take it. Take KLACID exactly as directed by your doctor. This may differ from the information contained in this leaflet.
  • The dose of KLACID will depend on the infection to be treated.
  • For respiratory tract infections and skin infections, the usual adult dose is one KLACID 250 mg tablet twice a day.
  • For more severe infections, the dose can be increased to one KLACID 500 mg tablet twice a day.
  • For respiratory tract infections the usual dose for children is 7.5 mg/kg twice a day or as directed by your doctor.
    For children under 12 years of age, KLACID Powder for Oral Liquid should be used.
  • Your doctor will adjust the amount or frequency of your doses according to the infection being treated and the severity of your condition.
  • If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take KLACID

KLACID Tablets

KLACID tablets should be swallowed whole with a glass of water.

KLACID Powder for Oral Liquid

Shake the bottle well and accurately measure the dose with a medicine measure.

Shaking the bottle before use and using a medicine measure will make sure that you get the correct dose.

The measuring syringe that is provided with the bottle can be used to measure the correct volume of medicine.

When to take KLACID

  • KLACID should be taken at about the same time each day.
  • This will allow your medicine to have the best effect and help you remember to take it.
  • The prepared suspension can be taken with or without meals and can be taken with milk.

How long to take it

Keep taking KLACID until you finish the pack or bottle, or for as long as your doctor tells you.

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

Do not stop taking KLACID, 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 KLACID.

If you forget to take KLACID

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 continue taking your medicine as you would normally.

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

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

If you take too much KLACID

If you think that you have taken too much KLACID, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

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

5. What should I know while taking KLACID?

Things you should do

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

Tell your doctor if you become pregnant while taking KLACID.

Call your doctor straight away if you:

  • get severe diarrhoea. Do this even if it occurs several weeks after stopping KLACID. 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.
  • experience any heart palpitations, changes in heartbeat, dizziness or fainting while taking KLACID.

If you are having any urine tests, tell your doctor you are taking KLACID as it may affect the results of some laboratory tests.

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

Remind any doctor, dentist or pharmacist you visit that you are taking KLACID.

Things you should not do

  • Do not take KLACID to treat any other complaints unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how KLACID affects you.

Looking after your medicine

KLACID Tablets:

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack, they will not keep well.

Keep KLACID tablets in a cool dry place below 25°C and protected from light.

KLACID Powder for Oral Liquid:

Keep KLACID Powder for Oral Liquid in a cool dry place below 30°C and protected from light.

The reconstituted suspension can be used for up to 14 days when stored below 30°C. DO NOT REFRIGERATE.

Store it in a cool dry place away from moisture, heat or sunlight. Do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it. A locked cupboard at least 1.5 metres above the ground is a good place to store medicines.

When to discard your medicine

Discard any unused suspension 14 days after reconstitution.

Getting rid of any unwanted medicine

If you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • stomach cramps and pains
  • nausea, vomiting and 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 (belching)
  • stomach distension (bloating)
  • flatulence
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • yellowing of the eyes or skin (jaundice)
  • feeling generally unwell and having poor appetite
  • hearing disturbances
  • chest pain
  • dizziness, confusion, hallucinations, convulsions
  • fainting, irregular heartbeat
  • any type of skin rash, itching, hives
  • severe diarrhoea, especially if bloody
  • severe upper stomach pain, with nausea and vomiting (pancreatitis)
Tell your doctor straight away if you notice any of these symptoms as you may need urgent medical care.
  • swelling to the face, lips, mouth, throat or neck which may cause difficulty in swallowing or breathing or sudden collapse
Stop taking KLACID and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

After you have finished taking KLACID

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

  • severe stomach or abdominal cramps
  • watery and severe diarrhoea, which may also be bloody (this may occur several weeks after you stop taking KLACID)
  • 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. Tell your doctor 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 KLACID, even if it is not on this list.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What KLACID Tablet contains

