Instructions for use FROMILID® UNO
The use of the following drugs is strictly contraindicated due to the possible development of severe consequences of drug interactions
Cisapride, pimozide, astemizole, terfenadine
An increase in the concentration of cisapride in the blood serum was observed when used together with clarithromycin, which can lead to a prolongation of the QT interval and the occurrence of arrhythmias, incl. ventricular tachycardia, ventricular fibrillation and ventricular tachycardia of the “pirouette” type. Similar effects were observed with the combined use of clarithromycin and pimozide.
It was noted that antibiotics of the macrolide group change the metabolism of terfenadine, as a result of which its concentration in the blood serum increases, which can also lead to a prolongation of the QT interval and the appearance of arrhythmias, incl. ventricular tachycardia, ventricular fibrillation and ventricular tachycardia of the “pirouette” type. In one study of 14 healthy volunteers, the simultaneous use of clarithromycin and terfenadine showed an increase in serum concentrations of the acid metabolite terfenadine by 2-3 times and a prolongation of the QT interval, which was not clinically significant. Similar effects were observed with the combined use of astemizole and other macrolide antibiotics.
Ergotamine/dihydroergotamine
Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with signs of acute ergotism, which is characterized by vasospasm and ischemia of the limbs and other tissues, including the central nervous system. The use of clarithromycin and these drugs is contraindicated.
Effect of other drugs on the pharmacokinetics of clarithromycin
Medicines that are CYP3A inducers (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin and reduced effectiveness. In addition, it may be necessary to monitor plasma concentrations of the CYP3A inducer, which may be increased due to the inhibition of CYP3A by clarithromycin (see also the prescribing information for the corresponding CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin resulted in increased rifabutin concentrations and decreased clarithromycin plasma concentrations, while increasing the risk of uveitis.
The following drugs have known or suspected effects on clarithromycin blood concentrations, so dose adjustments or alternative therapy may be necessary.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Potent inducers of cytochrome P450 isoenzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin, reducing its concentration in the blood plasma, but increasing the concentration of 14-OH-clarithromycin, a microbiologically active metabolite. Because The microbiological activity of clarithromycin and 14-OH-clarithromycin is different against different bacteria; the expected therapeutic effect may not be achieved due to the combined use of clarithromycin and inducers of isoenzymes of the cytochrome P450 system.
Fluconazole
Css of the active metabolite 14-OH-clarithromycin did not change significantly when combined with fluconazole. No clarithromycin dose change is required.
Ritonavir
The use of ritonavir and clarithromycin led to a significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, AUC increased by 77%. There was complete inhibition of the formation of 14-OH-clarithromycin. Due to the large therapeutic range, a dose reduction of clarithromycin is not required in patients with normal renal function. In patients with renal failure, dose adjustment is necessary:
- with a CC of 30-60 ml/min, the dose of clarithromycin should be reduced by 50%; with a CC of <30 ml/min, the dose of clarithromycin should be reduced by 75%. Doses of clarithromycin exceeding 1 mg/day should not be used with ritonavir.
The same dose adjustment should be made in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.
Effect of clarithromycin on the pharmacokinetics of other drugs that are CYP3A substrates
Concomitant use of clarithromycin, a known inhibitor of the CYP3A isoenzyme, and a drug primarily metabolized by CYP3A, leads to an increase in the concentration of this drug in the blood plasma, which, in turn, may enhance or prolong the therapeutic effect and the risk of adverse reactions.
Caution should be exercised when using clarithromycin in patients receiving therapy with drugs that are CYP3A substrates, especially if these drugs have a narrow therapeutic index (for example, carbamazepine) and/or are extensively metabolized by this isoenzyme.
Dosage adjustments and, if possible, close monitoring of serum concentrations of a drug metabolized by CYP3A in patients concomitantly receiving clarithromycin may be necessary.
The following drugs or groups of drugs are known (or suspected) to be metabolized by the same isoenzyme CYP3A:
- alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfen adin, triazolam and vinblastine . A similar mechanism of interaction was noted with the use of phenytoin, theophylline and valproate, which are metabolized by another isoenzyme of the cytochrome P450 system.
Antiarrhythmic drugs
There are post-marketing reports of the development of ventricular tachycardia of the torsade de pointes type that occurred with the simultaneous use of clarithromycin with quinidine or disopyramide. It is recommended to carry out ECG monitoring for timely detection of QT interval prolongation. Plasma concentrations of these drugs should be monitored during clarithromycin therapy.
