TECHNOLOGY OVERVIEW: PHARMACEUTICALS

TECHNOLOGY OVERVIEW: PHARMACEUTICALS ISSUE 8.0 OCTOBER 1997 MACROLIDES IN COMMUNITY-ACQUIRED PNEUMONIA AND OTITIS MEDIA based primarily on the Technical Report: A Therapeutic and Economic Evaluation of Macrolide Antibiotics RF Tasch, KC Kunz, MA Marentette and DA Redelmeier Overview prepared by Christine Perras, BSc Phm Pharmaceutical Associate, CCOHTA

Cite as: Canadian Coordinating Office for Health Technology Assessment. Macrolides in Community-acquired pneumonia and otitis media. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1997. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CCOHTA. Legal Deposit - 1997 National Library of Canada ISSN 1203-9012

The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization, funded by the federal, provincial and territorial governments. It was established to encourage the appropriate use of health technology by influencing decision-makers through the scientific evaluation of medical procedures, devices and drugs. The effectiveness and cost of technology and its impact on health are examined. This overview has been prepared by staff at CCOHTA and is based primarily on the technical report: A Therapeutic and Economic Evaluation of Macrolide Antibiotics. 1 This overview attempts to put the original study into a clinical perspective. This overview does not necessarily reflect the opinions of the original investigators. To obtain copies of publications please contact: CCOHTA Publications 110-955 Green Valley Crescent Ottawa, Ontario, Canada, K2C 3V4 Telephone: (613) 226-2553 Fascimile: (613) 226-5392 Email: pubs@ccohta.ca or download full-text from http://www.ccohta.ca Vous pouvez aussi vous procurer la version française Les macrolides dans le traitement de la pneumonie d origine extra-hospitalière et de l otite moyenne à l OCCETS. 1 Tasch RF, Kunz KC, Marentette MA, Redelmeier DA. A therapeutic and economic evaluation of macrolide antibiotics. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1997.

REVIEWERS Reviewers for overview are: Rachel F. Tasch, MBA Abbott Laboratories Ltd. Technology Assessment Group, Montreal, Quebec St. Laurent, Quebec Dr. Andreas Laupacis Chair, CCOHTA Scientific Advisory Panel Director, Clinical Epidemiology Unit Ottawa Civic Hospital Ottawa, Ontario Reviewers for technical report were: Dr. George G. Zhanel Dr. T. J. Marie Abbott Laboratories Eli Lilly Inc. Pfizer Canada Inc. Dr. Andreas Laupacis Dr. Nicolaas Otten Ms. Christine Perras Faculty of Medicine and Pharmacy University of Manitoba Winnipeg, Manitoba Department of Medicine, Division of Infectious Diseases Dalhousie University Halifax, Nova Scotia St. Laurent, Quebec Scarborough, Ontario Kirkland, Quebec Chair, CCOHTA Scientific Advisory Panel Director, Clinical Epidemiology Unit Ottawa Civic Hospital Ottawa, Ontario Director, Pharmaceuticals and Extramural Research CCOHTA, Ottawa, Ontario Pharmaceutical Associate CCOHTA, Ottawa, Ontario This report was reviewed by external reviewers and by members of CCOHTA s Scientific Advisory Panel. These individuals kindly provided comments on drafts of this report. This final document incorporates most of the Reviewers' comments, however, CCOHTA takes sole responsibility for its form and content.

