Food has no significant effects on pharmacokinetics of IR clarithromycin and thus the product may be given irrespective of food intake. With regard to Nuobang®, administration under fasting conditions is associated with approximately 30% lower area under the plasma concentration-time curve (AUC) for clarithromycin relative to administration with food. Therefore, it should be taken with food to maximize bioavailability. Physicians and pharmacists should pay attention to this biopharmaceutical requirement and strengthen patient education.
Compared to the triple therapy, the dual therapy has a lower eradication rate of H pylori. Moreover, regimens which contain clarithromycin as the single antibiotic are more likely to be associated with the development of clarithromycin resistance among patients who fail therapy. When the IR clarithromycin tablet is combined with PPI as dual therapy, the dose needs to be tailored to 500 mg three times daily.
The SR clarithromycin has obvious advantages over the IR product when they are prescribed for the same indications[3,4]. However, the novelty of the SR product and its administration of only once a day would decrease the benefit for patients and their compliance if given twice daily as detected in most prescriptions.
Concordance between indications and diagnoses
Chronic gastritis is an inflammation of the lining of the stomach that occurs gradually and persists for a prolonged time. It can be classified based on the underlying etiologic agent (e.g. H pylori, bile reflux, nonsteroidal anti-inflammatory drugs, autoimmunity, allergic response) and the histopathological pattern. Diagnosis of chronic gastritis is broad and disconcordant with indications described in the package insert of clarithromycin. It should be further specified if patients test positive for H pylori (i.e. H pylori-associated chronic gastritis instead of chronic gastritis) and the rationale also applies to diagnoses of gastric ulcer, peptic ulcer and duodenal ulcer.
Gastro-oesophageal reflux disease (GERD) is an unapproved indication for IR or SR clarithromycin. Although a significant proportion of patients with GERD have H pylori infection, it is unclear whether or not H pylori should be treated. Eradication therapy is currently not recommended for most of GERD patients with H pylori infection[1,2]. Relief of abdominal pain of unknown origin was also an unapproved indication for clarithromycin-based therapy. Seven prescriptions for mesenteric lymphadenitis treatment included monotherapy with clarithromycin (n = 1), dual therapy with clarithromycin-levofloxacin (n = 3), clarithromycin-cefdinir (n = 1), clarithromycin-amoxicillin/clavulanate potassium (n = 2). Given the predominance of Y. enterocolitica in mesenteric lymphadenitis infection, initial oral antibiotic selection from third-generation cephalosporins, broad spectrum penicillins, fluoroquinolones and doxycycline may be considered. Recently, association of mesenteric lymphadenitis with mycoplasma was revealed by Tao et al. Among 108 patients with mesenteric lymphadenitis in that study, 36 patients (33%) were Mycoplasma-IgM positive. The switch to macrolide azithromycin provided a benefit for patients with an unsatisfactory response to third-generation cephalosporins or broad spectrum penicillins. In our survey, follow-up indicated that the combination of macrolide clarithromycin with levofloxacin, amoxicillin/clavulanate potassium or cefdinir showed satisfactory results in patients suffering from mesenteric lymphadenitis.
Clarithromycin IR based triple therapy or dual therapy is indicated for the treatment of patients with H pylori infection. However, the efficacy and safety of clarithromycin SR treatment for H pylori infection have not been established, as indicated in the prescribing information for Biaxin Xl Filmtab®. There have been three studies on clinical efficacy of clarithromycin SR -based triple therapy to cure H pylori infection. Coelho et al observed that the combination of lansoprazole 30 mg, clarithromycin SR 500 mg and furazolidone 400 mg, once daily for 7 d, was inexpensive, safe and an effective alternative for anti-H pylori therapy in family members of gastric cancer patients. Chu et al proved that one-week once-daily course of lansoprazole 30 mg, clarithromycin SR 500 mg and metronidazole 800 mg was a safe, well-tolerated, easy to comply with, and efficacious treatment for H pylori infection. A randomized controlled trial study by Liou et al provided the direct evidence that clarithromycin SR 1000 mg once daily can be used as an alternative to clarithromycin IR 500 mg twice daily for the treatment of H pylori-associated peptic ulcer disease. In that study, 161 patients with H pylori-associated peptic ulcer were randomized to receive one-week triple therapy with either clarithromycin SR 1000 mg once daily or clarithromycin IR 500 mg twice daily combination with amoxicillin 1000 mg twice daily and esomeprazole 40 mg once daily. The eradication rates were comparable in the two groups. Further clinical trials with a larger sample size are required to establish the efficacy and safety of clarithromycin SR. Effective communication between patients and gastroenterologists are rather necessary prior to initiation of off-label use of clarithromycin SR.
