Pharmacological action of Fromilid
The antibiotic Fromilid exhibits activity against the following microorganisms:
- intracellular bacteria (Chlamydiatrachomatis, Legionellapneumophila, Chlamydiapneumoniae, Mycoplasmapneumoniae, Ureaplasmaurealyticum);
- all mycobacteria, except V. tuberculosis;
- gram-negative bacteria (Neisseriameningitidis, Moraxellacatarrhalis, Helicobacterpylori, Haemophilusducreyi and Haemophilusinfluenzae, Neisseriameningitidis, Campylobacter spp., Pasteurellamultocida, Bordetellapertussis);
- gram-positive bacteria (Listeriamonocytogenes, Staphylococcus spp. and Streptococcus spp., Corynebacterium spp.);
- some anaerobic bacteria (Peptococcus spp., Eubacterium spp., Clostridium perfringens, Toxoplasmagondii, Propionibacterium spp.).
Fromilid after oral administration is well absorbed from the gastrointestinal tract. The content of the drug in biological fluids and tissues affected by the inflammatory process exceeds its content in the blood plasma ten times.
Fromilid 500 mg 14 pcs. tablets in Moscow
The use of the following medications concomitantly with clarithromycin is contraindicated due to the potential for serious side effects
Cisapride, pimozide, terfenadine and astemizole
When clarithromycin was taken concomitantly with cisapride, pimozide, terfenadine or astemizole, an increase in the concentration of the latter in the blood plasma was reported, which can lead to prolongation of the QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including torsade de pointes) and ventricular fibrillation (see section “Contraindications”).
Ergot alkaloids
Post-marketing studies show that with simultaneous use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with ergotamine drugs are possible: vascular spasm, ischemia of the limbs and other tissues, including the central nervous system (CNS). The simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see section "Contraindications").
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications") due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and simultaneous use with clarithromycin increases their serum concentrations, which leads to an increased risk of developing myopathy, including Rhabdomyolysis Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these drugs. If clarithromycin is necessary, lovastatin or simvastatin should be discontinued during therapy.
Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins whose metabolism does not depend on the CYP3A isoenzyme (for example, fluvastatin). If concomitant use is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be monitored.
Midazolam for oral administration
With the simultaneous use of midazolam and clarithromycin in the form of tablets (500 mg 2 times a day), there was a 7-fold increase in the AUC of midazolam after oral administration. Concomitant use of clarithromycin with midazolam for oral administration is contraindicated.
Effect of other drugs on clarithromycin
Drugs that are inducers of the CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort preparations) can induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin and, consequently, a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the CYP3A inducer in the blood plasma, which may increase due to the inhibition of the CYP3A isoenzyme by clarithromycin. With simultaneous use of rifabutin and clarithromycin, an increase in the concentration of rifabutin and a decrease in the concentration of clarithromycin in blood plasma was observed with an increased risk of developing uveitis.
The following drugs have a proven or suspected effect on clarithromycin plasma concentrations and may require dose adjustment or switch to alternative treatment if used concomitantly with clarithromycin
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and, thus, reduce the concentration of clarithromycin in the blood plasma and weaken the therapeutic effect, and at the same time increase the concentration in the blood plasma of 14-OH- clarithromycin is a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against various bacteria, the therapeutic effect may be reduced with simultaneous use of clarithromycin and inducers of the cytochrome P450 system.
Etravirine
The plasma concentration of clarithromycin decreases when used concomitantly with etravirine, but the plasma concentration of the active metabolite 14-OH-clarithromycin increases. Because 14-OH-clarithromycin has low activity against MAC infections, overall activity against these pathogens may be altered, and alternative treatments should be considered for the treatment of MAC.
Fluconazole
Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in mean clarithromycin minimum steady-state concentration (Cmin) and AUC by 33% and 18%, respectively. However, simultaneous administration did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required when taking fluconazole simultaneously.
Ritonavir
A pharmacokinetic study showed that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. When co-administered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182% and AUC increased by 77%. Complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with renal failure, it is advisable to consider the following dose adjustment options: with CC 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. Similar dosage adjustments should be considered in patients with reduced renal function if ritonavir is used as a pharmacokinetic enhancer when using other HIV protease inhibitors, including atazanavir and saquinavir (see section "Bidirectional Drug Interactions").
Ritonavir should not be taken concomitantly with clarithromycin in doses exceeding 1 g/day.
Effect of clarithromycin on other drugs
Antiarrhythmic drugs (quinidine and disopyramide)
Ventricular tachycardia of the “pirouette” type may occur with the simultaneous use of clarithromycin and quinidine or disopyramide. When clarithromycin is coadministered with these drugs, ECG monitoring should be performed regularly to monitor for QT prolongation, and serum concentrations of these drugs should also be monitored.
