Active ingredients: Clarithromycin
Clarithromycin Acid 250 mg film-coated tablets
CLARITHROMYCIN DOC Generici 500 mg film-coated tablets
Why is Clarithromycin - Generic Drug used? What is it for?
Each tablet contains 250 mg or 500 mg of clarithromycin. Clarithromycin Accord belongs to a group of medicines called macrolide antibiotics. Antibiotics stop the growth of bacteria that cause infections.
Your medicine can be used to treat infections such as:
- Upper respiratory tract infections such as infections of the tonsils (tonsillitis) and throat (pharyngitis), as an alternative when antibiotics called "β-lactams" are not appropriate.
- Acute inflammation of the middle ear (acute otitis media) in children.
- Lower respiratory tract infections, such as lung infections (pneumonia).
- Inflammation of the bone cavities surrounding the nose (sinusitis) and acute worsening of chronic bronchitis in adults and adolescents over 12 years of age.
- Mild to moderate infections of the skin and soft tissues.
In appropriate combination with other antibiotics and an appropriate ulcer healing medicine, Clarithromycin is used to kill Helicobacter pylori (H. pylori is a stomach colonizing bacterium) in adult patients with Helicobacter pylori associated ulcers ( see paragraph 3).
Clarithromycin tablets are indicated in adults and children aged 12 years and over. Other pharmaceutical forms are also available for use in children aged 6 months to 12 years, such as clarithromycin oral suspension.
Contraindications When Clarithromycin - Generic Drug should not be used
Do not take Clarithromycin tablets if:
- you are allergic (hypersensitive) to clarithromycin or any of the other ingredients of this medicine (listed in section 6) or to other macrolide antibiotics, for example erythromycin or azithromycin
- you are taking ergotamine or dihydroergotamine. These medicines are used to treat migraines
- are taking medicines called terfenadine or astemizole used to treat hay fever and other allergies, as combining these medicines can in some cases cause severe heartbeat disturbances
- you are taking ticagrelor or ranolazine. These are medicines used to prevent stroke or heart attack
- is taking colchicine. This is a medicine used to treat gout
- you are taking pimozide. This medicine is used to treat mental problems
- you are taking cisapride. This medicine is used to treat stomach problems
- you are taking HMG-CoA reductase inhibitors commonly known as statins, such as lovastatin or simvastatin, used to treat blood cholesterol. Your muscles may become weaker
- suffer from a heart disease that causes changes in heart rhythm (known as prolongation of the QT interval)
- suffer from severe hepatic insufficiency in association with reduced kidney function
- have low blood potassium levels. If any of the above apply to you, do not take this medicine and talk to your doctor.
Precautions for use What you need to know before taking Clarithromycin - Generic Drug
Talk to your doctor or pharmacist before taking Clarithromycin:
- if you have mild to moderate liver problems and kidney problems. Your doctor may need to adjust your dose. Contact your doctor if you develop signs and symptoms of liver disorder such as anorexia, jaundice, dark urine, itching or abdominal pain
- if you have H. pylori infection - follow your doctor's advice carefully, as careless use of clarithromycin can result in the appearance of resistant microorganisms
- if you have an allergic reaction to certain other antibiotics (lincomycin and clindamycin). C "is the risk of an allergic reaction as for clarithromycin (cross-sensitivity)
- if you have a severe acute allergic reaction with fever (high), red spots on the skin, joint pain and / or eye inflammation known as Stevens-Johnson syndrome. Clarithromycin therapy should be discontinued immediately and appropriate treatment initiated urgently
- if you have a severe allergic reaction with blistering and peeling skin known as toxic epidemic necrolysis (TEN). Clarithromycin therapy should be discontinued immediately and appropriate treatment initiated urgently
- if you suspect that during prolonged or repeated use of Clarithromycin you have developed a new infection. This may be called "superinfection" with organisms resistant to clarithromycin
- if you experience severe or prolonged diarrhea during or after using Clarithromycin. Tell your doctor immediately, as clarithromycin can in very rare cases cause severe inflammation of the large intestine (pseudomembranous colitis)
- if you know that you have a disease of the blood vessels of the heart
- if you have / have had a slow or irregular heartbeat
- if you have a weak heart
- if you have low levels of magnesium in your blood. The rhythm of his heartbeat may be involved in these cases
- if you are pregnant. You should not take these tablets without a "thorough evaluation of the benefits and risks, particularly during the first three months of pregnancy (see" Pregnancy and breastfeeding ").
- if you are taking colchicine medicines. The combination of clarithromycin and colchicine is contraindicated
- if you are taking atorvastatin or rosuvastatin for cholesterol and have signs of muscle weakness. Your doctor may need to reduce your dose of these statins
- if you are taking a combination of clarithromycin and benzodiazepines such as alprazolam, triazolam and midazolam (see "other medicines and Clarithromycin tablets")
- if you are taking other medicines which can affect your hearing. The hearing loss will be monitored during and after therapy
- if you have pneumonia. Your doctor will check for the possibility of resistance to some antibiotics
- if you use oral hypoglycaemics or insulin. Blood glucose must be closely monitored
- if you use oral anticoagulants at the same time as clarithromycin. There is a risk of severe bleeding.
If you are not sure if any of these apply to you, talk to your doctor or pharmacist before taking clarithromycin.
Interactions Which drugs or foods can modify the effect of Clarithromycin - Generic Drug
Talk to your doctor if you are taking any of the following medicines:
- While you are taking Clarithromycin, do not take cisapride, a medicine used to treat stomach problems, pimozide, used to treat mental problems, terfenadine or astemizole, medicines used to treat hay fever and other allergies, "ergotamine or dihydroergotamine, medicines used to treat migraines. Combining Clarithromycin with these medicines can cause severe heart rhythm disturbances.
- Do not take lovastatin or simvastatin, medicines used to lower cholesterol. Your muscles may become weak.
- Take care with atorvastatin and rosuvastatin because of the risk of developing the muscle weakness mentioned above.
- Do not take ergotamine or dihydroergotamine, medicines used to treat migraines.
- Warfarin, a coumarin anticoagulant used to thin the blood.
- Nateglinide, repaglinide or insulin, used against diabetes. Your doctor will check your blood sugar.
- Medicines used to treat irregular heartbeat, such as disopyramide, quinidine or digoxin.
- Medicines used to treat epilepsy such as phenytoin, phenobarbital, valproic acid or carbamazepine.
- Theophylline, used to treat asthma.