Active ingredient
(main ingredient)
Each KLACID 250 mg tablet contains 250 mg of clarithromycin.
Each KLACID 500 mg tablet contains 500 mg of clarithromycin.
Other ingredients
(inactive ingredients)
  • croscarmellose sodium
  • povidone
  • silicon dioxide
  • microcrystalline cellulose
  • purified talc
  • hyprolose
  • hypromellose
  • sorbitan mono-oleate
  • stearic acid
  • magnesium stearate
  • propylene glycol
  • sorbic acid
  • vanillin
  • titanium dioxide
  • quinoline yellow
  • pregelatinised maize starch (in the 250 mg tablets only)
Potential allergensKLACID tablets contain sorbates

What KLACID Powder for Oral Liquid contains

Active ingredient
(main ingredient)
Each 5 mL of KLACID Powder for Oral Liquid contains 250 mg of clarithromycin.
Other ingredients
(inactive ingredients)
  • povidone
  • castor oil
  • silicon dioxide
  • xanthan gum
  • potassium sorbate
  • citric acid
  • titanium dioxide
  • maltodextrin
  • sucrose
  • fruit punch flavour
Potential allergensKLACID powder for oral liquid contains sugars, sorbates and sulfites

Do not take this medicine if you are allergic to any of these ingredients.

What KLACID looks like

KLACID 250 mg tablets are yellow, oval, film-coated tablets. Each blister pack contains 14 tablets (AUST R 79564).

KLACID 500 mg tablets are pale yellow, oval, film-coated tablets (AUST R 52473).

KLACID Powder for Oral Liquid 250 mg/5 mL has a white to pale yellow colour with a fruit punch aroma (AUST R 56729). The reconstituted suspension has a tendency towards grittiness.

Who distributes KLACID

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in May 2022.

KLACID® is a Viatris company trade mark

Klacid_cmi\May22/00

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Klacid

Active ingredient

Clarithromycin

Schedule

S4

 

1 Name of Medicine

Clarithromycin.

2 Qualitative and Quantitative Composition

Klacid (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.
Klacid tablets contain sorbates. Klacid powder for oral liquid contains sugars, sorbates and sulfites. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The Klacid 250 mg tablet is yellow, oval and film-coated, containing 250 mg clarithromycin.
The Klacid 500 mg tablet is pale yellow, oval and film-coated, containing 500 mg clarithromycin.
Klacid Powder for Oral Liquid consists of a granulation of clarithromycin and carbomer 934 coated with hypromellose phthalate. Water is added to reconstitute the suspension prior to use. After mixing, each 5 mL contains 250 mg of clarithromycin.

4 Clinical Particulars

4.1 Therapeutic Indications

Klacid (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.
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.
Klacid (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 Klacid 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.

4.2 Dose and Method of Administration

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.

Renal impairment.

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.

Note.

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

Paediatric patients.

The recommended daily dosage of Klacid Powder for Oral Liquid in children is 7.5 mg/kg twice a day up to a maximum dose of 500 mg twice a day. The prepared suspension can be taken with or without meals and can be taken with milk. The usual duration of treatment is 5 to 10 days depending on the pathogen involved and the severity of the condition. Treatment for streptococcal pharyngitis should be 10 days.
Table 1 is a suggested guide for determining dosage.
In children with creatinine clearance less than 30 mL/min/1.73 m2, the dosage of clarithromycin should be reduced by one-half, i.e. up to 250 mg once daily or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

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 treated again 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.
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.
Experience in patients older than 65 years is limited. The recommended starting dose for elderly patients with calculated creatinine clearance of greater than 30 mL/min is 500 mg 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)).

Paediatric patients.

The recommended dosage for children (< 12 years) with disseminated or local mycobacterial infections is 7.5 to 15 mg/kg twice daily, not exceeding a maximum dose of 500 mg twice daily.
B. Prophylaxis of mycobacterial infections. The recommended dosage of clarithromycin in HIV infected adults with CD4 lymphocyte counts < 75 cells/mm3 for prophylaxis of disseminated Mycobacterium avium complex infections is 500 mg 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.