During post-marketing use, cases of hypoglycemia have been reported with concomitant use of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood while using clarithromycin and disopyramide.
Oral hypoglycemic agents/insulin
With the simultaneous use of clarithromycin and oral hypoglycemic agents (for example, sulfonylureas) and/or insulin, severe hypoglycemia may occur. Concomitant use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of the CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Careful monitoring of blood glucose concentrations is recommended.
Interactions due to CYP3A isoenzyme
Concomitant use of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, may be associated with a mutual increase in their concentrations, which may increase or prolong both therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic index (for example, carbamazepine), and/or drugs that are extensively metabolized by this isoenzyme. If necessary, the dose of the drug taken simultaneously with clarithromycin should be adjusted. Also, whenever possible, serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should be monitored.
The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin: alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (eg, warfarin), atypical antipsychotics (eg, quetiapine), quinidine , rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, inhibitors of the CYP3A isoenzyme include the following drugs that are contraindicated for simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see section “Contraindications”). Drugs that interact in this manner through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid.
Indirect anticoagulants
When taking warfarin and clarithromycin simultaneously, bleeding, a marked increase in INR and prolongation of prothrombin time are possible. In case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.
Omeprazole
Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). With simultaneous use of clarithromycin and omeprazole, steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34%, respectively). The average gastric pH over 24 hours was 5.2 (when taking omeprazole alone) and 5.7 (when taking omeprazole simultaneously with clarithromycin).
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may result in increased phosphodiesterase inhibitory effects. When using these drugs concomitantly with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.
Theophylline, carbamazepine
With the simultaneous use of clarithromycin and theophylline or carbamazepine, it is possible to increase the concentration of these drugs in the systemic circulation.
Tolterodine
The primary metabolism of tolterodine occurs through the CYP2D6 isoenzyme. However, in part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through the CYP3A isoenzyme. In this population, inhibition of CYP3A results in significantly higher serum tolterodine concentrations. In populations that are poor metabolizers of CYP2D6, a dose reduction of tolterodine may be required when coadministering CYP3A inhibitors such as clarithromycin.
Benzodiazepines (eg, alprazolam, midazolam [intravenous solution], triazolam)
With the simultaneous use of midazolam and clarithromycin tablets (500 mg 2 times a day), there was an increase in midazolam AUC by 2.7 times after intravenous administration of midazolam. If midazolam intravenous solution is used concomitantly with clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment of midazolam. Administration of a drug through the oral mucosa, which bypasses presystemic drug elimination, is likely to result in an interaction similar to that observed with intravenous midazolam rather than oral administration.
The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on the CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.
With simultaneous use of clarithromycin and triazolam, effects on the central nervous system, such as drowsiness and confusion, are possible. Therefore, if concurrent use occurs, it is advisable to monitor for symptoms of CNS impairment.
Interactions with other drugs
Colchicine
Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein. It is known that clarithromycin and other macrolides are inhibitors of the CYP3A and Pgp isoenzymes. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A may result in increased effects of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, most often in elderly patients. Some of the reported cases occurred in patients with renal failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").
Digoxin
Digoxin is suspected to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are used concomitantly, inhibition of Pgp by clarithromycin may result in increased effects of digoxin. Concomitant use of digoxin and clarithromycin may also lead to increased serum concentrations of digoxin. Some patients have experienced clinical symptoms of digoxin toxicity, including potentially fatal arrhythmias. When clarithromycin and digoxin are taken concomitantly, serum digoxin concentrations should be carefully monitored.
Zidovudine
Concomitant use of clarithromycin tablets and zidovudine orally by adult HIV-infected patients may result in a decrease in the steady-state plasma concentration of zidovudine. Because clarithromycin interferes with the absorption of zidovudine when taken orally, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart. This interaction was not observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when administered concomitantly orally in adult patients, such an interaction is unlikely to occur when clarithromycin is administered intravenously.
Phenytoin and valproic acid
There is evidence of interaction between inhibitors of the CYP3A isoenzyme (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs, when used concomitantly with clarithromycin, it is recommended to determine their serum concentrations, as there are reports of their increase.
Bidirectional drug interactions
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with moderate renal failure (creatinine clearance 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with CC less than 30 ml/min, the dose of clarithromycin should be reduced by 75% using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg/day should not be used concomitantly with protease inhibitors.
Blockers of "slow" calcium channels
When using clarithromycin simultaneously with blockers of “slow” calcium channels that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), caution should be exercised as there is a risk of arterial hypotension. With simultaneous use, plasma concentrations of clarithromycin and slow calcium channel blockers may increase. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase plasma concentrations of itraconazole, while itraconazole may increase plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for symptoms of increased or prolonged pharmacological effects of these drugs.