- Benzodiazepines used as sedatives, such as midazolam or triazolam, or used to treat anxiety and depression such as alprazolam. You may experience drowsiness and confusion; you should report all side effects affecting your nervous system in detail to your doctor.
- Rifabutin, rifapentine or rifampicin, used to treat some infections.
- Ciclosporin, sirolimus or tacrolimus, used after an organ transplant.
- Ritonavir, zidovudine, nevirapine, atazanavir, efavirenz or etravirine used for the treatment of HIV infected patients.
- Omeprazole or lansoprazole, used to stop acid buildup in the stomach.
- Antacids and ranitidine, used to treat stomach problems / heartburn.
- Colchicine, a medicine used in the treatment of gout.
- Aminoglycosides, medicines used to treat infections; can cause deafness.
- Sildenafil, tadalafil and vardenafil, medicines used to treat erection problems. A dose reduction of these medicines may be needed.
- Tolterodine used to treat urinary incontinence. A dose reduction of this medicine may be needed.
- Itraconazole used in the treatment of fungal infections. A prolongation of the effects of both itraconazole and clarithromycin may occur.
- Verapamil, amlodipine and diltiazem used to treat hypertension. Hypotension and increased heart rate may occur.
- St. John's Wort, a plant product used to treat depression.
If any of the above apply to you, talk to your doctor or pharmacist.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those obtained without a prescription. This also includes herbal medicines.
CLARITHROMYCIN DOC Generici with food and drink
You can take this medicine with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine as the safety of use during pregnancy and breastfeeding is not known.
Driving and using machines
It is not yet known how this medicine affects your ability to drive or use machines. You may feel dizzy, confused, or off balance after taking this medicine. If this happens to you, do not drive or use machines.
Dose, Method and Time of Administration How to use Clarithromycin - Generic Drug: Posology
Your doctor has decided which dose is right for you. The dose depends on the type and severity of the infection. Always follow your doctor's instructions exactly and those on the medicine box label. If you do not understand these instructions, or are in any doubt, you should consult your doctor or pharmacist.
The tablets should be swallowed with at least half a glass of water.
Instructions for the usual dose are given below:
Adults, the elderly and children over 12 years of age:
- Usual dose: 250 mg 2 times a day (once in the morning and once in the evening) for 6 to 14 days
- High dose treatment: your doctor may increase the dose to 500 mg twice a day or may extend the treatment to 14 days if you have a "severe infection."
Treatment should be continued for at least 2 days after symptoms disappear.
Use in peptic ulcers caused by H. pylori infections:
500 mg of clarithromycin twice daily for 7 days is usually used in combination with other medicines.
Patients with kidney problems:
If you have severe kidney problems, your doctor will cut the dose in half, for example 250 mg once a day or in case of severe infections 250 mg twice a day, and reduce the treatment to a maximum of 14 days.
Use in children up to 12 years of age:
The recommended dose is 7.5 mg / kg twice a day (once in the morning and once in the evening) for 5 to 10 days
Treatment should be continued for at least 2 days after symptoms disappear.
Weight Dose
30 - 40 kg 250 mg twice a day
If your child has severe kidney problems, your doctor will cut the dose in half, for example 7.5 mg / kg once a day and reduce the treatment to a maximum of 14 days.
Clarithromycin in tablet form is not suitable for children under 12 years of age with a body weight of less than 30 kg. Other pharmaceutical forms are more suitable for these patients, such as the oral suspension.
Overdose What to do if you have taken too much Clarithromycin - Generic Drug
If you take more Clarithromycin tablets than you should
If you or someone else swallows many tablets all at once or if you think a child has swallowed one tablet, contact the nearest emergency department or your doctor immediately.
Too much of this medicine can cause vomiting and stomach pains.
Please take this leaflet, any remaining tablets and the container with you to the hospital or doctor so that they know which tablets have been taken.
If you forget to take Clarithromycin
If you forget to take a tablet, take one as soon as you remember, unless it is almost time for the next one. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Clarithromycin
Do not stop taking your medicines because you feel better. It is important that you complete the prescribed treatment, otherwise the problem may return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Clarithromycin - Generic Drug
Like all medicines, Clarithromycin Accord can cause side effects, although not everybody gets them.
The most frequent and common adverse reactions associated with clarithromycin therapy in both adults and children are abdominal pain, diarrhea, nausea, vomiting and altered taste. These adverse reactions are usually mild in intensity and are also known for other macrolide antibiotics (see list below).
The following list shows the adverse reactions reported from clinical studies and from postmarketing experience in relation to clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, prolonged-release tablets and modified-release tablets; therefore not all of the following undesirable effects could refer to the tablets you are taking.
Reactions considered, at least possibly, associated with clarithromycin are reported by frequency using the following convention: very common (more than 1 case in 10 treated individuals), common (less than 1 case in 100 treated individuals), uncommon (less than 1 case per 100 treated individuals, but more than 1 case per 1,000 treated individuals), very rare (less than 1 case per 10,000 treated individuals) and not known (frequency cannot be estimated from the available data). The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
If any of these symptoms occur, stop taking clarithromycin, tell your doctor immediately or go to the emergency room of the nearest hospital:
- You may have an allergic reaction after taking this medicine. This allergic reaction may include: difficulty in breathing and swelling of the lips, face and neck, hives, which can range in severity from itchy skin hives to severe blistering of the skin or ulcers of the lips, eyes, nose, mouth and genitals to life-threatening shock (anaphylactic shock). This occurs in less than 1 in 100 people treated, but in more than 1 in 1000.
- You may have severe and prolonged diarrhea. Diarrhea can have blood or mucus. This may indicate inflammation of the large intestine (pseudomembranous colitis, frequency not known).
- You may have a severe hypersensitivity reaction affecting the mucous membranes, fever (high), red blotchy skin, joint pain and / or eye inflammation (Stevens-Johnson syndrome) or a severe and sudden hypersensitivity reaction with fever, blisters on the skin / peeling of the skin (toxic epidermal necrolysis), drug rash with abnormal blood cells (eosinophilia) and systemic symptoms (known as DRESS) (see section 2 "Take special care with Clarithromycin, especially if" and "Taking Clarithromycin. Generic with other medicines ").
- He may have liver failure. This has occurred in very rare cases with a fatal outcome and particularly in patients with pre-existing liver disease or patients taking other medicines that are harmful to the liver (see section 2 "Take special care with Clarithromycin tablets especially if").
- You can experience severe blood abnormalities with high fever, sore throat and mouth ulcers (agranulocytosis). The frequency with which it occurs is not known.