The combination of clarithromycin with omeprazole has a synergic effect. The Cmax, AUC0-24, and T1/2 derived from omeprazole increased by 30%, 89%, and 34%, respectively by the concomitant administration. The mean 24-h gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin. On the other hand, by concomitant administration of omeprazole, clarithromycin concentrations in the gastric tissue and mucus increased (e.g. clarithromycin mucus concentrations 2 h after application increased by about 9-fold). Simultaneous administration of lansoprazole, amoxicillin and clarithromycin increases the serum concentrations of lansoprazole and the active 14-OH-clarithromycin metabolite significantly. Compared to treatment with esomeprazole alone, the mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively, during triple therapy (esomeprazole magnesium 40 mg qd, clarithromycin 500 mg bid and amoxicillin 1000 mg bid for 7 days). The AUC and Cmax of rabeprazole and 14-hydroxyclarithromycin (active metabolite of clarithromycin) increased, although the AUC and Cmax for clarithromycin were not different following combined administration consisting of rabeprazole, amoxicillin and clarithromycin compared to values following single administration. Although there is no significant pharmacokinetic interaction between clarithromycin and pantoprazole, clarithromycin has a better effect in H pylori treatment when pantoprazole is used concomitantly.
Clarithromycin is a potent inhibitor of CYP3A4 and P-gp. Concomitant administration of clarithromycin and any of the following CYP3A4 substrates is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine, as described in standard information sources. In this survey, such prescriptions were not found. Coadministration of clarithromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, plasma concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
Triazolobenziodidiazepines (e.g. triazolam and alprazolam) and related benzodiazepines (e.g. midazolam) have been observed of CYP3A based drug interactions with erythromycin products and/or with clarithromycin in postmarketing experience. For example, intestinal and hepatic CYP3A inhibition by clarithromycin can significantly reduce the clearance of midazolam, resulting in an increase in the AUC of midazolam by 8-fold following oral dose in the elderly. Zolpidem is extensively metabolized, mainly by CYP3A4. Thus, a prescription containing alprazolam, zolpidem and clarithromycin has a high risk for excessive sedation (Table 4). Pharmacotherapy monitoring and dosage adjustment for these sedative drugs should be implemented accordingly.
Clarithromycin may increase the levels/effects of amlodipine. Levoamlodipine is an eutomer of amlodipine and the first enantiomerically pure dihydropyridine calcium channel blockers. Levoamlodipine is also mainly metabolized by CYP3A4, so its levels/effects may also be affected by clarithromycin. A case of vasodilatory shock possibly resulting from a clarithromycin-nifedipine interaction was reported by Gerónimo-Pardo et al. A potentially significant pharmacokinetic interaction between clarithromycin and carbamazepine was identified in two patients with long-standing epilepsy who were given omeprazole/clarithromycin therapy for H pylori gastritis. Serum carbamazepine levels were augmented by clarithromycin and returned to the therapeutic range following cessation of clarithromycin therapy. Empirically in such cases carbamazepine dose need to be tailored by 30% to 50%.
Clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised atorvastatin AUC by 82% and Cmax by 56%. Hence, clarithromycin should be avoided in patients taking atorvastatin and similarly metabolized HMG-CoA inhibitors. Sipe et al reported a case of rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. The antiplatelet effects of the prodrug clopidogrel can be reduced by concomitant administration of erythromycin or troleandomycin. The proposed mechanism is inhibition of CYP3A4 activity, which is responsible for the conversion of clopidogrel to its active metabolite. Clarithromycin also inhibits CYP3A4 activity and is also expected to affect clopidogrel metabolism. Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if clarithromycin is co-administered with clopidogrel.