BACKGROUND SUMMARY REMARKS The use of erythromycin is limited by its side effect profile, its weak activity against gram negative pathogens and its dosing schedule. In comparison, azithromycin and clarithromycin, have an increased spectrum of activity and fewer side effects. However, the cost of the newer macrolides are higher. A study commissioned by CCOHTA entitled A Therapeutic and Economic Evaluation of Macrolide Antibiotics 1 evaluated the different macrolides available on the Canadian market for the treatment of community-acquired pneumonia (CAP) and otitis media. Specifically the study had two objectives: 1) to compare the efficacy of the three macrolides, and 2) to conduct an economic evaluation to determine the costs and the additional benefits offered by the newer macrolides. This overview is based on the findings of the commissioned study. CONCLUSIONS Community-Acquired Pneumonia 1) Considering clinical efficacy failure rates and side effect discontinuation rates, azithromycin and clarithromycin are more effective than erythromycin (94 and 93% success rates respectively, compared to 85% success rate). 2) Considering drug costs and physician out-patient visits only, erythromycin is the least expensive treatment option per patient per episode ($67 compared to $78 for azithromycin or clarithromycin).. 3) The cost-effectiveness analysis revealed that the cost to achieve an additional treatment success with the newer macrolides would be $123 to $131 when compared to erythromycin. 4) When provincial differences in drug and physician visit costs are considered, erythromycin remains the least expensive strategy across all provinces. Otitis Media 1) All three macrolides have similar effectiveness (differences of 1 to 2% in success rates) and similar expected costs per patient per episode ($1 to $2 differences). 2) A cost-effectiveness analysis was not performed due to the similarity in expected cost and effectiveness. 1 Canadian Coordinating Office for Health Technology Assessment

Study Limitations MACROLIDES IN COMMUNITY-ACQUIRED PNEUMONIA AND OTITIS MEDIA 1) Clinical: The clinical efficacy failure rates and the side effect discontinuation rates were calculated by weighting each of the individual study rates against the number of patients. No formal hypothesis testing was done to determine statistical significance. 2) Economic: The costs were calculated using Saskatchewan prices. The cost of hospitalization, the cost of managing side effects or drug interactions and the cost of laboratory tests and procedures were not considered. If azithromycin or clarithromycin produced a small decrease in the rate of hospitalization, it would affect the cost-effectiveness ratio. Canadian Coordinating Office for Health Technology Assessment 2

INTRODUCTION 2,3 Erythromycin, discovered in the 1950's, was the first antibiotic classified as a macrolide. It was marketed as an alternative to penicillin for infections caused by Streptococci, Staphylococci, and Pneumococci. It was later discovered that it also had activity against Mycoplasma, Helicobacter, Chlamydia, and Legionella species. The use of erythromycin is limited by its pharmacokinetic properties (e.g., poor oral bioavailability, short duration of action necessitating frequent daily dosing), its high incidence of gastrointestinal adverse effects (gastric irritation, nausea, diarrhea), and its weak activity against common respiratory pathogens such as Haemophilus influenzae. Over the years, many preparations of erythromycin (e.g., enteric coated tablets, capsules and different salts) were developed in an attempt to improve the bioavailability of the drug and the side effect profile. Two newer macrolides, azithromycin and clarithromycin, recently introduced in Canada, offer improved pharmacokinetic and side effect profiles and an expanded spectrum of activity compared to erythromycin. Pharmacokinetic Properties Adverse Effects Spectrum of Activity The newer macrolides have longer half-lives and enhanced tissue penetration, permitting once or twice daily dosing. Azithromycin, like erythromycin, needs to be taken on an empty stomach. Clarithromycin can be taken with or without food. To date, less drug interactions have been reported with azithromycin and clarithromycin, although not all drug interactions reported with erythromycin have been studied in the newer macrolides. Azithromycin and clarithromycin have a reduced incidence of abdominal pain, nausea, vomiting, and diarrhea compared to erythromycin. In addition to being effective against organisms susceptible to erythromycin, azithromycin is more active against Gram-negative organisms such as Haemophilus influenzae and Neisseria gonorrhea. Clarithromycin is more active against Gram-positive organisms and against H. influenzae than erythromycin. Both exhibit greater activity against Chlamydia trachomatis, Haemophilus ducreyi and Ureaplasma ueralyticum. The newer macrolides are also used in the treatment of respiratory tract infections, some of the sexually transmitted diseases, and skin and soft tissue infections. The commissioned study reviewed the use of macrolides in community-acquired pneumonia and otitis media. It did not evaluate the use of macrolides in other types of infection nor was a complete review done on comparing the macrolides to other classes of antibiotics. 3 Canadian Coordinating Office for Health Technology Assessment