Saquinavir
Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers increased the plasma AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with with saquinavir alone. The AUC and Cmax values of clarithromycin were approximately 40% higher than with clarithromycin alone. When these two drugs are used concomitantly for a limited time at the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies using saquinavir soft gelatin capsules may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not be consistent with the effects observed with saquinavir/ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.
Indications for use Fromilid
According to the instructions, the use of Fromilid or Fromilid analogues is indicated for the following diseases:
- inflammatory processes of the respiratory tract of infectious origin (tonsillopharyngitis, bacterial and atypical pneumonia, acute bronchitis, acute sinusitis, otitis media, chronic bronchitis);
- infections of the skin and soft tissues (furunculosis, erysipelas, wound infection, carbunculosis, etc.);
- mycobacterial diseases - M. Lepra, M. kansasi, M. Leprae, M. Marinum, M. avium complex.
- chlamydia;
- Helicobacter pylori infection (in a complex therapy regimen);
- preventive measures for patients with AIDS;
- other infectious and inflammatory processes provoked by microbes sensitive to this antibiotic.
Overdose
Symptoms of an overdose of clarithromycin when taken orally in large doses are gastrointestinal disorders. Mental status changes, paranoid behavior, hypoxemia, and hypokalemia were reported in a patient with a history of bipolar disorder following administration of 8000 mg clarithromycin.
It is recommended to take measures to evacuate the unabsorbed drug from the gastrointestinal tract (inducing vomiting, gastric lavage, taking activated charcoal, etc.) and carrying out symptomatic treatment. For drugs from the group of macrolides, including clarithromycin, hemo- and peritoneal dialysis has been proven to be ineffective in reducing their concentration in the blood serum.
Side effect
The use of Fromilid or Fromilid analogues can cause the following side symptoms (according to reviews of Fromilid): anxiety, psychosis, sleep disturbances, headaches, unreasonable fears, nausea, diarrhea, vomiting, myalgia, stomach pain, tinnitus (in rare cases, up to hearing loss), allergic reactions, development of pathogen immunity to antibiotics.
There are reviews of Fromilid confirming that long-term use of the antibiotic in some cases contributes to bleeding of unknown origin.
Instructions for use
According to the instructions, Fromilid in tablet form should be taken orally, swallowed whole, with plenty of liquid.
Adults and children over 12 years of age (with a body weight of more than 33 kg) are usually prescribed 0.25 g of antibiotic every 12 hours.
For the treatment of severe infections, acute sinusitis, and infections caused by Haemophilus influenzae, 0.5 g of clarithromycin is prescribed every 12 hours. Duration of therapy is one to two weeks.
For the eradication of Helicobacter pylori, the drug Fromilid according to the instructions is prescribed in a dose of 0.25 - 0.5 g twice a day, usually for a week, in combination with other drugs.
For children under 12 years of age (with body weight less than 33 kg), the antibiotic Fromilid is prescribed as a suspension at a daily dose of 15 mg/kg body weight. The dose is usually divided into two doses. The suspension should be washed down with a small amount of liquid (it is not recommended to chew the suspension granules because of their bitter taste). Duration of treatment is one to two weeks.
To prevent the spread and treatment of infection caused by Mycobacterium avium complex, 0.5 g of the drug is prescribed every 12 hours. The maximum dose per day is 2 g.
The recommended daily dose of the drug for children is 0.015 g. The dose should be divided into two doses. The maximum daily dose is 1 g. Duration of treatment is six months or more.
Release form and composition
Fromilid uno is produced in the form of long-acting, film-coated tablets: biconvex, oval, marked U on one side; at the fracture, a brown-yellow film shell and a white or almost white rough mass stand out (in blisters of 5 pcs., 1 blister in a cardboard pack; in blisters of 7 pcs., in a cardboard pack 1 or 2 blisters).
1 tablet contains:
- active ingredient: clarithromycin – 500 mg (equivalent to the content of the active substance – 980–1020 mcg/mg);
- auxiliary ingredients: sodium calcium alginate, sodium alginate, lactose monohydrate, polysorbate-80, povidone, colloidal silicon dioxide, magnesium stearate, talc;
- film shell: hypromellose, yellow iron oxide dye (E 172), titanium dioxide (E 171), propylene glycol, talc.
Drug interactions
Concomitant use of clarithromycin with steophylline, carbamazepine, digoxin, lovastatin, simvastatin, triazolam, midazolam, phenytoin, cyclosporine, disopyramide, rifabutin, tacrolimus, and traconazole increases the risk of side effects of the above drugs. The simultaneous use of Fromilid and astemizole, cisapride, pimozid and terfenadine in the treatment increases the risk of possible development of life-threatening arrhythmias.
Concomitant use of clarithromycin, lincomycin, and clindamycin increases the risk of cross-resistance.