Omeprazole
The use of clarithromycin in combination with omeprazole in healthy adult volunteers resulted in an increase in the Css of omeprazole. When omeprazole was used alone, the average pH value of gastric juice when measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.
Sildenafil, tadalfil and vardenafil
There is a possibility of increased plasma concentrations of PDE inhibitors (sildenafil, tadalafil and vardenafil) when used together with clarithromycin, which may require a reduction in the dose of PDE inhibitors.
Theophylline, carbamazepine
The results of clinical studies have shown that there is a slight but statistically significant increase in the concentration of theophylline or carbamazepine in the blood plasma when used simultaneously with clarithromycin. A dose reduction may be required.
Tolterodine
A dose reduction of tolterodine may be necessary when used with clarithromycin.
Triazolbenzodiazepines (eg, alprazolam, midazolam, triazolam)
The combined use of oral midazolam and clarithromycin should be avoided. When administering midazolam intravenously with clarithromycin, the patient should be carefully monitored for timely dose adjustment.
The same precautions should be taken when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), the development of a clinically significant interaction with clarithromycin is unlikely. There are post-marketing reports of drug interactions and CNS side effects (such as drowsiness and confusion) when clarithromycin and triazolam are used together. The patient's condition should be monitored, taking into account the possibility of enhancing the pharmacological effect on the central nervous system.
Other types of interaction
Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). It is known that clarithromycin and other macrolide antibiotics are capable of inhibiting CYP3A and Pgp. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A by clarithromycin may result in increased colchicine exposure. Patients should be monitored for clinical signs of colchicine toxicity.
With the simultaneous use of clarithromycin and statins, fibrates, colchicine, allopurinol, cases of rhabdomyolysis have been reported.
According to post-marketing studies, the simultaneous use of colchicine and clarithromycin can cause colchicine toxicity (sometimes fatal), especially in elderly patients, incl. against the background of renal failure.
During post-marketing surveillance, increased digoxin plasma concentrations have been reported in patients receiving clarithromycin concomitantly with digoxin. Some patients developed signs of digoxin toxicity, incl. potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients receiving it with clarithromycin.
Concomitant use of clarithromycin tablets and zidovudine in HIV-infected patients may cause a decrease in plasma Css of zidovudine. This can be largely avoided by maintaining an interval between doses of clarithromycin and zidovudine. This interaction has not been reported with the use of clarithromycin suspension and zidovudine or dideoxynosine in children. This interaction is unlikely with intravenous infusions of clarithromycin.
There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not believed to be metabolized by CYP3A (eg, phenytoin and valproate). It is recommended to determine plasma concentrations of these drugs when coadministering them with clarithromycin. Increased plasma concentrations have been reported.
Bidirectional drug interactions between clarithromycin and atazanavir, itraconazole, and saquinavir are also possible.
The development of arterial hypotension, bradycardia and lactic acidosis has been reported with the combined use of clarithromycin and verapamil.
Clarithromycin does not interact with oral contraceptives.
Fromilid uno (tablet p/o 500 mg No. 14 extended.)
A country
Slovenia
The country of production may vary depending on the batch of goods. Please check with the operator for detailed information when confirming your order.
Active substance
Clarithromycin
Compound
The active substance is Clarithromycin.
pharmachologic effect
Antibacterial (bacteriostatic), antiulcer. When taken orally, it is quickly and fairly completely absorbed. Food slows absorption without significantly affecting bioavailability. In plasma it binds to serum proteins. It is immediately oxidized in the liver to form the main metabolite 14-hydroxyclarithromycin (has pronounced antimicrobial activity against Haemophilus influenzae). Penetrates well into body fluids and tissues, creating concentrations 10 times higher than the level in blood serum. Excreted in the urine in unchanged form and in the form of metabolites. Active against intracellular microorganisms (Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia trachomatis and Chlamydia pneumoniae, Ureaplasma urealyticum), gram-positive (Streptococcus spp. and Staphylococcus spp., Listeria monocytogenes, Corynebacterium spp.) and gram -negative bacteria (Haemophilus influenzae and haemophilus ducreyi, Moraxella catarrhalis, bordetella pernsis, neisseria meningitidis, Borrelia Burgdorferi, Pasteuralla multocida, Campylla Obacter spp., Helicobacter pylori), some anaerobes (Eubacterium spp., Peptococcus spp., Propionibacterium spp., Clostridium Perfringens , Bacteroides melaninogenicus), Toxoplasma gondii and all mycobacteria except V. tuberculosis.