UTILIZATION DATA According to an analysis using the outpatients prescription drug database of Saskatchewan covering the period of April 1 to September 30, 1993 (and prior to the introduction of azithromycin and clarithromycin): In CAP, erythromycin was the most frequently prescribed antibiotic (34%) followed by amoxicillin/ ampicillin (31%) and cephalexin (20%). In otitis media, amoxicillin/ ampicillin was the most frequently prescribed antibiotic (63%) followed by co-trimoxazole (14%) and erythromycin (11%). For comparison purposes, Intercontinental Medical Statistics (Canadian Disease & Therapeutic Index) kindly provided CCOHTA with data on antibiotic usage in Canada from September 1995 to September 1996. In CAP, erythromycin was the most frequently used product (20.8%) followed by cephalosporins (20.7%) and clarithromycin (14.4%). In otitis media, amoxicillin was the most frequently used product (30.9%) followed by co-trimoxazole (10%) and cefaclor (9.8%). Erythromycin was the fourth most mentioned product (7.2%). PARAMETERS OF THE EVALUATION Therapy Evaluated Erythromycin (in community-acquired pneumonia) and erythromycin-sulfisoxazole (in otitis media) were compared to azithromycin (Zithromax ) and clarithromycin (Biaxin ). Target Audience and Perspective The intended audience of the analysis was the provincial and territorial health care systems, and other third party payers. The Ministry of Health perspective included the costs of the medications and physician visit costs but not hospitalization costs. Type of Analysis A cost-effectiveness analysis was conducted. It was based on data obtained from a literature review and from a retrospective analysis of the Saskatchewan drug database (1993 data) and used a decision model. Outcomes of Interest The evaluation focused on clinical trials which reported clinical success rates (defined as cure and improvement) and discontinuation rates due to side effects. Canadian Coordinating Office for Health Technology Assessment 4

Cost Elements Included Direct costs used were drug and physician visit costs. The evaluation did not include the costs of hospitalization, laboratory tests and procedures, and medical costs borne by patients. Time Horizon The time horizon chosen was 28 days. Discounting was not applied. EFFICACY The clinical literature analysis of the commissioned study included prospective, randomized studies published since 1985 which compared a macrolide to another macrolide or another antibiotic in nonhospitalized patients. Clinical efficacy failure rates and rates of discontinuation due to side effects were recorded for the macrolide antibiotics. An average clinical efficacy failure rate was computed by weighting each of the rates reported in individual studies by the number of patients included in the efficacy analysis. Similarly, an average discontinuation rate due to side effects was obtained by weighting each of the individual study rates by the number of patients eligible for the safety analysis. Results of the clinical analysis are shown in Table 1. Table 1: Weighted Average Rates from Clinical Trials (95% confidence intervals) CAP Erythromycin Clarithromycin Azithromycin d/c* due to side-effects 10.4% (8.5%-12.7%) 3.7% (2.2%-5.8%) 1.2% (0.3%-3.1%) Clinical efficacy failure 5.1% (3.3%-7.5%) 2.9% (1.4%-5.4%) 4.9% (0.5%-17.6%) Otitis Media Erythromycinsulfisoxazole Clarithromycin Azithromycin d/c* due to side-effects 2.1% (0.4%-6.2%) 1.9% (1.0%-2.6%) 0.3% (0.1%-0.7%) Clinical efficacy failure 6.0% (2.6%-11.9%) 7.9% (6.1%-10.2%) 6.6% (5.3%-8.2%) * d/c = discontinuation EFFECTIVENESS The commissioned study used a decision-analytic model. It was assumed that the patient was seen by a general practitioner and was not hospitalized. Four outcomes were considered in the model (Table 2). Two groups had a successful outcome with or without a follow-up physician visit. Groups 3 and 4 were deemed to have failed therapy due to side effects or lack of clinical efficacy and both groups required another prescription. 5 Canadian Coordinating Office for Health Technology Assessment

