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Clarithromycin Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name]
Generic Name: Clarithromycin Tablets
Trade name: Bacitracin U®
English name:Clarithromycin Tablets
Hanyu Pinyin:Kelameisu Pian
[Ingredients]
The main ingredient of this product is clarithromycin.
Chemical name:6-O-Methylerythromycin
Chemical structure formula:
Molecular Formula:C38H69NO 13
Molecular weight:747.96
[Properties]
This product is a film-coated tablet, which appears white or off-white after removing the coating.
[Indications]
Clarithromycin is indicated for the treatment of infections caused by pathogenic bacteria to which it is sensitive, including:
1. Lower respiratory tract infection (bronchitis, pneumonia): caused by Haemophilus parainfluenzae, Cattamora, Streptococcus pneumoniae, Legionella pneumophila, Clostridium perfringens, Staphylococcus aureus, Mycoplasma pneumoniae or Chlamydia pneumoniae;
2. Upper respiratory tract infections (pharyngitis, sinusitis): caused by Streptococcus pyogenes, Haemophilus influenzae, Cattamora, Streptococcus pneumoniae, Streptococcus griseus, gonococcus, Staphylococcus aureus, and anaerobic bacteria;
3. Skin and soft tissue infections (folliculitis, cellulitis, dermatitis): caused by Staphylococcus aureus, Streptococcus pyogenes, Propionibacterium acnes, Streptococcus gramineus, etc.
4. Local or diffuse infections: local or diffuse infections caused by Mycobacterium avium or Mycobacterium intracellulare, and local infections caused by Mycobacterium turtles, Mycobacterium accidentalis, or Mycobacterium kansasii;
5. Mixed infections: clarithromycin is indicated forCD4 lymphocyte counts less than or equal to100/mm3of Prevention of mixed infections caused by Mycobacterium avium diffuse in HIVinfected patients;
6. Eradication of H. pylori: In the presence of gastric acid inhibitors, clarithromycin is also indicated for eradication of H. pylori, thereby reducing the recurrence of duodenal ulcers;
7. Odontogenic infections: Treatment of odontogenic infections caused by sensitive pathogenic bacteria.
See [Pharmacology and Toxicology] for the in vitro antibacterial spectrum of clarithromycin.
[Specifications] 0.25g[dosage]
The recommended adult dose of clarithromycin generic tablets is 12 per 12hourly by mouth0.25g(1tablet). In severe infections, the dose is increased to every12hours orally0.5g(2) “font-family:Arial”>tablets) for a regular course of 5 to 14days for community-acquired pneumonia and sinusitis The course of treatment is 6 to 14days.
Creatinine clearance less than 30mL/min in patients with renal impairment, halve the dose of clarithromycin regular tablets, i.e., every 24hours by mouth. span>0.25g(11tablet), or for severe infections every12tablets family:Arial”>hourly orally0.25g(1tablet), and no more than 14 consecutive treatments span>days.
The recommended adult dose for patients with Mycobacterium avium infection is clarithromycin regular tablets every12hourly by mouth0.5g(2tablets) for AIDSpatients with diffuse bird-intracellular Mycobacterium avium complex (MAC) infection should be continued until clinically significant, and clarithromycin generic tablets should be used in combination with other anti-mycobacterial agents.
Treatment of non-tuberculous mycobacterial infections should also be continuous.
Prevention of birds-Mycobacterium intracellulare complex (MAC) at the recommended adult dose of clarithromycin regular tablets per12hourly orally 0.5g(2tablets) .
The dose for treatment of odontogenic infections is clarithromycin regular tablets per 12 “font-family:Arial”>hourly by mouth0.25g(1tablet), take5 tablets span>day.
The recommended dose for eradication of H. pylori infection is:
Triple dose: clarithromycin generic tablets per12hour0.5g(2tablets), lansoprazole per12hourly0.03gand amoxicillin per 12hours1g. /span>treatment10days; clarithromycin Clarithromycin generic tablets every12hours0.5g(2tablets), amoxicillin every12hours1gand omeprazole every12hourly0.02gtreatment7 to 10days.
Dialytic: Clarithromycin generic tablets every8days. family:Arial”>hour0.5g(2tablets) and omeprazole per24hourly0.04gtreatment14days before adjusting omeprazole every24days. Roman”>24hours0.02gor0.04gtreatment14days; clarithromycin regular tablets per8day =”font-family:Arial”>hourly0.5g() “font-family:Times New Roman”>2tablets) in combination with lansoprazole every24hourly0.06gtreatment14days, with additional gastric acid inhibitors required for complete ulcer healing.
[Adverse Reactions]
Clarithromycin is well tolerated. The most frequent and common adverse reactions to clarithromycin in adults and children are abdominal pain, diarrhea, nausea, vomiting, and abnormal taste. These adverse reactions are usually mild and are consistent with the known safety information for macrolide antibiotics. Clinical trials have found no significant difference in the incidence of gastrointestinal adverse reactions in patients with pre-existing Mycobacterium infection compared with those without.