Powder for oral liquid - preparation for use.

250 mg/5 mL powder for suspension.

An appropriate amount of water (see paragraphs below) should be added to the powder in the bottle and shaken until all of the particles are suspended. Avoid vigorous and/or lengthy shaking. Shake prior to each subsequent use to ensure resuspension.
Add 27 mL of water to the powder in the 50 mL bottle and shake to yield a reconstituted suspension containing 250 mg/5 mL.
Add 36 mL of water to the powder in the 70 mL bottle and shake to yield a reconstituted suspension containing 250 mg/5 mL.
Add 52 mL of water to the powder in the 100 mL bottle and shake to yield a reconstituted suspension containing 250 mg/5 mL.

4.3 Contraindications

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; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clarithromycin should not be given to patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of QT interval).
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).
Concomitant administration of clarithromycin and lomitapide 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.
Clarithromycin must not be given to patients with electrolyte disturbances such as hypomagnesaemia or 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.

Prophylaxis of Mycobacterium avium complex infection.

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

Patients with duodenal ulcers.

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

Colchicine.

There have been postmarketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see 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 (e.g. triazolam and alprazolam) and related benzodiazepines (e.g. 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.

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 generalised exanthematous pustulosis (AGEP)), Stevens-Johnson Syndrome, toxic epidermal necrolysis, and 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 hypoglycemic agents/ insulin.

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

Oral anticoagulants.

There is a risk of serious haemorrhage and significant elevations in 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.
Caution should be exercised when clarithromycin is co-administered with direct acting oral anticoagulants such as dabigatran, rivaroxaban and apixaban, particularly to patients at high risk of bleeding (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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) can 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.

Excipients.

Clarithromycin powder for oral liquid contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
When prescribing to diabetic patients, the sucrose content should be taken into account.

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 Klacid tablets has not been studied in children less than 12 years of age. For children under 12 years of age Klacid Powder for Oral Liquid should be used.

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.

Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischaemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see Section 4.3 Contraindications).

Oral midazolam.

When midazolam was coadministered 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 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, 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 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 subtherapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.

Efavirenz, nevirapine, rifampicin, 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 ClCr 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with ClCr < 30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be coadministered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see 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 coadministration 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.

Oral hypoglycemic agents/insulin.

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

CYP3A based interactions.

Coadministration 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.
The following drugs or drug classes are known or suspected to be metabolised by the same CYP3A isoenzyme (not a comprehensive list): alprazolam, astemizole, carbamazepine, cilostazol, cisapride, ciclosporin, disopyramide, domperidone, ergot alkaloids, ibrutinib, lomitapide, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the CYP450 system include phenytoin, theophylline and sodium valproate.

Direct acting oral anticoagulants (DOACs).

The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents particularly to patients at high risk of bleeding (see Section 4.4 Special Warnings and Precautions for Use).

Omeprazole.

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and t1/2 increased by 30%, 89% and 34% respectively), by the concomitant administration of clarithromycin. The mean 24 hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was coadministered with clarithromycin.

Sildenafil, tadalafil and vardenafil.

Each of these phosphodiesterase inhibitors is metabolised, at least in part, by CYP3A and CYP3A may be inhibited by concomitantly administered clarithromycin. Coadministration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are coadministered with clarithromycin.

Theophylline.

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 mg or 500 mg 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 metaboliser population.

Triazolobenzodiazepines (e.g. triazolam and alprazolam) and related benzodiazepines (e.g. midazolam).