Table 2: Outcome Groups Group Outcome Initial Visit with Rx Follow-up Visit Follow-up Rx 1 success yes no no 2 success yes yes no 3 d/c* due to side effects yes yes yes 4 clinical efficacy failure yes yes yes * d/c = discontinuation Treatment patterns for patients who received erythromycin for pneumonia or erythromycinsulfisoxazole for otitis media were obtained from the Saskatchewan database. From April 1, 1993 to September 30, 1993, 427 patients with CAP and 1,042 patients with otitis media received a prescription for an erythromycin product. Example of Calculations: Erythromycin in CAP By using the treatment patterns from the Saskatchewan database and the weighted average obtained from the clinical studies on erythromycin in CAP, 10.4% of 427 patients (or 45 patients) would discontinue therapy due to side effects (group 3). Of the remaining 382 patients, there would be 5.1% or 19 patients for whom the drug would be ineffective (group 4). Thus, 363 patients would have a successful course of therapy (groups 1 and 2). There were 66% of CAP patients receiving erythromycin who had no follow-up physician visit and 34% who did, according to the Saskatchewan database. This represents 242 patients in success outcome group 1 and 121 patients in success outcome group 2. This distribution pattern was also applied to clarithromycin and azithromycin. The number of patients in each group is shown in Table 3a. Table 3a: Distribution of Patients in Each Outcome Group: Cap Group Erythromycin Clarithromycin Azithromycin 1 242 266 267 2 121 133 134 3 45 16 5 4 19 12 21 In otitis media, similar calculations were done (Table 3b). Based on the Saskatchewan data, 57% of otitis media patients had no follow-up physician visit and 43% did. Canadian Coordinating Office for Health Technology Assessment 6

Table 3b: Distribution of Patients in Each Outcome Group: Otitis Media Group Erythromycinsulfisoxazole Clarithromycin Azithromycin 1 546 537 553 2 412 406 417 3 22 18 3 4 62 81 69 From tables 3a and 3b above, the following success and failure rates for the different macrolides were calculated (Table 4). In turn, these numbers were used in the decision tree to calculate the expected cost per patient per episode (see Results section). Table 4: Success and Failure Rates for the Different Macrolides Therapy Outcome (group #) CAP Otitis Media Erythromycin a Success (groups 1 and 2) 85% 92% Failure (groups 3 and 4) 15% 8% Clarithromycin Success (groups 1 and 2) 93% 91% Failure (groups 3 and 4) 7% 9% Azithromycin Success (groups 1 and 2) 94% 93% Failure (groups 3 and 4) 6% 7% a erythromycin in pneumonia and erythromycin-sulfisoxazole in otitis media COSTS Initial and follow-up costs of prescriptions and physician visits during a 28 day period were used. Prescription Costs i) Community-Acquired Pneumonia The erythromycin preparations evaluated in CAP were: erythromycin base 250 mg and 333 mg tablets as well as enteric coated capsules; and erythromycin ethylsuccinate-sulfisoxazole 40 mg/ ml oral suspension. An average total cost per erythromycin prescription was obtained from the Saskatchewan database. 7 Canadian Coordinating Office for Health Technology Assessment

Drug costs for azithromycin and clarithromycin were obtained from the manufacturers based on the following doses: azithromycin 500 mg on the first day of therapy followed by 250 mg on days 2 to 5; clarithromycin 250 mg twice daily for 10 days. ii) Otitis Media Drug costs were obtained from the manufacturers for the following doses: erythromycin ethylsuccinate-sulfisoxazole oral suspension 50 mg/ kg/ day for 10 days; clarithromycin oral suspension 15 mg/ kg/ day for 10 days; azithromycin 10mg/ kg on day 1 and 5mg/ kg on days 2 to 5. Based on the age distribution in the Saskatchewan database, 78.1% of the patients ranged from newborns to 5 year-old children; 21.7% were between the ages of 6 to 15 years and the remainder, 0.2%, were adults over the age of 15 years. Their weights were assumed to be 10 kg, 30 kg and 60 kg respectively. Initial prescription costs were calculated using the drug acquisition cost, a 10% wholesaler mark-up, a pharmacist dispensing fee of $6.76 and a 35% patient co-payment. Follow-up prescription costs were obtained from the Saskatchewan database. The following prescription costs were used in the evaluation (Table 5). Table 5: Prescription Costs Drug CAP Otitis Media Erythromycin a $12.20 $19.83 Clarithromycin $25.54 $21.02 Azithromycin $25.56 $19.78 Follow-up prescription b $12.38 $14.70 a erythromycin in pneumonia and erythromycin-sulfisoxazole in otitis media b average cost from the Sasktachewan database Physician Out-Patient Visit Costs Physician visit costs were obtained from the Saskatchewan Health Payment Schedule for Physician Services. The costs of initial and follow-up visits were $36.30 and $18.70 respectively. According to the database, some patients incurred more than one initial and follow-up visit (i.e., two visits on the same day) such that weighted average costs were used in the model (Table 6). Canadian Coordinating Office for Health Technology Assessment 8