Adverse reactions reported in clinical trials and post-marketing on clarithromycin tablets are categorized by frequency of occurrence as follows:
Common (frequency of occurrence ≥1/100to<1/10): insomnia, taste disturbance, headache, diarrhea, vomiting, indigestion , nausea, abdominal pain, abnormal liver function tests, skin rash, excessive sweating;
Unusual (occurring ≥1/1,000to<1/100): candidiasis, vaginal infections, leukopenia, neutropenia granulocytopenia, eosinophilia, hypersensitivity reactions, anorexia, decreased appetite, anxiety, nervousness, dizziness, drowsiness, tremor, vertigo, hearing impairment, tinnitus, ECGQTprolonged interval, palpitations, gastritis, stomatitis, tongue inflammation, bloating, constipation, dry mouth, belching, flatulence, cholestasis, hepatitis, elevated alanine aminotransferase, elevated aspartate aminotransferase, gamma– span>elevated glutamyl transferase, pruritus, urticaria, malaise, weakness, chest pain, chills, fatigue, elevated blood alkaline phosphatase, elevated blood lactate dehydrogenase;
unknown (frequency of occurrence cannot be assessed based on available data)*: pseudomembranous colitis, dysbiosis, granulocytosis, thrombocytopenia, anaphylaxis, angioedema, psychosis, confusion, depression, disorientation, hallucinations, dream abnormalities, mania, convulsions, loss of taste, olfactory abnormalities, loss of smell, sensory abnormalities, loss of hearing, tip-twisting ventricular tachycardia, ventricular tachycardia, ventricular fibrillation, hemorrhage, acute pancreatitis, tongue discoloration, tooth discoloration, liver failure, hepatocellular jaundice, severe cutaneous adverse reactions (SCAR) (e.g., acute generalized eruptive pustulosis (AGEP)),),Stevens-Johnson syndrome, toxic epidermal necrolysis with eosinophilia and systemic symptoms of drug rash (DRESS), acne, rhabdomyolysis**, myopathy, renal failure, interstitial nephritis, international normalized ratio (International normalized ratio, INR) is elevated, prolonged prothrombin time, and abnormal urine color.
*Since these reactions are reported from a population of uncertain size, it is not always possible to reliably evaluate their occurrence frequency or establish a causal relationship with drug exposure. Patient exposure to clarithromycin is estimated to exceed1 billion patient treatment days. In addition, fatal liver failure has been reported in very few cases and is mostly associated with severe underlying disease and/ or concomitant administration of other drugs.
**In some case reports of rhabdomyolysis, clarithromycin was used in combination with statins, fibrates, colchicine, and allopurinol in combination with statins, betablockers, colchicine, and allopurinol.
Postmarketing reports of drug interactions and CNS effects (e.g., drowsiness and confusion) have been reported following the combination of clarithromycin with triazolam. Monitoring for enhanced central nervous system (CNS) pharmacologic effects is recommended. It has been monitored for 6months to12months. Roman”>12year-old children in clinical trials with pediatric clarithromycin suspensions. Therefore, 12year-old children should be given pediatric clarithromycin suspension. The incidence, type, and severity of adverse reactions are similar to those in adults.
Immunocompromised patients
AIDSpatients and other immunocompromised patients treated chronically with higher doses of clarithromycin Bifidobacterial infections, it is difficult to distinguish whether the adverse event may be related to clarithromycin administration or human immunodeficiency virus (HIV) disease signs or complications of the disease.
For adult patients, the total daily dose of clarithromycin is1g , the most common adverse reactions include nausea, vomiting, taste changes, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, and serum glutathione aminotransferase (SGOT) and serum glutathione aminotransferase (SGPT) is elevated. In addition, infrequent adverse reactions include shortness of breath, insomnia, and dry mouth.
In immunocompromised patients, some specific laboratory findings are evaluated based on the analysis of significant abnormal values (e.g., very high or very low values). Based on these criteria, approximately2%to3% of daily doses1gclarithromycin patients with serum glutamic oxalacetic transaminase (SGOT) and serum glutamic acid transaminase () and serum glutamic acid transaminase () transaminase (SGPT) levels were severely and abnormally elevated, and leukocyte and platelet counts were abnormally low. In addition, a small number of patients in both dose groups developed azotemia.
A lower percentage of patients will have elevated blood urea nitrogen levels.
[Contraindicated]
This product is contraindicated in patients with known hypersensitivity to macrolide antibiotics or their excipients.
Clarithromycin is contraindicated in combination with any of the following drugs: astemizole, cisapride, pimozide, terfenadine, which when combined with the above drugs may causeProlonged QTinterval and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and tip-twist ventricular tachycardia.
Clarithromycin is contraindicated in combination with ergotamine or dihydroergotamine as it may lead to ergometrine toxicity.
Clarithromycin is contraindicated in combination with oral midazolam.
Clarithromycin is contraindicated in the presence ofQT. family:Arial”>interval prolongation or a history of ventricular arrhythmias, including tip-twisting ventricular tachycardia.
Clarithromycin is contraindicated in association with the treatment of ventricular tachycardia primarily throughCYP3A4metabolized byHMG-CoAreductase inhibitors (statins). Lovastatin or simvastatin in combination, otherwise there may be a risk of rhabdomyolysis. These drugs should be discontinued while receiving clarithromycin therapy.
Clarithromycin is contraindicated in patients with hypokalemia (with prolongedQTinterval risk).
Clarithromycin is contraindicated in patients with severe hepatic insufficiency with renal insufficiency.
Clarithromycin (and otherCYP3A4potent inhibitors) are prohibited in combination with colchicine.
Clarithromycin is contraindicated in combination with ticagrelor or ranolazine.
[Precautions]
The use of any antibiotic therapy such as clarithromycin to treat infections caused by H. pylori can lead to the emergence of drug-resistant bacteria.
In the absence of prudent risk/benefit assessment, pregnant women should not take clarithromycin, especially during the first trimester of pregnancy.
Similar to other antibiotics, long-term use of clarithromycin can lead to dual infections with drug-resistant bacteria and fungi, which need to be discontinued and treated appropriately.
Clarithromycin is mainly metabolized by the liver. Therefore, this product should be used with caution in patients with hepatic impairment. Clarithromycin should be used with caution in patients with moderate to severe renal impairment and in the elderly over 65 years of age.