Other possible side effects that can occur with clarithromycin are:
common side effects (less than 1 in 10 people treated, but more than 1 in 100)
- Migraine, difficulty sleeping (insomnia).
- Stomach problems such as nausea (nausea), stifling (vomiting), indigestion (dyspepsia), stomach pain (abdominal pain) or diarrhea, taste changes, strange taste in the mouth (metallic or bitter taste).
- Thrush of the mouth (moniliasis). This causes pustules in the mouth sometimes accompanied by white spots.
- Skin rash, edema (hyperhidrosis).
- Changes in blood tests used to monitor kidney and liver function.
uncommon side effects
- Unusual bleeding or unexplained bruising (prolonged prothrombin time).
- Reduction in the number of circulating white blood cells (leukopenia, neutropenia), leading to an increased risk of infections, decrease in the number of circulating cells that allow blood to clot which leads to an increased tendency to bleed (thrombocythemia), abnormalities of blood cells (eosinophilia).
- Joint pain and muscle pain (arthralgia, myalgia), muscle spasms, stiffness.
- Liver and gallbladder problems (usually temporary and reversible) with inflammation of the liver (hepatitis) and involvement of the flow of bile (cholestasis) with or without yellowing of the skin and whites of the eyes (jaundice).
- Inflammation of the mouth (stomatitis), intestines or stomach.
- Infection, vaginal infection.
- Hypersensitivity.
- Anxiety, nervousness, need to scream, dizziness, sleepiness, tremor, spinning sensation (vertigo), hearing loss, ringing in the ears (tinnitus), asthma, nosebleeds.
- Alteration of heart rate and / or heart rhythm (QT prolongation, atrial fibrillation, cardiac arrest).
- Severe abdominal pain and back pain, inflammation of the stomach (gastritis), mouth (stomatitis), tongue (glossitis) or inflammation of the esophagus (esophagitis), constipation, dry mouth, belching and flatulence.
- Bullous inflammation of the skin, itching, hives, rash with small discolored flat spots, swelling.
- Anorexia, decreased appetite, malaise, red skin, weakness, chest pain, chills, fatigue.
very rare side effects (less than 1 in 10,000 people treated)
- Numbness and tingling in the arms and legs (paraesthesia).
Side effects with frequency not known:
- Inflammation of the intestine with severe diarrhea known as pseudomembranous colitis.
- St. Anthony's fire (erysipelas), acne.
- Unusual bleeding or bruising (prolonged prothrombin time), abnormal blood clotting, abnormal urine color.
- Severe allergic reactions causing swelling of the face or throat (angioedema).
- Psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, convulsions, loss of taste, alteration or loss of smell, deafness, tingling or numbness of the hands or feet.
- Cardiac arrest.
- Inflammation of the pancreas, tongue discoloration, tooth discoloration.
- Yellowing of the skin and whites of the eyes (jaundice), inflammation or kidney failure.
- Muscle weakness with loss of muscle tissue.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use Clarithromycin after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of that month.
Store below 30 ° C.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Clarithromycin tablets contains
- The active ingredient is clarithromycin.
- The other ingredients are:
Tablet core: croscarmellose sodium (E468), microcrystalline cellulose PH 102, magnesium stearate (E572), colloidal anhydrous silica (E551). Tablet coating: hypromellose 2910 E5 (E464), macrogol 8000, titanium dioxide (E171), yellow iron oxide (E172).
What Clarithromycin Accord looks like and contents of the pack
Clarithromycin 250 mg film-coated tablets are available in blisters containing 12 and 14 film-coated tablets.
Clarithromycin 500 mg film-coated tablets are available in blisters containing 14 film-coated tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CLARITHROMYCIN DOC GENERICI FILM-COATED TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Clarithromycin DOC Generici 250 mg:
1 film-coated tablet contains 250 mg of clarithromycin.
Clarithromycin DOC Generici 500 mg:
1 film-coated tablet contains 500 mg of clarithromycin.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Clarithromycin DOC Generici 250 mg:
Pale yellow, oval film-coated tablets debossed with "CLA250" on one side and "APO" on the other.
Clarithromycin DOC Generici 500 mg:
Pale yellow, capsule-shaped, film-coated tablets debossed with "CLA500" on one side and "APO" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Clarithromycin is indicated in adults and children aged 12 years and over (for adult-only formulations, such as tablets).
Clarithromycin is indicated for the treatment of the following bacterial infections, acute and chronic, caused by micro-organisms sensitive to clarithromycin:
• upper respiratory tract infections such as tonsillitis / pharyngitis, as an alternative when β-lactam antibiotics are not appropriate.
• acute otitis media in children.
• lower respiratory tract infections such as community acquired pneumonia.
• sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 years of age.
• mild to moderate infections of the skin and soft tissues.
• in appropriate combination with antibacterial therapeutic regimens and with an appropriate ulcer healing medicinal product for the eradication of Helicobacter pylori in adult patients with Helicobacter pylori associated ulcers (see section 4.2).
Official guidelines on the appropriate use of antibacterial agents, including national and local guidelines, should be considered.
04.2 Posology and method of administration
Dosage
The dose of clarithromycin depends on the type and severity of the infection and must be determined in each case by a physician.
Adults and adolescents (including the elderly)
Standard dose: the usual dose is 250 mg twice a day (in the morning and in the evening).
High dose treatment (severe infections): the usual dose can be increased to 500 mg twice a day in severe infections.
Pediatric population (over 12 years of age)
Use as in adults.
Elimination of Helicobacter pylori in adults
In patients with gastro-duodenal ulcers due to Helicobacter pylori infection, clarithromycin, as part of first-line triple therapy, is given at a dose of 500 mg twice daily. National recommendations on the eradication of Helicobacter pylori must be taken into account.
Dosage in renal insufficiency
Dose adjustments are generally not required, except for patients with severe renal impairment (creatinine clearance
Pediatric population (up to 12 years of age)
The recommended dose is 7.5 mg / kg twice a day (morning and evening).
The use of clarithromycin in tablet form is not recommended in children below 12 years of age with a body weight of less than 30 kg. The use of the pediatric clarithromycin suspension is more suitable in these patients.
Clinical studies have been conducted with the pediatric clarithromycin suspension in children from 6 months to 12 years of age. Therefore, the pediatric clarithromycin suspension (granules for oral suspension) should be used in children less than 12 years of age.
The effect in children under 3 years of age is not documented for the indication community-acquired pneumonia.
In patients with renal impairment and creatinine clearance below 30 ml / min, the dose of clarithromycin should be halved (e.g. 250 mg once daily or 250 mg twice daily in more severe infections). In these patients, treatment should not be extended beyond 14 days.