Table 6: Physician Visit Costs Visit CAP Otitis Media Initial visit $43.70 $44.52 Follow-up visit $21.31 $25.77 RESULTS (Note: All numbers have been rounded off) The differences in costs and success rates compared to erythromycin were determined for azithromycin and clarithromycin (Tables 7a and 7b). In CAP, erythromycin was the least expensive treatment option per patient per episode and also the least effective. Azithromycin and clarithromycin had similar cost and effectiveness. In otitis media, the three macrolides had similar costs and effectiveness. Table 7a: Cost and Effectiveness of Azithromycin and Clarithromycin Relative to Erythromycin: CAP Therapy Expected Cost per Patient per Episode Success Rate Erythromycin $67 85% Clarithromycin $78 93% Azithromycin $78 94% Table 7b: Cost and Effectiveness of Azithromycin and Clarithromycin Relative to Erythromycin-sulfisoxazole: Otitis Media Therapy Expected Cost per Patient per Episode Success Rate Erythromycin $78 92% Clarithromycin $79 91% Azithromycin $77 93% 9 Canadian Coordinating Office for Health Technology Assessment

Cost-effectiveness Analysis For pneumonia, it would cost $131 and $123 to achieve an additional treatment success with clarithromycin and azithromycin, respectively, compared to erythromycin (Table 8). For otitis media, a cost-effectiveness ratio was not calculated given the similarity in cost and effectiveness. Table 8: Cost-effectiveness of Clarithromycin and Azithromycin Compared to Erythromycin: CAP Clarithromycin Azithromycin Incremental cost $11 $11 Incremental effectiveness 8% 9% Incremental cost-effectiveness $131* $123* Sensitivity Analysis Sensitivity analyses were conducted on seven parameters: the results of the clinical analysis; the ranges of discontinuation rates due to side effect and clinical efficacy failure rates using the 95% confidence intervals; the distribution of patients in the success outcome groups; province-specific resource-use costs; drug prices; the elimination of patient co-payment; and comparison of amoxicillinclavulanate to azithromycin or clarithromycin in otitis media. In general, the model was robust to changes. Threshold Analysis To eliminate the cost differences between erythromycin and the newer macrolides, the prescription costs of clarithromycin and azithromycin would need to decrease to $14 (from $25). Even if treatment failure rates fell to 0%, the newer macrolides would remain more costly than erythromycin in pneumonia. Financial Impact The annual costs were calculated from the weighted average prescription cost* for each drug for each province, the provincial population weight compared to Saskatchewan, and the number of patients from the database (427 CAP patients and 1,042 otitis media patients) to obtain a cost for 6 months. This was multiplied by a factor of two to obtain a yearly cost. * The weighted average prescription cost was determined from the cost of the initial macrolide prescription (which included the provincial dispensing fee, mark-up and patient co-payment if applicable), the cost of initial and follow-up visits using the provincial rates, and the cost of the follow-up prescription as determined from the database analysis. Canadian Coordinating Office for Health Technology Assessment 10