This product is recommended with caution in patients with severe renal insufficiency.
Cases of abnormal liver function, including elevated liver enzymes, hepatocellular damage, and /or hepatic cholestasis, with or without jaundice. Such abnormal liver function may be severe but is usually reversible. Fatal liver failure has been reported, and this is usually associated with severe underlying disease or combined medications. Some patients may already have liver disease or be taking other drugs that are hepatotoxic. If signs and symptoms of liver disease develop, such as anorexia, jaundice, dark urine, itching, or abdominal pressure, patients are advised to discontinue therapy and seek medical attention.
Pseudomembranous colitis has been reported with almost all antimicrobial agents (including macrolides), ranging from mild to life-threatening. Clostridium difficile-associated diarrhea has been reported for most antimicrobials, including clarithromycin, and ranges in severity from moderate diarrhea to fatal colitis. Antimicrobial drug therapy can alter the normal colonic flora, which may lead to C. difficile overgrowth. The possibility of C. difficile-associated diarrhea must be considered in all patients who develop diarrhea following the use of antibiotic medications. Since the occurrence of C. difficile-associated diarrhea has been reported after more than two months of antimicrobial therapy, the patient’s medical history must be carefully reviewed. Therefore discontinuation of clarithromycin should be considered regardless of the indication for treatment. Microbiologically test the patient and administer appropriate therapy. Avoid the use of peristaltic inhibitors.
Colchicine: Post-marketing reports also suggest colchicine toxicity in combination with clarithromycin, especially in the elderly, and some of these occurred in patients with renal insufficiency. Some of these patients died. Clarithromycin is contraindicated in combination with colchicine.
Caution is advised when combining clarithromycin and triazolobenzodiazepines, triazolam, and midazolam administered intravenously or via the oral mucosa.
Cardiovascular events: cardiac repolarization and QT have been observed in macrolide therapy including clarithromycin. /span>interval prolongation, thereby triggering the risk of arrhythmias and tip-twisting ventricular tachycardia. Clarithromycin should be used with caution in the following patients because of the increased risk of ventricular arrhythmias, including tip-twisting ventricular tachycardia:
Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances, or clinically significant bradycardia should be cautiously treated with clarithromycin in the following patients:Patients with Patients with clinically significant bradycardia
Patients with electrolyte disturbances (e.g., hypomagnesemia). Clarithromycin is contraindicated in patients with hypokalemia
Combined with other agents that may prolongPatients with QTinterval drugs
Clarithromycin is prohibited in combination with astemizole, cisapride, pimozide, and terfenadine “font-family:Times New Roman”>
with congenital or acquiredQTinterval prolongation or history of ventricular arrhythmias is contraindicated in patients
Epidemiologic studies investigating the risk of adverse cardiovascular events with macrolides have shown mixed results. The results of some observational studies suggest a rare short-term risk of arrhythmias, myocardial infarction, and cardiovascular death associated with macrolides. Considering these findings, the risks should be weighed against the therapeutic benefits when prescribing clarithromycin.
Pneumonia: Susceptibility testing is important when prescribing clarithromycin for community-acquired pneumonia because some Streptococcus pneumoniae become resistant to macrolides. If empiric therapy is clinically ineffective, antibiotic susceptibility testing should be considered and adjusted to a sensitive antibiotic for treatment. In the case of hospital-acquired pneumonia, clarithromycin needs to be used in combination with other appropriate antibiotics.
Mild to moderate skin and soft tissue infections: These infections are usually caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolide antibiotics. Therefore it is important to implement susceptibility testing. If empiric treatment is clinically ineffective, antibiotic susceptibility testing should be considered and treatment should be adjusted to a sensitive antibiotic. In cases where beta-lactam antibiotics cannot be used (e.g., allergy), other antibiotics such as clindamycin should be chosen. Currently, macrolides are considered effective for some skin and soft tissue infections, such as infections due to Corynebacterium minimale unusual acne, dermatophytosis, and infections that cannot be treated with penicillin.
If severe acute hypersensitivity reactions occur (e.g., allergic reactions, severe cutaneous adverse reactions (SCAR) (e.g., acute generalized eruptive pustulosis (AGEP)), Stevens-Johnson Syndrome and toxic epidermal necrolysis,DRESS syndrome (drug rash with eosinophilia and systemic symptoms)), then clarithromycin must be discontinued immediately and appropriate treatment implemented urgently.
If the patient is currently taking cytochrome-inducibleCYP3A4CYP3A4 “font-family:Arial”>enzyme, then caution should be exercised when co-administering clarithromycin.
Caution should also be taken for cross-resistance between clarithromycin and other macrolides and between lincomycin and clindamycin.
HMG-CoAreductase inhibitors: Combination of clarithromycin with lovastatin or simvastatin is prohibited. Caution is required when clarithromycin is combined with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients must be monitored for signs and symptoms of myopathy. If combination of clarithromycin and statins cannot be avoided, the lowest dose of a statin is recommended. Dose adjustment of statins or use of statins that are not dependent on CYP3Aenzyme metabolism (e.g., fluvastatin) should be considered.
Oral hypoglycemic agents/Insulin: Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylureas) and/ or insulin may result in Significant hypoglycemia. Careful monitoring of the patient’s blood glucose is recommended.
Oral anticoagulants: concomitant use of clarithromycin with warfarin may result in severe bleeding and an International Normalized Ratio ( INR) and prothrombin time are significantly elevated. Therefore, the international normalized ratio ( INR) and prothrombin time should be monitored closely in patients on concomitant clarithromycin and oral anticoagulants.