Duration of treatment
The duration of treatment with clarithromycin depends on the type and severity of the infection and must be determined in each case by a physician.
• The usual duration of treatment in children under 12 years of age is 5 to 10 days (for the pediatric suspension formulation).
• The usual duration of treatment in adults and children over 12 years of age is 6 to 14 days (for formulations for adults only).
• Treatment should continue for at least 2 days after the symptoms have disappeared.
• In infections with Streptococcus pyogenes (group A β-haemolytic streptococcus), the duration of treatment should be at least 10 days.
• Combination therapy for the eradication of Helicobacter pylori infection, for example 500 mg clarithromycin twice daily in combination with 1000 mg amoxicillin twice daily and 20 mg omeprazole twice daily, should be continued. for 7 days.
Method of administration
The tablets should be swallowed with at least half a glass of water.
Clarithromycin can be given regardless of food intake. Food has no effect on the extent of bioavailability. Food only slightly delays the onset of absorption of clarithromycin.
04.3 Contraindications
• Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, to other macrolide antibiotics or to any of the excipients listed in section 6.1.
• Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated as it may cause ergot toxicity (see section 4.5).
• Concomitant administration of clarithromycin with any of the following active substances is contraindicated: astemizole, cisapride, pimozide and terfenadine, as this may lead to QT interval prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsade de pointes (see section 4.5).
• Concomitant administration with ticagrelor or ranolazine is contraindicated.
• Clarithromycin should not be administered to patients with a history of QT interval prolongation or ventricular cardiac arrhythmia including torsades de pointes (see sections 4.4 and 4.5).
• Clarithromycin should not be administered concomitantly with HMG-CoA reductase inhibitors (statins) which are extensively metabolised by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).
• Like other potent CYP3A4 inhibitors, clarithromycin should not be used in patients who are taking colchicine.
• Clarithromycin should not be used in patients suffering from severe hepatic insufficiency in association with renal impairment.
• Clarithromycin must not be administered to patients with hypokalaemia (risk of QT interval prolongation, see section 4.4).
04.4 Special warnings and appropriate precautions for use
Doctors should not prescribe clarithromycin to pregnant women without a thorough benefit / risk assessment, particularly during the first three months of pregnancy (see section 4.6).
Clarithromycin is mainly excreted via the liver. Clarithromycin should therefore be administered with caution to patients with impaired hepatic function. Caution is also recommended when administering clarithromycin to patients with moderate to severe renal impairment.
Cases of fatal hepatic failure have been reported (see section 4.8). Some of these patients may have suffered from pre-existing liver disease or may have taken other hepatotoxic medicines. Patients should be advised to discontinue therapy and contact their physician if they experience signs and symptoms of liver distress such as anorexia, jaundice, dark urine, itching or abdominal pain.
Caution is recommended in patients with severe renal impairment (see section 4.2).
When renal function is poor, the dose of clarithromycin should be adequately reduced according to the degree of impairment (see section 4.2). The possibility of renal insufficiency should be considered in elderly patients.
Pseudomembranous colitis has been reported in association with almost all antibacterial agents, including macrolides, which can occur in mild to life-threatening severity. Diarrhea associated with Clostridium difficile (CDAD) with the use of almost all antibacterial agents, including clarithromycin, which can manifest itself as mild diarrhea to fatal colitis. Therapy with antibacterial agents alters the normal flora of the colon and this can cause an overgrowth of C. difficult. CDAD should be considered in all patients who present with diarrhea following antibiotic use. A thorough medical history is required as CDAD can occur more than two months after administration of the antibacterial agent. Consequently, CDAD may occur more than two months after administration of the antibacterial agent. Regardless of indication, discontinuation of clarithromycin therapy should be considered. An antibiogram should be performed and appropriate therapy initiated. The administration of medicinal products that inhibit peristalsis should be avoided.
There are reports from post-marketing experience of colchicine toxicity associated with the concomitant use of clarithromycin and colchicine, especially in the elderly, some of which refer to patients with renal insufficiency. Death has occurred in some of these patients (see section 4.5). Concomitant administration of clarithromycin and colchicine is contraindicated (see section 4.3).
Caution is recommended in concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam (see section 4.5).
Caution is recommended in concomitant administration of clarithromycin and other ototoxic medicinal products, especially with aminoglycosides. Monitoring of vestibular and auditory function should be performed during and after the conclusion of therapy.
Due to the risk of QT interval prolongation, clarithromycin should be used with caution in patients with coronary artery disease, history of cardiac ischaemia, ventricular arrhythmia, severe heart failure, uncontrolled hypomagnesaemia, bradycardia (
Pneumonia : in anticipation of the spread of the resistance of the Streptococcus pneumoniae to macrolides, it is important that susceptibility testing is done when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with appropriate additional antibiotics.
Mild to moderate skin and soft tissue infections : These infections are caused in most cases by Staphylococcus aureus And Streptococcus pyogenes, both potentially resistant to macrolides. Therefore it is important that sensitivity tests are carried out. In cases where antibiotics cannot be used betalactams (e.g. allergy), other antibiotics, such as clindamycin, may be first-choice medicines.
Macrolides are currently considered adequate only in some skin and soft tissue infections, such as those caused byCorynebacterium minutissimum, acne vulgaris, erysipelas and in situations where penicillin therapy cannot be performed.
If a severe acute hypersensitivity reaction occurs, such as anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment initiated urgently.
Clarithromycin should be used with caution when administered concomitantly with medicinal products known to induce cytochrome CYP3A4 enzyme (see section 4.5).
HMG-CoA reductase inhibitors (statins) : Concomitant use of clarithromycin and lovastatin or simvastatin is contraindicated (see section 4.3). Caution is required 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 concomitant use of clarithromycin and statins cannot be avoided, it is recommended that the lowest available dose of the statin be prescribed. The use of a statin (eg fluvastatin) whose metabolism is not dependent on CYP3A should be considered (see section 4.5).
Oral hypoglycemic agents / Insulin : Concomitant use of clarithromycin and oral hypoglycemic agents (such as sulfonylureas) and / or insulin may cause significant hypoglycaemia. Close monitoring of blood glucose is recommended (see section 4.5).
Oral anticoagulants : During co-administration of clarithromycin and warfarin, there is a risk of severe bleeding, a significant increase in International Normalized Ratio (INR) and a significant increase in prothrombin time (see section 4.5). INR and time of prothrombin should be monitored frequently when patients are receiving concomitant clarithromycin and oral anticoagulants.
The use of any antimicrobial therapy, including that with clarithromycin, to treat infection with H. pylori it can select drug-resistant organisms.
As with other antibiotics, prolonged use can lead to proliferation of resistant bacteria and fungi colonization. If superinfection occurs, appropriate therapy should be selected.
Attention should also be paid to the possibility of cross-resistance between clarithromycin and other macrolides, such as lincomycin and clindamycin.
04.5 Interactions with other medicinal products and other forms of interaction
The use of the following medicines is strictly contraindicated due to the possibility of developing serious effects caused by drug interactions:
Cisapride, pimozide, astemizole and terfenadine
In patients treated with clarithromycin and cisapride concomitantly, increased levels of cisapride have been reported. This may result in QT interval prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients who have taken clarithromycin and pimozide concomitantly (see section 4.3).
The alteration of the metabolism of terfenadine caused by macrolides, which has caused an increase in terfenadine levels occasionally associated with cardiac arrhythmias such as prolongation of the QT interval, ventricular tachycardia, ventricular fibrillation and torsade de pointes has been reported (see section 4.3). In a study in 14 healthy volunteers, concomitant administration of clarithromycin and terfenadine resulted in a two- to three-fold increase in serum levels of the acid metabolite of terfenadine and prolongation of the QT interval which resulted in no detectable clinical effect. Similar effects. have been observed during concomitant administration of astemizole and other macrolides.
Ergotamine / Dihydroergotamine
Post-marketing experience has shown that co-administration of clarithromycin and ergotamine or dihydroergotamine is associated with acute ergot toxicity, characterized by vasospasm, ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of these medicinal products and clarithromycin is contraindicated (see section 4.3).
HMG-CoA reductase inhibitors
Concomitant use of clarithromycin and lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively metabolised by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentrations, increasing the risk of myopathy, including rhabdomyolysis. They have been reported. cases of rhabdomyolysis in patients who have taken clarithromycin concomitantly with these statins If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.
Caution is required when prescribing clarithromycin with statins. In situations where concomitant use of clarithromycin and statins cannot be avoided, it is recommended that the lowest available dose of the statin be prescribed. The use of a statin (eg fluvastatin) whose metabolism is not dependent on CYP3A. Patients should be monitored for signs and symptoms of myopathy.
Effects of other medicinal products on clarithromycin
CYP3A inducing medicinal products (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, Hypericum containing products) may induce the metabolism of clarithromycin. This can lead to sub-therapeutic levels of clarithromycin, decreasing its efficacy.
In addition, plasma levels of CYP3A inducers may need to be monitored, which may be increased due to inhibition of CYP3A by clarithromycin (see also relevant product information for administered CYP3A4 inhibitors).
The following medicinal products are known or suspected to affect circulating clarithromycin concentration; Clarithromycin dose adjustment or alternative therapy may be required.
Efavirenz, nevirapine, rifampin, rifabutin and rifapentine
Potent inducers of the cytochrome P-450 metabolic system such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine can accelerate the metabolism of clarithromycin and, consequently, reduce its plasma levels, 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 in different bacteria, the intended therapeutic effect could be compromised with concomitant administration of clarithromycin and enzyme inducers.
A 39% decrease in the AUC of clarithromycin and a 34% increase in the AUC of the active metabolite 14-OH were observed when clarithromycin is used concomitantly with the CYP3A4 inducer efavirenz.
Etravirine
Exposure to clarithromycin is decreased by etravirine; however, the concentration of the active metabolite, 14-OH-clarithromycin, is increased. Since 14-OH-clarithromycin is less effective against Mycobacterium avium complex (MAC), the overall against this pathogen can be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg once daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in steady-state mean minimum clarithromycin concentration (Cmin) and area under the curve (AUC ) by 33% and 18%, respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole No dose adjustment of clarithromycin is required.
Ritonavir
A pharmacokinetic study has shown that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours results in a marked reduction in the metabolism of clarithromycin. With concomitant administration of ritonavir, clarithromycin Cmax increased by 31%, Cmin by 182% and AUC by 77%. Substantially complete inhibition of 14-OH-clarithromycin formation was noted. Due to the large therapeutic window of clarithromycin, no dose reduction is required in patients with normal renal function. However, in patients with renal impairment the following dose adjustments should be considered: in patients with CLCR between 30 and 60 ml / min the dose of clarithromycin should be reduced by 50%. In patients with CLCR
Similar dose adjustments should be considered in patients with impaired renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see below, "Bidirectional drug interactions")
Interaction in Helicobacter Pylori eradication regimes
Although plasma concentrations of clarithromycin and omeprazole may be increased when given in combination, no dose adjustment is required. At recommended doses, there is no clinically significant interaction between clarithromycin and lansoprazole. Increased plasma concentrations of clarithromycin may also occur when administered concomitantly with antacids or ranitidine. No dose adjustment is required. There are no pharmacokinetic interactions with the relevant antibiotics used for Helicobacter pylori eradication therapy.
Effect of clarithromycin on other medicinal products
CYP3A-mediated interactions
Concomitant administration of clarithromycin, a known inhibitor of CYP3A and P-glycoprotein transport, and a medicinal product metabolised primarily by CYP3A may result in an increase in drug concentrations which may lead to an increase or prolongation of both the therapeutic and adverse effects of the drug. concomitant medicinal product. Clarithromycin should be used with caution in patients receiving other medicinal products known to be substrates of the CYP3A enzyme, especially if the CYP3A substrate has a low margin of safety (eg carbamazepine) and / or the substrate is extensively metabolised by it. In patients in whom clarithromycin is administered concomitantly, dose adjustment may be considered and, whenever possible, serum concentrations of medicinal products metabolised primarily by CYP3A should be closely monitored.
The following drugs or classes of drugs are known or suspected to be metabolised by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, anticoagulant oromeprazole warfarin, see section 4.4), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Medicinal products interacting similarly through other isoenzymes belonging to the cytochrome P-450 system include phenytoin , theophylline and valproate.
Antiarrhythmics
Cases of torsades de pointes associated with the concomitant use of clarithromycin and quinidine or disopyramide have been reported in post-marketing experience. ECG monitoring for QT interval prolongation is required during co-administration of clarithromycin with these medicinal products. Serum levels of quinidine and disopyramide should be monitored during therapy with clarithromycin.