Indications for use
Infections of the upper respiratory tract and ENT organs (tonsillopharyngitis, otitis media, acute sinusitis), lower respiratory tract (acute bronchitis, exacerbation of chronic bronchitis, bacterial and atypical pneumonia), skin and soft tissues, mycobacterial infection (M.avium complex, M. cansasii, M.marinom, M.leprae), peptic ulcer of the duodenum and stomach caused by Helicobacter pylori (combination therapy).
Mode of application
The tablets should be taken during meals: swallowed whole with a small amount of liquid; do not break. Adults and children over 12 years of age are prescribed 500 mg/day. (1 tablet). For the treatment of severe infections, the daily dose is increased to 1000 mg/day. (2 tablets). Duration of treatment is usually 7-14 days
Interaction
Increases the concentration in the blood of drugs metabolized in the liver with the participation of enzymes of the cytochrome P450 complex: warfarin and other indirect anticoagulants, carbamazepine, theophylline, astemizole, cisapride, thiazolam, midazolam, cyclosporine, digoxin, ergot alkaloids, etc., reduces the absorption of zidovudine.
Side effect
Nausea, vomiting, change in taste, abdominal pain, diarrhea, pseudomembranous colitis, stomatitis, glossitis, dizziness, headache, anxiety, fear, insomnia, nightmares, increased activity of liver enzymes, cholestatic jaundice, allergic (urticaria, Stevens syndrome - Johnson et al.) and anaphylactoid reactions.
Contraindications
Hypersensitivity, severe liver disease, porphyria, pregnancy and breastfeeding.
Overdose
Symptoms: nausea, vomiting, diarrhea. Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis are not effective.
special instructions
Prescribe with caution against drugs metabolized by the liver (it is recommended to measure their concentration in the blood). In case of combination with warfarin or other indirect anticoagulants, it is necessary to monitor the prothrombin time. If you have a history of heart disease, simultaneous use with terfenadine, cisapride, or astemizole is not recommended.
Dispensing conditions in pharmacies
On prescription
Fromilid
Use during pregnancy and breastfeeding
The use of Fromilid® in the first trimester of pregnancy is contraindicated.
The use of Fromilid® in the second and third trimesters of pregnancy is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk for the fetus.
If it is necessary to use the drug during lactation, breastfeeding should be stopped.
Use for liver dysfunction
Contraindicated in severe liver failure, hepatitis (history).
The drug should be used with caution in case of liver failure.
Use for renal impairment
For patients with impaired renal function (creatinine clearance less than 30 ml/min or serum creatinine level more than 3.3 mg/dl), the dose should be halved or the interval between doses should be doubled.
The drug should be used with caution in patients with moderate to severe renal failure.
Use in children
Contraindication: children under 6 months of age (for the dosage form - granules for the preparation of a suspension for oral administration) - there is insufficient experience regarding the effectiveness and safety of use; children under 12 years of age and/or children weighing less than 33 kg (for dosage form - film-coated tablets).
special instructions
When prescribing the drug, it should be taken into account that there is cross-resistance among macrolide antibiotics.
In patients with mild to moderate hepatic impairment, there is no need to reduce the dose of the drug if renal function is normal. In patients with severe renal impairment, the dose should be reduced.
In the presence of chronic liver diseases, it is necessary to regularly monitor serum enzymes.
When prescribing drugs metabolized in the liver simultaneously, it is recommended to monitor their concentration in the blood serum.
Antibiotic treatment alters the normal intestinal flora, so superinfection caused by resistant microorganisms may develop.
The patient should be warned that in case of severe persistent diarrhea, which may be due to pseudomembranous colitis, he should consult a doctor.
Prothrombin time should be periodically monitored in patients receiving clarithromycin concomitantly with warfarin or other oral anticoagulants.
125 mg of granules for the preparation of an oral suspension of 125 mg/5 ml contains 1.6 g of sucrose, so the drug is contraindicated in children with congenital fructose intolerance, glucose/galactose malabsorption syndromes or sucrase-isomaltase enzyme deficiency.
Use in pediatrics
Currently, there is insufficient data on the effectiveness and safety of the drug in children under 6 months of age.
Impact on the ability to drive vehicles and operate machinery
The drug does not affect the speed of psychomotor reactions when driving a car or operating machinery.