The annual costs presented in Tables 9a and 9b are the approximate cost of treatment if all CAP or otitis media patients were to use only erythromycin compared to using only azithromycin or clarithromycin. Note that using azithromycin for otitis media in some provinces would incur small savings. However, these figures are based on insignificant differences (i.e. $1) in total expected cost between erythromycin-sulfisoxazole and azithromycin or clarithromycin. Since there appears to be no differences in efficacy and costs between the macrolides when used in otitis media, the results reported in Table 9b should be interpreted with caution. Table 9a: Approximate Costs to Provinces: CAP Province Total Treatment Cost per Year for Erythromycin ($) Additional Cost of Using Azithromycin or Clarithromycin ($) Saskatchewan 52000 15000 British Columbia 166000 74000 Alberta 147000 38000 Manitoba 36000 16000 Ontario 433000 247000 Quebec 319000 96000 New Brunswick 23000 16000 Nova Scotia 36000 11000 P.E.I. 4000 2000 Newfoundland 18000 10000 11 Canadian Coordinating Office for Health Technology Assessment

Table 9b: Approximate Costs to Provinces: Otitis Media Province Total Treatment Cost per Year for Erythromycinsulfisoxazole ($) Additional Cost of Using Clarithromycin ($) Additional Cost of Using Azithromycin ($) Saskatchewan 162000 3000 (800 savings) British Columbia 551000 16000 (2,000 savings) Alberta 453000 9000 (2,000 savings) Manitoba 124000 4000 (800 savings) Ontario 1572000 48000 (8,000 savings) Quebec 988000 24000 (5,000 savings) New Brunswick 88000 3000 (500 savings) Nova Scotia 109000 4000 (500 savings) P.E.I. 10000 5000 4000 Newfoundland 63000 3000 (400 savings) STUDY LIMITATIONS The results of the commissioned study need to be interpreted in light of the limitations described below. Clinical The commissioned study evaluated the use of macrolides in community-acquired pneumonia and otitis media but not in other types of respiratory tract infections, skin infections and sexually transmitted diseases. The analysis did not compare the macrolides to other non-macrolide antibiotics and the impact of the newer macrolides on the entire antibiotic market. The clinical efficacy failure rates and the side effect discontinuation rates were calculated by weighting each of the individual study rates against the number of patients. A true meta-analysis was not performed. No formal hypothesis testing was done to determine statistical significance. The literature search identified 392 articles on pneumonia. Thirteen trials met the selection criteria for inclusion in the clinical analysis. Of note is the fact that 159 non-english articles were eliminated. The inclusion of non-english articles that meet the other inclusion criteria might change the results of the evaluation. Furthermore, there were very few head to head trials comparing azithromycin and clarithromycin in both conditions. Point estimates for azithromycin in pneumonia and erythromycin- Canadian Coordinating Office for Health Technology Assessment 12

sulfisoxazole in otitis are based on only four studies (44 patients in the clinical efficacy analysis) and two studies (133 patients in the clinical efficacy analysis) respectively. The drug database was analyzed for the months of April to September only, which may not be representative of the true prevalence of respiratory tract infections. The model did not account for compliance, although it is argued that compliance may influence the side-effects and clinical efficacy failure rates observed in the clinical trials. Nonetheless, compliance is not measured explicitly. There are differences in lengths of therapy (azithromycin is given for 5 days compared to 10 days for erythromycin and clarithromycin), administration schedules (azithromycin is given once daily compared to twice daily for clarithromycin and three to four times daily for erythromycin), and side effects, which may affect compliance. Economic The costs were calculated using Saskatchewan prices. The cost of hospitalization, the explicit cost of managing side effects and drug interactions, and the cost of laboratory tests and procedures were not considered. If azithromycin or clarithromycin produced a small decrease in the rate of hospitalization, it would affect the cost-effectiveness ratio. Physician out-patient follow-up visit costs were assumed to be the same irrespective of the drug prescribed. 13 Canadian Coordinating Office for Health Technology Assessment

REFERENCES 1. Tasch RF, Kunz KC, Marentette MA, Redelmeier DA. A therapeutic and economic evaluation of macrolide antibiotics. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 1997. 2. Cornish P. The new macrolides: azithromycin and clarithromycin. Canadian Journal of Clinical Pharmacology 1995;2(4):153-166. 3. Cornish P. The new macrolides: azithromycin and clarithromycin. Focus on New Drugs (Metro Toronto Hospitals Drug Information Service) 1994;13(3):20-41. Canadian Coordinating Office for Health Technology Assessment 14

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