There have been post-marketing reports of hypoglycaemia following 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 some hypoglycaemic medicinal products such as nateglinide and repaglinide, inhibition of the CYP3A enzyme by clarithromycin may be relevant and this interaction may cause hypoglycaemia when these medicinal products are used concomitantly. Careful blood glucose monitoring is recommended.
Omeprazole
Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg once daily) in healthy adult individuals. Steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and t1 / 2 increased by 30%, 89% and 34% respectively) by concomitant administration of clarithromycin. The mean 24-hour gastric pH was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was administered concomitantly with clarithromycin.
Sildenafil, tadalafil and vardenafil
All of these phosphodiesterase inhibitors are metabolised, at least in part, by CYP3A which can be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil could lead to increased exposure to phosphodiesterase inhibitors. A dose reduction of sildenafil, tadalafil and vardenafil should be considered when these medicinal products are co-administered with clarithromycin.
Theophylline and carbamazepine
Clinical trial results indicate a modest but statistically significant (p ≤ 0.05) increase in circulating theophylline or carbamazepine levels when either of these drugs are concomitantly administered with clarithromycin. A dose reduction may need to be considered.
Tolterodina
Tolterodine is metabolised primarily via the cytochrome P-450 (CYP2D6) isoform 2D6. However, in a subset of the CYP2D6-free population, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A causes a marked increase in the serum concentrations of tolterodine. In the presence of CYP3A inhibitors, such as clarithromycin, a dose reduction of tolterodine may be required in the CYP2D6-free population.
Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)
When midazolam was administered concomitantly with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient should be closely monitored to allow for dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines that are not cleared by CYP3A (temazepam, nitrazepam, lorazepam) a clinically relevant interaction with clarithromycin is unlikely.
There are post-marketing reports of drug interactions and central nervous system (CNS) effects (eg somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring of the patient for increased CNS pharmacological effects is recommended.
Ciclosporin, tacrolimus and sirolimus
Concomitant administration of the oral form of clarithromycin with cyclosporine or tacrolimus leads to a more than 2-fold increase in the plasma Cmin of cyclosporine and tacrolimus. Similar effects can be expected with sirolimus. Plasma levels of cyclosporine, tacrolimus or sirolimus should be carefully monitored when initiating treatment with clarithromycin in patients treated with one of the immunosuppressants mentioned above, and their doses should be reduced if necessary. Discontinuation of clarithromycin in these patients also requires complete monitoring of cyclosporine, tacrolimus or sirolimus plasma levels to define dose adjustment.
Warfarin
The effects of anticoagulants may be enhanced if clarithromycin is used in patients receiving warfarin. Therefore, prothrombin time should be monitored frequently in these patients.
Other drug interactions
Aminoglycosides
Caution is advised in concomitant administration of clarithromycin and other ototoxic medicinal products, especially with aminoglycosides (see section 4.4).
Colchicine
Colchicine is a substrate of 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 concomitantly, inhibition of Pgp and / or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).
Digoxin
Digoxin is believed to be a substrate of the efflux transporter P-glycoprotein (Pgp).
Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased digoxin exposure. Elevated serum digoxin concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported during post-marketing surveillance. Some patients have shown similar clinical signs to those of digoxin toxicity, including life-threatening arrhythmias. Serum digoxin concentrations should be monitored closely while patients are receiving concomitant digoxin and clarithromycin therapy.
Zidovudine
Concomitant oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Since clarithromycin appears to interfere with the absorption of concomitantly administered orally administered zidovudine, this interaction can generally be avoided by staggering the doses of clarithromycin and zidovudine in order to interpose a 4-hour interval between each administration. This interaction does not appear to occur in patients. HIV infected pediatrics taking clarithromycin suspension concomitantly with zidovudine or didanosine This interaction is unlikely when clarithromycin is administered by intravenous infusion.
Phenytoin and valproate
There are spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, with medicinal products not believed to be metabolised by CYP3A (eg phenytoin and valproate). Determination of the serum levels of these medicinal products is recommended when administered into concomitant with clarithromycin An increase in serum levels has been reported.
Bidirectional drug interactions
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of CYP3A, and a "bidirectional drug interaction has been shown. Concomitant administration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) resulted in an increase of two times of clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Due to clarithromycin's large therapeutic window, no dose reduction should be required in patients with normal renal function. In patients with moderate renal impairment (creatinine clearance 30 to 60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance
Calcium channel blockers
Caution is advised in concomitant administration of clarithromycin and calcium channel blockers metabolised by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as much as those of calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmia and lactic acidosis have been observed in patients who have taken clarithromycin and verapamil at the same time.
Itraconazole
Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, resulting in a bidirectional drug interaction. Clarithromycin may lead to increased plasma levels of itraconazole while itraconazole may increase plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for signs and symptoms of potentiation or prolongation of the pharmacological effects of these drugs.
Saquinavir
Clarithromycin and saquinavir are both substrates and inhibitors of CYP3A, and a "bidirectional drug interaction has been shown. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily)" 12 healthy volunteers resulted in steady-state saquinavir AUC and Cmax values 177% and 187% higher, respectively, than those seen when saquinavir monotherapy was administered. Clarithromycin AUC and Cmax values were approximately higher. 40% of those seen with clarithromycin alone. When the two medicinal products are co-administered, in the formulations and doses studied, for a limited period of time, no dose adjustment is required. Observations from the studies drug interactions performed using the soft gelatin capsule formulation could not be representative of the effects seen using the saquinavir hard gelatin capsule formulation. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir / ritonavir combination therapy. When saquinavir is co-administered with ritonavir, an assessment of the potential effects of ritonavir on clarithromycin should be undertaken.
04.6 Pregnancy and lactation
Pregnancy
The safety of clarithromycin for use during pregnancy has not been established. Based on variable results from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded.
Therefore, use during pregnancy is not recommended without a careful risk / benefit assessment.
Feeding time
The safety of clarithromycin use during breastfeeding has not been established. Clarithromycin is excreted through breast milk.
04.7 Effects on ability to drive and use machines
There are no data on the effects of clarithromycin on the ability to drive or use machines. The possibility that dizziness, vertigo, confusion and loss of orientation may occur with the use of the drug should be considered before patients drive or use machinery.
04.8 Undesirable effects
to. Summary of the safety profile
The most frequent and common adverse reactions associated with clarithromycin therapy in both the adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste disturbance. These adverse reactions are usually mild in intensity and are consistent with the known safety profile for macrolide antibiotics (see section b of section 4.8).
There was no significant difference in the incidence of these gastrointestinal adverse reactions between the patient populations with and without pre-existing mycobacterial infections during clinical trials.
b. Tabular summary of adverse reactions
The table below shows the adverse reactions reported from clinical studies and post-marketing experience with immediate release tablets, granules for oral suspension, powder for solution for injection, prolonged release tablets and modified release tablets.
Reactions considered, at least possibly, associated with clarithromycin are listed by system organ class and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100,
1 ADRs reported only for powder formulation for solution for injection
2ADRs reported for prolonged-release tablet formulation only
3 ADRs reported only for the granules formulation for oral suspension
4ADRs reported for immediate release tablet formulation only
5,7,9,10 See section a
6,8,11 See section c
c. Description of some adverse reactions
Injection site phlebitis, injection site pain, injection site vascular pain, and injection site inflammation are specific reactions of the clarithromycin intravenous formulation.
In some of the reported cases of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see sections 4.3 and 4.4).
There are post-marketing reports of drug interactions and central nervous system (CNS) effects (eg somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Patient monitoring is recommended for possible potentiation of CNS pharmacological effects ( see section 4.5).
There have been rare reports of clarithromycin prolonged-release tablets in faeces, many of which have been reported in patients with anatomic (including ileostomy or colostomy) or functional abnormalities of the gastrointestinal tract resulting in a shortened gastrointestinal transit time. In many cases, the discovery of tablet residues occurred at the same time as the onset of diarrhea. In patients who have found tablet residues in the stool and whose condition has not improved, it is recommended that the medicine be replaced with a different clarithromycin formulation (e.g. suspension) or another antibiotic.
Special populations: adverse reactions in immunocompromised patients (see section e).
d. Pediatric population
Clinical studies have been conducted with pediatric clarithromycin suspension in children from 6 months to 12 years of age. Therefore, pediatric clarithromycin suspension should be used in children less than 12 years of age. There are insufficient data to do this. to recommend a dosing regimen for use of the clarithromycin IV formulation in patients younger than 18 years of age.
The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
And. Other special populations
Immunocompromised patients
In AIDS patients and other immunocompromised patients on long-term therapy with high doses of clarithromycin due to mycobacterial infections, it is often difficult to distinguish adverse events possibly associated with clarithromycin administration from signs of disease due to infection with the virus. of HIV or to intercurrent pathologies.
In adult patients, the most frequently reported adverse reactions in patients receiving total daily doses of 1000 mg and 2000 mg clarithromycin are: nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, flatulence, headache, constipation, impaired hearing, increased serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT). Less frequently dyspnoea, insomnia and dry mouth may occur. In patients receiving 1000 mg and 2000 mg the incidences are similar, while in patients receiving a total daily dose of 4000 mg of clarithromycin, the frequencies generally increase approximately 3 to 4 fold. In these immunocompromised patients, evaluation of laboratory values was performed by analyzing those severely abnormal values ( eg placed outside the upper or lower limit) for the specific test 2% - 3% of patients receiving clarithromycin 1000 mg or 2000 mg daily had a severely abnormal rise in SGOT and SGPT, and abnormally reduced white blood cell and platelet counts. A smaller percentage of these patients in these two dose groups also had increased blood urea nitrogen levels. A slightly higher incidence of abnormal values was found in patients receiving 4000 mg per day. parameters except for the white blood cell count.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms of intoxication
Ingestion of large quantities of clarithromycin has been reported to induce gastrointestinal symptoms. A patient with a history of bipolar disorder ingested 8 g of clarithromycin and presented with altered mental status, paranoid behavior, hypokalaemia and hypoxemia.
Treatment of intoxication
Adverse reactions caused by overdose should be treated with prompt elimination of unabsorbed medicinal product and supportive therapy. As with other macrolides, serum levels of clarithromycin should not be expected to be significantly affected by hemodialysis and peritoneal dialysis.
Severe acute allergic reactions such as anaphylactic shock have been rarely observed. Treatment with clarithromycin should be discontinued at the first signs of hypersensitivity, and the necessary precautions taken.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: macrolides.
ATC code: J01F A09
Mechanism of action
Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal subunit of susceptible bacteria and inhibits RNA-dependent bacterial protein synthesis. It is highly potent against a wide variety of gram-positive and gram-negative, aerobic and anaerobic. Clarithromycin minimum inhibitory concentrations (MICs) are generally 2-fold lower than erythromycin MICs.
The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal to or 2 times higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is 2 times more active than the parent compound.
Resistance mechanism
Macrolide resistance is mediated through alteration of the macrolide binding site, modification of the antibiotic and / or active drug efflux. The development of resistance can be chromosome-linked or plasmid-mediated and can be induced or In macrolide-resistant microorganisms the adenine-methylating enzymes of ribosomal RNA are expressed. Clarithromycin is a strong inducer of this enzyme. Consequently, binding of the antibiotic to the 50s ribosomal subunit is inhibited. Because of this, macrolide-resistant microorganisms that bind the methylation site of the 50s ribosomal subunit generally demonstrate cross-resistance with lincosamides (e.g. lincomycin) and streptogramin B. C "is also the possibility of cross-resistance between clarithromycin and other macrolides (e.g. erythromycin and azithromycin), as well as with clindamycin.
In addition, macrolides act as bacteriostatic by inhibiting the activity of the ribosomal peptidyltransferase.
Most methicillin-resistant strains of staphylococci are Streptococcus pneumoniae penicillin resistant are also resistant to macrolides such as clarithromycin.
Superinfection with other resistant microorganisms can occur after treatment of pathogens sensitive to clarithromycin.
Intervals (Breakpoints)
In 2004 the Clinical Laboratory Standards Institute (CLSI, formerly NCCLS) determined the following sensitivity ranges for clarithromycin:
• Staphylococcus spp .: sensitive ≤ 2 mcg / ml, resistant ≥ 8 mcg / ml
• Haemophilus spp: sensitive ≤ 8 mcg / ml, resistant ≥ 32 mcg / ml
• S. pneumoniae: sensitive ≤ 0.25 mcg / ml, resistant ≥1 mcg / ml
• Streptococcus spp., Outside of S. pneumoniae: sensitive ≤ 0.25 mcg / ml, ≥1 mcg / ml
resistant
• Helicobacter pylori: sensitive ≤ 0.25 mcg / ml, resistant ≥ 1 mcg / ml
The prevalence of acquired resistance for selected species may vary geographically and with time and local information on the type of resistance is desirable, particularly for the treatment of severe infections. As necessary, expert advice should be sought when the local prevalence of resistance has increased to such an extent that the efficacy of the agent is uncertain in at least some types of infections.
* for notes on resistances see "Resistance mechanism "
Other information
The sensitivity and resistance of Streptococcus pneumoniae and Streptococcus ssp. clarithromycin can be predicted by testing for erythromycin.
Most of the clinical experience from randomized controlled trials indicates that 500 mg clarithromycin twice daily for 7 days in combination with other antibiotics, for example amoxicillin or metronidazole and for example omeprazole (given at approved doses) determine a percentage of eradication of the "H. pylori> 80% in patients with gastro-duodenal ulcers. As expected, significantly lower eradication rates were observed in patients with isolated baseline levels of metronidazole-resistant H.pylori.
Therefore, in choosing an appropriate combination regimen for H. pylori, local information on the prevalence of resistance and local guidelines for therapy should be considered. In addition, in patients with persistent infection, the potential development of secondary resistance (in patients with susceptible primary strains) should be considered for a new re-treatment regimen.
05.2 "Pharmacokinetic properties
Absorption
After oral administration clarithromycin is rapidly and well absorbed from the gastrointestinal tract - mainly in the duodenum - and is subject to strong first pass metabolism. Absolute bioavailability is approximately 50%. Food may slightly delay the onset of absorption of clarithromycin, but does not affect absolute bioavailability. In addition, clarithromycin tablets can be administered with or without meals.
The chemical structure of the clarithromycin molecule (6-0-methilerithromycin) is responsible for its resistance to the action of gastric hydrochloric acid.
In adult patients, the maximum plasma concentrations of clarithromycin following oral administration were 1 to 2 mcg / ml (250 mg twice daily) and 2.8 mcg / ml (500 mg twice daily), respectively. The maximum plasma concentration of the active metabolite 4-hydroxyclarithromycin was 0.6 mcg / mL (250 mg twice daily) and 0.83 to 0.88 mcg / mL (500 mg twice daily), respectively. The pharmacokinetics of clarithromycin are not linear, however, steady state plasma concentrations of clarithromycin are reached after 2 or 3 days of administration.
Distribution
Clarithromycin rapidly penetrates various body tissues and body fluids. In adults the volume of distribution ranges from 200 to 400 liters. Clarithromycin provides tissue concentrations that are several times higher than circulating drug levels. Increased levels were found in both the tonsils and lungs. Clarithromycin also penetrates through the gastric mucus.
At therapeutic levels, clarithromycin is 80% bound to plasma proteins.
Biotransformation and Elimination
Clarithromycin is metabolised rapidly and in large quantities in the liver by the cytochrome P-450 enzyme system. Metabolic processes mainly include N-dealkylation, oxidation and sterospecific hydroxylation at the C14 position.
The pharmacokinetics of clarithromycin are not linear due to the fact that it reaches saturation in the liver at high doses. After oral administration the elimination half-life increases from 2-4 hours for the 250 mg twice daily dose to 5 hours for the 500 mg twice daily dose. After oral administration of 250 mg twice daily l "half-life of the active metabolite 4-hydroxyclarithromycin was 5-6 hours.
After oral administration of radioactively labeled clarithromycin, 70-80% of the radioactivity was found in the faeces. Approximately 20-30% of the clarithromycin dose is excreted unchanged in the urine. This distribution increases with increasing dose. In patients with renal impairment, plasma concentrations of clarithromycin may increase in the absence of dose adjustment.
Total plasma clearance of clarithromycin is approximately 700 mL / min (11.7 mL / s), and the corresponding renal clearance is approximately 170 mL / min (2.8 mL / s).
Kidney failure
In patients with renal insufficiency, increased plasma levels of clarithromycin and its active metabolite have been observed.
05.3 Preclinical safety data
In repeat dose studies (4 weeks), the toxicity of clarithromycin was related to dose and duration of treatment. The primary target organ was the liver in all species, with liver injury observed after 14 days, in dogs and monkeys. The systemic plasma levels associated with this toxicity are unknown but the toxic dose (300 mg / kg / day) it was higher than the recommended treatment dose in humans.
Other tissues affected were the stomach, thymus and other lymphoid tissues as well as the kidneys. At doses close to therapeutic doses, conjunctival infection and lacrimation occurred only in the dog. At a dose of 400 mg / kg / day some dogs and monkeys developed corneal opacity and / or edema.
There was no evidence of clarithromycin mutagenic potential during the in vitro and in vivo studies.
Reproduction studies have shown that administration of clarithromycin to rabbits (at twice the recommended clinical dose for humans) and monkeys (at ten times the recommended clinical dose for humans) leads to a "Increased incidence of abortions. Levels of these doses were clearly related to maternal toxicity. Teratogenic studies in rats showed neither embryotoxicity nor teratogenesis by clarithromycin. However, cardiovascular abnormalities were observed in rats treated with doses of 150 mg / kg. Studies in mice revealed a variable (3-30%) incidence of cleft palate at doses that were 70 times higher than the recommended clinical dose for humans.
Clarithromycin was found in the milk of lactating animals.
In 3-day-old mice and rats, the LD50 values were approximately half that of adult animals. Juvenile animals had similar toxicity profiles to adult animals, although an increase in nephrotoxicity in adult animals has been reported in some studies. Neonatal rats: A weak reduction in erythrocytes, platelets and leukocytes was also found in young animals.
Clarithromycin has not been tested for carcinogenesis.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core:
Croscarmellose sodium (E468)
Microcrystalline cellulose PH 102
Magnesium stearate (E572)
Colloidal anhydrous silica (E551)
Tablet coating:
Hypromellose 2910 E5 (E464)
Macrogol 8000
Titanium dioxide (E171)
Yellow iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store below 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
CLARITHROMYCIN DOC Generici 250 mg: blister (PVC / PVdC) containing 12 and 14 film-coated tablets.
CLARITHROMYCIN DOC Generici 500 mg: blister (PVC / PVdC) containing 14 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
DOC Generici S.r.l. - Via Turati 40 - 20121 Milan - Italy.
08.0 MARKETING AUTHORIZATION NUMBER
CLARITHROMYCIN DOC Generici 250 mg film-coated tablets - 12 tablets in PVC / PVdC blister - AIC 038497018.
CLARITHROMYCIN DOC Generici 250 mg film-coated tablets - 14 tablets in PVC / PVdC blister - AIC 038497020.
CLARITHROMYCIN DOC Generici 500 mg film-coated tablets - 14 tablets in PVC / PVdC blister - AIC 038497032.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: December 2008.
Date of most recent renewal: December 2012.
10.0 DATE OF REVISION OF THE TEXT
January 2015.