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus may increase the pharmacologic effect of these benzodiazepines. Concomitant administration of oral midazolam and clarithromycin is contraindicated. If intravenous midazolam is coadministered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Drug delivery of midazolam via oromucosal route, which could bypass presystemic 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, coadministration of 250 mg clarithromycin, a mechanism based inhibitor of CYP3A4, increased the repaglinide AUC by 40% and Cmax by 67%, and increased the mean incremental AUC of serum insulin by 51% and the maximum concentration by 61%. The exact mechanism of this interaction is not clear.

Other drug interactions.

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 (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are administered together, inhibition of P-gp 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 (P-gp) by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentration should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine.

Simultaneous oral administration of clarithromycin and zidovudine in HIV infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can largely be avoided by staggering the doses of clarithromycin and zidovudine by at least two hours. This interaction does not appear to occur in paediatric HIV infected patients taking clarithromycin suspensions with zidovudine or didanosine.

Phenytoin and sodium valproate.

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

Itraconazole.

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

Saquinavir.

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

Interactions that have been investigated, for which outcome was negative.

Didanosine.

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

Indinavir.

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

Ketoconazole.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in rats have not shown any evidence of effects on fertility or reproductive performance following daily oral dosing up to 150 mg/kg/day in females (1.4-fold the MRHD based on body surface area), and up to 500 mg/kg/day in males (5-fold the MRHD on a body surface area basis).
(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 apprised 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. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations with use of macrolides including clarithromycin during pregnancy provide conflicting results. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks.
The safety of clarithromycin for use during breastfeeding of infants has not been established. Clarithromycin and other macrolides are excreted in human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7% of the maternal weight-adjusted dose of clarithromycin.

4.7 Effects on Ability to Drive and Use Machines

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials 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 2.

Hepatic system.

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

Immunocompromised and HIV/ AIDS patients.

In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.
In adult patients, the most frequently reported adverse drug events by patients treated with total daily doses of 1000 mg of clarithromycin are reported in Table 2.
Approximately 2% to 3% of these patients who received 1000 mg of clarithromycin daily had seriously abnormal elevated levels (greater than three times upper limit of normal) of aspartate transaminase (AST) and alanine transaminase (ALT) and abnormally low white blood cell (less than 2 x 109/L) or platelet (less than 75 x 109/L) counts. A lower percentage of patients in these two dosage groups also had elevated blood urea levels. Slightly higher incidences of abnormal laboratory values were also noted with these patients for all parameters except for white blood cell count (WBC).

Elderly patients.

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

Other reported side effects.

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

Postmarketing experience.

Adverse events have been reported during 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. (See Table 3.)
There have been postmarketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Colchicine; Section 4.4 Special Warnings and Precautions for Use).

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 https://www.tga.gov.au/reporting-problems.

4.9 Overdose

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. One patient who had a history of bipolar disorder ingested eight grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxemia.
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 13 11 26 (Australia).

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.

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 4.

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-OH clarithromycin. This metabolite is as active or one to twofold less active than the parent compound for most organisms, except against H. influenzae where it is twice as active.
Clarithromycin was found to be 2 to 10 times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse subcutaneous abscess and mouse respiratory tract infections caused by S. pneumoniae, S. aureus, S. pyogenes and H. influenzae. In guinea pigs with Legionella infection, this effect is more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50 mg/kg/day of erythromycin.