[For Pregnant and Lactating Women]
The safety of clarithromycin in pregnant and lactating women has not been confirmed. Clarithromycin can be excreted in breast milk and its harmful effects on embryonic development cannot be ruled out in animal studies in mice, rats, rabbits, and monkeys. Therefore, in the absence of a risk/benefit assessment, it is contraindicated in pregnant and lactating women.
[Pediatric Use]
Dry suspension of clarithromycin is recommended.
[Geriatric use]
See [Pharmacokinetics] Geriatric Subjects content.
[Drug Interactions]
The following drugs are prohibited due to potentially serious effects caused by their pharmacological interactions.
Cisapride, pimozide, astemizole, and terfenadine
Elevated levels of cisapride have been reported in patients co-administering cisapride and clarithromycin. Concomitant administration resulted inprolonged QTintervals and arrhythmias including ventricular tachycardia, ventricular fibrillation, and tip-twisting ventricular tachycardia in patients on combined clarithromycin and pimozide. A similar effect was observed in patients on a combination of clarithromycin and pimozide.
It has been reported in the literature that macrolide antibiotics can affect the metabolism of terfenadine, thereby elevating its blood levels and occasionally causing arrhythmias, such as the development of prolonged QTintervals, ventricular tachycardia, ventricular fibrillation, and tip-twist ventricular tachycardia. In a study of 14 healthy volunteers, concomitant use of clarithromycin and terfenadine resulted in blood concentrations of the acidic metabolite of terfenadine. span>2to 3fold increase, QT The interval was prolonged without a detectable clinical response. Similar interactions have been observed with the combination of astemizole and other macrolides.
Ergot alkaloids
Postmarketing reports of the combination of clarithromycin and ergotamine or dihydroergotamine have been associated with acute ergometrine toxicity as evidenced by vasospasm and ischemia in the extremities and other tissues, including the central nervous system. Combination of clarithromycin with these drugs is contraindicated.
Oral midazolam
midazolam with clarithromycin tablets (0.5g, every 12hours) When combined, the area under the drug-time curve after oral administration of midazolam (AUC) increased by7fold. Therefore, oral midazolam is prohibited in combination with clarithromycin.
HMG-CoAReductase inhibitors (statins)
When clarithromycin and lovastatin or simvastatin are used concomitantly, because these statins are transCYP3A4extensively metabolized, can lead to elevated plasma concentrations, which will increase the risk of myopathy, including rhabdomyolysis.
Cases of rhabdomyolysis have been reported in patients on clarithromycin in combination with these statins. If treatment with clarithromycin is unavoidable, lovastatin or simvastatin should be withheld for the duration of treatment.
Caution should be exercised when combining clarithromycin with a statin. When combination of clarithromycin and a statin is unavoidable, the lowest dose of a statin on record is recommended. Statins that are not dependent on CYP3Ametabolism (e.g., fluvastatin) should be considered. Patients should be monitored for signs and symptoms of myopathy.
inducedCYP3A of drugs (rifampicin, phenytoin, carbamazepine, phenobarbital, and gentamicin) can induce metabolism of clarithromycin. This leads to a reduction in the therapeutic level and efficacy of clarithromycin.
In addition, monitoring of CYP3Ainducing agent is necessary, it may be elevated by the inhibition of CYP3Aby clarithromycin (seeCYP3AInhibitors instructions).
The combination of rifampin and clarithromycin resulted in increased serum levels of rifampin and decreased serum levels of clarithromycin, which were associated with an increased risk of uveitis.
The following drugs have been shown or are suspected to affect clarithromycin blood levels, necessitating dose adjustment of clarithromycin or consideration of the possibility of replacement therapy.
Efavirenz, nevirapine, rifampin, rifabutin, and rifapentine
CytochromeP450 Strong inducers of the metabolic system, such as efavirenz, nevirapine, rifampin, rifabutin, and rifapentine accelerate the metabolism of clarithromycin, thereby decreasing the plasma levels of clarithromycin while elevating14- “font-family:Arial”>plasma levels of hydroxyclarithromycin, a metabolite that also has microbial activity. Because the microbial activity of clarithromycin and 14-hydroxyclarithromycin is different for different bacteria, during the concomitant administration of clarithromycin and enzyme inducers The therapeutic effect can be weaker than expected during concurrent administration of clarithromycin and enzyme inducers.
Etravirine
Etravirine leads to reduced exposure of clarithromycin to the active metabolite14-hydroxykratomycin in elevated concentrations. Since 14-hydroxyclarithromycin decreases anti-bird-intracellular mycobacterial complex (MAC) activity, the overall activity against this pathogen is altered, thus necessitating the need to treat birds-Intracellular Mycobacterium avium complex (MAC) was evaluated for the selection of clarithromycin in the treatment of Mycobacterium avium complex (MAC).
Fluconazole
21 cases of healthy volunteers taking fluconazole concomitantly (0.2g per24hourly) and clarithromycin (0.5geveryhour). span>12hour), resulting in a mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve ( AUC) were elevated by 33%and18%. Co-administration of fluconazole did not significantly affect the steady-state concentration of the active metabolite 14-hydroxyclarithromycin. No clarithromycin dose adjustment is required.
Ritonavir
Pharmacokinetic studies have shown that concomitant use of ritonavir (0.2 gevery8hours) and clarithromycin (0.5g every12hourly) will significantly inhibit the metabolism of clarithromycin. When both of these drugs were administered together, the maximum concentration of clarithromycin (Cmax) was elevated31%and the lowest concentration (Cmin) was elevated by 182%and the area under the blood concentration curve (AUC) increased by . span>77%and observeda14-hydroxykratomycin formation was completely inhibited.
Because of the large therapeutic window of clarithromycin, no dose reduction is required if the patient has normal renal function. However, in patients with renal failure who are also treated with ritonavir, the following dose adjustment regimen should be considered: If the patient’s creatinine clearance is 30 mL/minto60mL/min, the dose of clarithromycin should be reduced50%; if the patient’s creatinine clearance is below30mL/min, the drug dose should be reduced by75%. =”font-family:Arial”>. When administered concomitantly with ritonavir, care should be taken to avoid daily doses of clarithromycin exceeding1g.
Ritonavir as otherHIVpharmacological enhancers of protease inhibitors (e.g., atazanavir and saquinavir) should be considered for similar dose adjustments when used in patients with decreased renal function (see Bidirectional Drug Interactions).
Antiarrhythmics
Marketing reports have included cases of tip-twisting ventricular tachycardia after co-administration of clarithromycin and quinidine or propyzamide. Electrocardiographic (ECG) monitoring should be performed in combination with clarithromycin to detect potentialQTinterval prolongation, and serum concentrations of these drugs should be monitored during treatment.
There have been cases of hypoglycemia following the combination of clarithromycin and propyzamide in post-marketing reports. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and propyzamide.
Oral hypoglycemic agents/ Insulin
In combination with clarithromycin and some hypoglycemic agents, such as nateglinide and repaglinide, clarithromycin can have an effect onCYP3Ainhibition and cause hypoglycemia. Careful monitoring of blood glucose levels is recommended.
Based onCYP3A Interactions
Clarithromycin is known to inhibitCYP3A, and its combination with a drug that is primarily metabolized via CYP3Aincreases the concentration of that drug and can increase or prolong the efficacy and adverse effects.
Taking other knownCYP3Aenzyme substrates should be used with caution, especially if the drug has a narrow safety range (e.g., carbamazepine) and/or the drug is extensively metabolized by this enzyme.
Dose adjustment may be considered and, where possible, patients co-administered with clarithromycin should be closely monitored for major transCYP3Ametabolized drug serum concentrations.
The following drugs or classes of drugs are known or suspected to be mediated by the sameCYP3Aisoenzyme metabolism: alprazolam, oral anticoagulants (e.g., warfarin), astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, propyzamide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and perphenazine. This list is not comprehensive. Other drugs that cause interactions by similar mechanisms by isozymes within the cytochromeP450system include phenytoin, theophylline, and valproic acid.
Omeprazole
Giving healthy adult subjects concurrent doses of clarithromycin (0.5gevery8hours) and omeprazole (hour) ( “font-family:Times New Roman”>0.04gevery24hourly). Due to concomitant administration with clarithromycin, steady-state plasma concentrations of omeprazole were elevated (Cmax,AUC0-24andandt1/2are higherby 30% respectively span>, 89%and and span>34%).
When omeprazole was administered alone or when omeprazole was administered concomitantly with clarithromycin, the mean24hour intragastric fluidpHvalues were. span>5.2and5.7.
Sildenafil, tadalafil and vardenafil
These phosphodiesterase inhibitors are all inhibited through, or at least partially throughCYP3Ametabolism, which is inhibited in combination with clarithromycinCYP3A. The combination of clarithromycin with sildenafil, tadalafil, or vardenafil results in increased exposure to phosphodiesterase inhibitors. Therefore, dose reductions of sildenafil, tadanafil, and vardenafil should be considered when these drugs are used concomitantly with clarithromycin.
Theophylline, carbamazepine
Clinical studies have shown that when either of carbamazepine and theophylline is administered concomitantly with clarithromycin, a small but statistically significant (p≤0.05) increase. Dose reduction is necessary.
Tolterodine
Tolterodine is mainly produced through the cytochromeP450of2D6isoforms (CYP2D6) metabolism. However, in a population subgroup lacking CYP2D6, the main metabolic pathway is through CYP3A. In this population subgroup, CYP3Ainhibition leads to significantly higher serum concentrations of tolterodine. Dose reductions of tolterodine may be required in the presence of CYP3Ainhibitors, as well as in the presence of CYP2D6dose reduction of clarithromycin in a population of patients who show weak metabolism.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When midazolam is combined with clarithromycin tablets (0.5g every 12hours) when administered concurrently, after intravenous midazolam injection midazolam’sAUCwas elevated2.7 fold. If intravenous midazolam is administered concomitantly with clarithromycin, the patient should be monitored closely so that the dose can be adjusted. If midazolam is administered via the oral mucosa, it may bypass circulating pre-drug elimination, a situation similar to that of midazolam administered intravenously compared to oral administration. The same precautions apply to other transCYP3Ametabolized benzodiazepines, including triazolam and alprazolam. For benzodiazepines that are not metabolized by CYP3A (temazepam, nitrazepam, lorazepam), there is no significant clinical interactions with clarithromycin.
Postmarketing reports of drug interactions and CNS effects (e.g., drowsiness and confusion) have been reported following the combination of clarithromycin and triazolam. Monitoring for enhanced central nervous system (CNS) pharmacologic effects is recommended.
Other drug interactions
Colchicine
Colchicine isCYP3Aand transporterP-glycoprotein (Pgp) substrates. Clarithromycin and other macrolides can inhibit CYP3AandPgp. When co-administering clarithromycin and colchicine, because clarithromycin inhibitsCYP3Aand/orPgp, thereby increasing colchicine exposure. Concurrent use of clarithromycin and colchicine is prohibited.
Digoxin
Digoxin is a substrate of transporterPgpof the substrate, clarithromycin inhibitsPgp. When digoxin and clarithromycin are used together, inhibition of Pgp by clarithromycin leads to increased exposure to digoxin. Elevated serum concentrations of digoxin have also been reported in patients on concomitant clarithromycin and digoxin during postmarketing surveillance. Some patients exhibited clinical signs consistent with digoxin toxicity, including potentially fatal cardiac arrhythmias. Patients should be closely monitored for digoxin serum concentrations when combining digoxin and clarithromycin.
Zidovudine
ForHIV-infected In adult patients, co-administration of clarithromycin and zidovudine decreases the steady-state concentration of zidovudine. Clarithromycin may interfere with the absorption of zidovudine when both drugs are taken orally at the same time; therefore, it is recommended that the two drugs be taken at different times, with dosing intervals of at least 4hours. No such interaction occurs with concomitant administration of clarithromycin dry mix and zidovudine or desoximetasone in pediatric patients withHIVinfection.
Phenytoin and valproic acid
There have been spontaneous or published reports showingCYP3Ainhibitors (including clarithromycin) interact with drugs that are not metabolized byCYP3A, such as phenytoin and valproic acid. valproic acid) interact with each other. Elevated serum levels have been reported. It is recommended that serum levels be measured when these drugs are used in combination with clarithromycin.
Bidirectional drug interactions
Azanavir
Clarithromycin and atazanavir are both CYP3Asubstrates and inhibitors, and there are bidirectional drug interactions. The combination of clarithromycin (0.5 g per12hourly) and atazanavir (0.4gevery24hours) resulted in increased clarithromycin exposure2fold. 14-Reduction in hydroxyclavulanic acid exposure70% and atazanavirAUCincreasedby 28%. Because of the wide therapeutic window of clarithromycin, no dose reduction is required for patients with normal renal function. In patients with moderate renal impairment (creatinine clearance30-60mL/min), the dose of clarithromycin should be reduced50%. For patients with creatinine clearance less than 30mL/min, the appropriate clarithromycin formulation should be selected and the dose reduced75%. Clarithromycin should not be co-administered with protease inhibitors at daily doses exceeding1g.
Calcium channel blockers
Due to the risk of hypotension, it is recommended to coadminister clarithromycin with transCYP3A4metabolized calcium channel blockers (e.g., verapamil, amlodipine, diltiazem) should be used with caution. Drug interactions can lead to increased blood levels of clarithromycin and calcium channel blockers. Symptoms of hypotension, bradycardia, and lactic acidosis have been observed in patients on combined clarithromycin and verapamil.
Itraconazole
Clarithromycin and Itraconazole are bothCYP3Asubstrates and inhibitors that lead to bidirectional drug interactions. Clarithromycin can elevate plasma levels of itraconazole, which in turn can elevate plasma levels of clarithromycin. Patients on combined clarithromycin and itraconazole should be closely monitored for indications or symptoms of enhanced or prolonged pharmacologic effects.
Saquinavir
Clarithromycin and saquinavir are bothCYP3Asubstrates and inhibitors, and there are bidirectional drug interactions. 12 healthy volunteers were co-administered with clarithromycin (0.5g per12hourly) and saquinavir (softgels,1.2g every8hour), resulting in a steady-stateAUC of saquinavir New Roman”>AUCandCmaxhour =”font-family:Arial”>are higher than when used alone177%and187%, clarithromycin’sAUCandCmaxwas elevated by approximately40% than when used alone. Dose adjustment was not required for the combined administration of the two drugs for a limited period of time at the doses and dosage forms studied here. The results of drug interaction studies using saquinavir softgels may not be representative of those using saquinavir hardgels. The results of drug interaction studies with saquinavir alone may not be representative of the effects of saquinavir/ ritonavir treatment. The potential effects of ritonavir on clarithromycin need to be considered when saquinavir and ritonavir are combined.
[Drug overdose]
If too high a dose of clarithromycin is ingested, adverse gastrointestinal reactions may occur. A patient with bipolar disorder who ingested 8 gclarithromycin developed altered mental status, paranoia, hypokalemia, and hypoxemia.
Once an overdose of clarithromycin is detected, the unabsorbed drug should be removed immediately and appropriate supportive therapy should be initiated. Similar to other macrolides, the serum concentration of clarithromycin is not affected by hemodialysis or peritoneal dialysis.
[Pharmacology and Toxicology]
Pharmacological effects
Clarithromycin belongs to a semi-synthetic class of macrolide antibiotics. Clarithromycin binds to the bacterial ribosomal50Ssubunit, thereby inhibiting its protein synthesis and producing antibacterial effects. In vitro, it has antibacterial activity against both standard and clinical isolates, and against a wide range of aerobic and anaerobic Gram-positive and Gram-negative bacteria. Usually, the minimum inhibitory concentration (MIC) of clarithromycin is the logarithmic dilution of the minimum inhibitory concentration of erythromycin.
In vitro data show that clarithromycin inhibits Legionella pneumophila and Mycoplasma pneumoniae and kills Helicobacter pylori, with stronger activity under neutral than acidic conditions. In vitro and in vivo data indicate that it has a clinically significant effect on Mycobacterium bovis. In vivo data show that Enterobacter spp., Pseudomonas spp. and other non-lactose-metabolizing Gram-negative bacteria are insensitive to clarithromycin.
Clarithromycin is effective against most strains of in vitro and clinical infections (see Indications and Usage for details).
Aerobic Gram-positive bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Listeria monocytogenes.
Aerobic gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Catamorax, gonococcus, and Legionella pneumophila.
Other: Mycoplasma pneumoniae, Chlamydia pneumoniae.
Bacteroides: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium turtles, Mycobacterium incidentalis, Mycobacterium avium and Mycobacterium intracellulare.
β-lactamase production does not affect clarithromycin activity.
Note: Most neopenicillin-resistantI family:Arial”>andII strains are resistant to clarithromycin.
Helicobacteria: Helicobacter pylori. 104 patients after isolation and culture of Helicobacter pylori prior to treatment and clarithromycinMICassay was performed. Of these, 4 had drug-resistant strains,2with moderately susceptible strains,98susceptible strains.
The following in vitro data are available, but their clinical significance is unknown. Clarithromycin has in vitro activity against most of the following microorganisms, but its safety and efficacy for clinical infection treatment remain to be determined due to the lack of adequate clinical trials.
Aerobic Gram-positive bacteria: lactic-free Streptococcus, Streptococcus pneumoniae (CC “font-family:Arial”>,F,Gclade), Streptococcus gramineus.
Aerobic Gram-negative bacteria: Bordetella pertussis, Pasteurella multocida.
Anaerobic gram-positive bacteria: Clostridium perfringens, Peptostreptococcus niger, Propionibacterium acnes.
Anaerobic gram-negative bacteria: melanogenic Pseudomonas aeruginosa.
Spirochetes: Burkholderia spirochetes, Paleococcus dense spirochetes.
Campylobacter: Campylobacter jejuni.
Clarithromycin is primarily metabolized in humans and other primates to the biologically active14- hydroxy-clarithromycin, a metabolite that is as active as clarithromycin against most The activity of the metabolites on most microorganisms is the same as or only 1/2oror1/4, but twice as active against Haemophilus parainfluenzae as clarithromycin. In vitro or in vivo, against different strains of Haemophilus influenzae, clarithromycin and 14-hydroxyl =”font-family:Times New Roman”>-Clarithromycin has a superimposed or synergistic effect.
Clarithromycin was found to be more active than erythromycin in several animal infection models2to10fold. For example, clarithromycin was more active than erythromycin in systemic infections in mice, subcutaneous abscesses in mice, and respiratory infections in mice caused by Streptococcus, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae, and more significantly in Legionella infection in guinea pigs, i.e., clarithromycin administered intraperitoneally at a dose of1.6 mg/kg/d, which is higher than that of erythromycin50 mg/kg/d is more effective.
Toxicological studies
Genotoxicity:
AmesTests have shown that drug concentrations of 1.5 mg per disc25μgor lower, no mutagenic effects were seen; concentrations of50μgwas toxic to all test strains.
Fertility and reproductive function effects test results showed that150-160mg/kg/d span style=”font-family:Arial”>dose showed no effect on libido, fertility, number of births and offspring and development in male and female rats. Wistar rats (administered orally) andSDrats (oral and intravenous administration) and New Zealand rabbits and macaques did not show teratogenic effects of clarithromycin in teratogenic tests. Only rare and non-statistically significant cardiovascular abnormalities were observed in an additional test in SDrats (6%), largely due to the natural expression of genetic alterations within the population. Two mouse studies also showed that 70 times the daily human clinical dose () family:Times New Roman”>500 mg, twice daily), a cleft palate (3% to 30% ), but 35 times the human This was not seen at the maximum daily clinical dose. This result suggests a gestational toxicity rather than a teratogenic effect.
Pregnancy20day after giving monkeys10times the daily human clinical higher dose (500 mg, taken twice daily) of clarithromycin can cause miscarriage. This is mainly due to the gestational toxicity of the drug at very high doses. In a complementary trial, monkeys given2.5to5 times the maximum daily dose of clarithromycin without endangering the embryo.
RatsIparagraph I500 mg/kg/ddose in a reproductive toxicity test (approximately35times the maximum daily clinical dose in humans) administered80day, no sexual impairment was seen in male rats due to long-term administration of high doses of clarithromycin.
[Pharmacokinetics]
Absorption
Extensive studies on the pharmacokinetics of clarithromycin after oral administration to animals and adults have shown that clarithromycin is rapidly absorbed orally with an absolute bioavailability of50%. There is no accumulation at multiple doses and the mode of metabolism is unchanged. Eating increases bioavailability by approximately25%, but this increase is not clinically significant for within the recommended dose range. Food had no effect on the pharmacokinetics of clarithromycin.
Distribution, biotransformation, and clearance
In vitro
In vitro studies have shown that concentrations of0.45to4.5µg/mL, the average binding rate of human plasma protein for clarithromycin was70%; at a concentration of45µg/mL, the binding rate decreased to 41%, suggesting saturation of the binding site, but this concentration is much higher than the therapeutic concentration of the drug.
In vivo
The results of animal experiments showed that the concentration of clarithromycin was several times higher in tissues than in the circulatory system, except in the central system. Usually, the highest concentration of the drug was found in the liver and lung, with a tissue to plasma concentration ratio of 10to20.
Healthy Subjects
Clarithromycin0.25gevery12hours, “font-family:Times New Roman”>2to3day to reach steady-state peak blood levels, clarithromycin and14- Hydroxyl-Steady-state peak concentration of clarithromycinCmaxare1and0.6µg/mL, with half-lives of, respectively. span>3~ 4and5～6hours.
0.5g per12hourly, clarithromycin and its14-hydroxyl metabolites reach steady-state peak blood levels at dose 5. . The steady-state peak blood levels were achieved at doses 5 and 5 and 57. Roman”>7doses later, the steady-state peak concentration of clarithromycinCmaxwere2.7and2.9µg/mL,14-hydroxy-clathrin The steady-state peak concentrations of clarithromycinCmaxwere0.88and0.83µg/mL. The half-lives were 4.5~4.8hours and6.9hours family:Arial”>to8.7hours.
At steady state,14-hydroxy-clarithromycin concentration does not increase proportionally with the dose of clarithromycin. The apparent half-life of clarithromycin and its14-hydroxy metabolite is prolonged at high doses. At high doses, the nonlinear pharmacokinetic behavior of clarithromycin and its 14-hydroxyl and hydroxyl and “font-family:Times New Roman”>N-demethylation products decreased predicting that the nonlinear metabolism of clarithromycin becomes more significant at high concentrations.
A single oral dose of clarithromycin in adults0.25gor1.2gwhen renal excretion was, respectively “font-family:Times New Roman”>37.9%and46.0% and fecal excretion was40.2%and respectively /span>29.1% (including one14.1% of subjects).
Patients
clarithromycin and its14-hydroxy metabolites are extremely well distributed in tissues and body fluids. Data from a few cases suggest that after oral administration of clarithromycin, the drug concentration in the cerebrospinal fluid does not reach the effective blood concentration, i.e., the drug concentration in the cerebrospinal fluid is only 1% of that in serum due to the blood-brain barrier~2%. Usually, the drug concentration in tissues is several times higher than in serum. Every 12hours, an oral dose of0.25gclarithromycin, tissue and serum concentrations in the tonsils were 1.6and0.8µg/mL, and tissue and serum concentrations were 8.8 and 1.7µg/mL.
Hepatic insufficiency.
In a study comparing the healthy subject group with the hepatic insufficiency group,0.25gclarithromycin every12hours for two days. The results, taken once on the third day, showed no significant differences in steady-state blood concentrations and systemic clearance of clarithromycin between the two groups. However, the hepatic insufficiency group14-hydroxy-Stable-state concentrations of clarithromycin were significantly lower. 14-hydroxy-The decrease in metabolic elimination of clarithromycin was partially offset by an increase in renal clearance of the prodrug. This suggests that no change in dosing is necessary in those with hepatic insufficiency but normal renal function.
Renal insufficiency
Study comparing multiple doses of 0.5g in people with normal and incomplete kidney functionclarithromycin pharmacokinetic profiles and found that clarithromycin and its14-hydroxyl metabolites, their blood concentrations, half-lives,Cmax, CminandAUC were higher than those in the renal insufficiency group, and the clearance rate constantKelimand renal excretion were lower, a change that correlated with the degree of renal insufficiency, with the weaker the renal function, the more pronounced the difference (see Dosage and Administration).
Elderly subjects
Study comparing healthy elderly male and female subjects with healthy young adult male subjects taking multiple doses of0.5g The safety and pharmacokinetic profile of clarithromycin showed that the older subjects were more likely than the young adult subjects to take clarithromycin and its14-hydroxyl metabolites had higher blood concentrations and slower clearance rates. However, when renal clearance was correlated with creatinine clearance, there was no difference between the two groups. This shows that the in vivo behavior of clarithromycin is related to renal function and not to age.
People with Mycobacterium avium infection
0.5gclarithromycin per12hourly in adultsHIV patients had similar steady-state blood levels as healthy subjects. However, Mycobacterium avium infection requires high-dose therapy, and clarithromycin concentrations are much higher than when the usual dose is used. AdultHIVinfected subjects taking daily1~2g(every12hours), clarithromycin steady-state concentrationCmaxwere22to4µg/mLand5to10µg/mL. The elimination half-life is prolonged at high doses. The high blood levels and prolonged elimination half-life are consistent with the known nonlinear pharmacokinetic properties of clarithromycin. .
Co-administration with omeprazole
studied0.5gclarithromycin every8hours, and0.04gOmeprazole every24hourly pharmacokinetics. The mean steady-state0.5 gclarithromycin, given as a single doseCmaxandCminare3.8and 1.8µg/mL, AUC0-8was22.9µg/hr/mL, Tmaxand half-lives of 2.1and5.3hours.
Meanwhile, a study of 0.5gclarithromycin every8hours, with0.04gOmeprazole every24 hourly pharmacokinetics of once-in-a-while co-administration. The prolonged half-life andAUC0-24become greater with omeprazole compared to omeprazole aloneAUC0-24andandT1/2increased by89% respectively span>and34%; compared with the clarithromycin and placebo combination groups, the steady-stateCmax, CminandAUC0-8increase by10% respectively, 27%and15%. At steady state, the gastric mucus concentration of clarithromycin was higher in the clarithromycin co-administered with omeprazole group than in the clarithromycin group6hours after administration >25fold higher gastric tissue concentration of clarithromycin than the clarithromycin and placebo combination group2fold.
[Storage】
Store in a dry place.
[Packaging】
Aluminum-plastic blister packaging (polyvinyl chloride/polyvinylidene chloride solid pharmaceutical laminated rigid tablets and pharmaceutical aluminum foil);6tablets/Plate×1board/box,6tablets/plate×2plate/box,6tablet/plate×3board/box,6tablets/Plate×4board/box;12tablets/plate×1plate/box,12 tablet/plate×2board/boxes,12tablets/plate×3board/box.
[Expiration Date] 24months
[Execution Standard ]
[Approval Number]
State Drug CertificateH19990225
[Pharmaceutical Marketing Licensee]
Company Name: Shandong Xinhua Pharmaceutical Co. Ltd
Registered Address: Zibo High-tech Industrial Development Zone, Chemical Industry Zone
Postal code:255000
Phone Number:0533-2166666
Fax Number:0533-2184991
[Producer]
Company Name: Shandong Xinhua Pharmaceutical Co. Ltd
Production Address: Zhangdian District, Zibo City, Shandong Province East Road14No.
Postal Code:255005
Phone Number:0533-2196361
Fax Number:0533-2196365