In a combination of clarithromycin, nifedipine, clopidogrel and atorvastatin (Table 4), at least 4 clinical significant pharmacokinetic interactions are involved, e.g. clarithromycin-nifedipine, clarithromycin-clopidogrel, clarithromycin-atorvastatin and atorvastatin-clopidogrel. Such a prescription with high risk of adverse drug interactions is irrational. Considering the short course of clarithromycin therapy, close monitoring and proper dose adjustment may be more practicable than to switch to alternatives not mainly metabolized by CYP3A4.
Clarithromycin may increase levels of ergoloid mesylate by inhibiting CYP3A4 metabolism, resulting in toxicity (ischemia, vasospasm) and the combined use is contraindicated. So the combination therapy of clarithromycin with amlodipine and ergoloid mesylate at conventional dosage is irrational. A case of mania due to prednisone-clarithromycin interaction was reported by Finkenbine et al, suggesting that pharmacotherapy monitoring should be performed during the concurrent therapy.
Triple therapy with a PPI, clarithromycin and either amoxicillin or metronidazole is the first-line treatment regimen to eradicate H pylori infection[1,2,27]. Significant differences are observed in the prevalence of metronidazole resistance between developed and developing countries[28-30]. High levels of resistance to metronidazole mainly relates to the wide application in parasite infection, dental infection and gynecological diseases in developing countries. Antimicrobial susceptibility tests performed in Zhejiang Province of China indicated that the antibiotic resistance rate increased perceptibly during the period of 2003-2007[31,32]. Among six antibiotics (metronidazole, amoxicilin, gentamycin, levofloxacin, furazolidone and clarithromycin), the rate of resistance to metronidazole (99.32%) appeared to be the highest and the levofloxacin resistance rate (0.51%) was the lowest. Amoxicillin rarely induces resistance. Fluoroquinolones are active against H pylori in vitro and have a synergistic effect with PPIs. Strains resistant to furazolidone are rare. Furthermore, there is no cross-resistance to metronidazole and furazolidone is effective in populations with a high prevalence of metronidazole resistance. The resistance status may explain the pattern of antibiotic use in this hospital, i.e. furazolidone and levofloxacin are used more widely than are metronidazole or tinidazole. Guo et al reported that H pylori eradication rates were significantly different in patients receiving OAC (omeprazole/amoxicillin/clarithromycin) and OFC (omeprazole/furazolidone/clarithromycin) compared to those receiving OMC (omeprazole/metronidazole/clarithromycin). The eradication rate for H pylori infection was 90.3%, 90.9% and 70.9% in OAC, OFC and OMC groups, respectively. Based on these results, one-week of triple therapy with OAC or OFC were recommended for Chinese patients with duodenal ulcers and chronic gastritis. Since furazolidone is cheap and the H pylori eradication rate is high, OFC regimen is recommended to be one of choices for H pylori eradication.
PPI-based double combinations were clearly inferior to triple regimens, which is in accordance with the evidence-based data and they are not recommended in the first-line treatment. However, concurrent therapy of ranitidine bismuth citrate and clarithromycin have a similar efficacy compared to the triple regimens[36-38]. Thus, the prescription of a combination of clarithromycin and ranitidine bismuth citrate in our survey is rational. A 7 d quadruple therapy based on PPI, bismuth, tetracycline and metronidazole is the more frequently accepted[1,2]. Our survey found that some patients received quadruple therapy regimens containing PPI, bismuth, clarithromycin, and one of antibiotics including amoxicillin, furazolidone or levofloxacin.
In conclusions, a retrospective utilization study of clarithromycin for gastrointestinal disease treatment was conducted. There is a great scope to improve the quality of clarithromycin prescribing, especially with regard to administration schedule, concordance between indications and diagnoses and management of drug interactions.