Susceptibility 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' indicated 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 results 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 twice a day, amoxicillin 1000 mg twice a day and omeprazole 20 mg daily for 10 days, or dual therapy with clarithromycin 500 mg three times a day 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.
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 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.
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 clarithromycin 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.hour/mL (fasting) and 0.84 ± 0.38 microgram/mL and 4.7 ± 1.7 microgram.hour/mL (nonfasting), respectively. In a study on the 500 mg tablets, the mean Cmax and AUC values were 1.6 ± 0.6 microgram/mL and 12.6 ± 4.0 microgram.hour/mL (fasting) and 2.5 ± 0.8 microgram/mL and 15.7 ± 4.9 microgram.hour/mL (nonfasting), respectively. The consequences for the clinical efficacy of the increase in bioavailability caused by food are not known.
In a study of the powder for oral liquid in adults (250 mg dose), food was found to reduce the bioavailability of clarithromycin. AUC was reduced from 7.2 ± 2.5 to 6.5 ± 3.7 microgram.hour/mL and Cmax was reduced from 1.24 ± 0.36 to 0.095 ± 0.44 microgram/mL. Tmax increased from 3.3 ± 1.2 to 5.3 ± 1.9 hours.
In a pharmacokinetic study (7.5 mg/kg/day dose) in children with respiratory or skin infections, food was found to increase the Cmax (3.59 ± 1.47 microgram/mL (fasting) to 4.58 ± 2.76 microgram/mL (nonfasting)) and AUC (10.0 ± 5.49 microgram.hour/mL (fasting) to 14.2 ± 9.39 microgram.hour/mL). The data are insufficient to allow any definitive statement regarding the timing of administration of Klacid powder for oral liquid with food.
In studies of fasting healthy adults, peak serum concentrations were attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations were attained in 2 to 3 days and were approximately 1 microgram/mL with a 250 mg dose administered every 12 hours and 2 to 3 microgram/mL with a 500 mg dose administered every 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 12 hours but is quite marked at higher doses. With a 250 mg every 12 hours dosing, the principal metabolite, 14-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 500 mg every 12 hours dosing, 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.

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 5). 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.

Pharmacokinetics in special populations.

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 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).

Helicobacter pylori infection with concomitant omeprazole administration.

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

Mycobacterial infection.

The steady-state concentrations of clarithromycin and 14-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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Klacid 250 mg tablets also contain the excipients: Croscarmellose sodium, Hyprolose, Hypromellose, Magnesium Stearate, Microcrystalline cellulose, Povidone, Pregelatinized Maize Starch, Propylene Glycol, Purified Talc, Quinoline Yellow, Silicon Dioxide, Sorbic Acid, Sorbitan mono-oleate, Stearic Acid, Titanium Dioxide, Vanillin.
Klacid 500 mg tablets also contain the excipients: Croscarmellose Sodium, Hyprolose, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Povidone, Propylene Glycol, Purified Talc, Quinoline Yellow, Silicon Dioxide, Sorbic Acid, Sorbitan Mono-oleate, Stearic Acid, Titanium Dioxide, Vanillin.
Klacid Powder for Oral Liquid also contains the following excipients: Fruit Punch Flavour XY-158-812-9 (ARTG No. 111762), castor oil, citric acid, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, titanium dioxide, and xanthan gum.

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 Klacid 250 mg tablets and Klacid 500 mg tablets below 25°C.
Store Klacid Powder for Oral Liquid below 30°C.
The reconstituted liquid can be used for up to 14 days when stored below 30°C. The reconstituted liquid should not be refrigerated.

6.5 Nature and Contents of Container

Klacid 250 mg tablets are available in PVC/PVDC/Aluminium Blister packs in quantities of 2*, 14 or 28* tablets.
Klacid 500 mg tablets are available in PVC/PVDC/Aluminium blister packs of 14* or 28* tablets.
Klacid Powder for Oral Liquid 250 mg/5 mL is available in HDPE bottles with polypropylene and LDPE child resistant caps containing 50 mL, 70 mL* or 100 mL*. A polypropylene and HDPE syringe is included for dosing.
* Strength/pack size currently not marketed in Australia.

Australian register of therapeutic goods (ARTG).

AUST R 52473 - Klacid clarithromycin 500 mg tablet blister pack.
AUST R 56729 - Klacid clarithromycin 250 mg/5 mL powder for oral liquid bottle.
AUST R 79564 - Klacid clarithromycin 250 mg tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Chemically, it is 6-O-Methyl Erythromycin A.
The molecular formula is C38H69NO13, the molecular weight is 747.96 and the structural formula is:

CAS number.

81103-11-9.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes