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WORLD HEALTH ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE
EDM/EC/ESD
ENGLISH ONLY
EXPERT COMMITTEE ON THE SELECTION AND USE OF ESSENTIAL MEDICINES
Geneva, 31 March - 3 April 2003
Agenda Item 2: Applications for Addition (azithromycin)
(Updated version received from MSF 27 February 2003)
APPLICATION FOR INCLUSION OF
AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
FROM
MÉDECINS SANS FRONTIÈRES
APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
CONTENTS
1.
Summary statement of the proposal for inclusion, change or deletion
4
2.
Name of the focal point in WHO submitting the application
4
3.
Name of the organization(s) consulted and/or supporting the application
4
4.
International Nonproprietary Name (INN, generic name) of the medicine
4
5.
Whether listing is requested as an individual medicine or as an example of a
therapeutic group
Information supporting the public health relevance
4
4
6.1.
4
6.
7.
6.2.
Trachoma burden
Treatment details
4
5
7.1.
Azithromycin general
5
7.2.
Genital Chlamydia infection
5
7.2.1.
7.2.2.
WHO Guideline
Diagnostic tests for Chlamydia
5
6
7.2.3.
Syndromic treatment of urethral discharge
6
7.2.4.
Studies
7
Trachoma
7.3.1.
Studies
8
8
7.3.2.
9
7.3.
8.
WHO guideline
Summary of comparative effectiveness in a variety of clinical settings:
8.1.
9.
Genital Chlamydia burden
9
Identification of clinical evidence
10
8.1.1.
Genital chlamydia infection
10
8.1.2.
Trachoma
10
8.2.
Summary of available data
11
8.3.
Summary of available estimates of comparative effectiveness
11
Summary of comparative evidence on safety
12
9.1.
Estimate of total patient exposure to date
12
9.2.
Description of adverse effects/reactions
12
9.3.
Identification of variation in safety due to health systems and patient factors
12
9.4.
Summary of comparative safety against comparators
13
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
CONTENTS (continued)
10.
Summary of available data on comparative cost and cost-effectiveness within
the pharmacological class or therapeutic group
13
10.1.
Range of costs of the proposed medicine
15
10.2.
10.1.1. Donation programme
15
Comparative cost-effectiveness presented as range of cost per routine outcome 16
11.
Summary of regulatory status of the medicine
16
12.
Availability of pharmacopoeial standards
17
13.
Proposed text for the WHO Model Formulary
17
14.
References
18
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
1.
SUMMARY STATEMENT OF THE PROPOSAL FOR INCLUSION, CHANGE OR DELETION
Azithromycin is proposed for inclusion into the core WHO Model list of essential medicines for
the treatment of genital Chlamydial infection and trachoma.
2.
NAME OF THE FOCAL POINT IN WHO SUBMITTING THE APPLICATION
Submitted by MSF via WHO/EDM. MSF asked WHO/STI for collaboration.
3.
NAME OF THE ORGANIZATION(S) CONSULTED AND/OR SUPPORTING THE APPLICATION
Médecins sans Frontières
4.
INTERNATIONAL NONPROPRIETARY NAME (INN, GENERIC NAME) OF THE MEDICINE
Azithromycin (rINN, BAN, USAN)
5.
WHETHER LISTING IS REQUESTED AS AN INDIVIDUAL MEDICINE OR AS AN EXAMPLE OF A
THERAPEUTIC GROUP
Azithromycin is the prototype of a subclass of macrolide antibiotics known as the azalides.
Listing as an individual medicine. If other equivalent molecules are developed, azithromycin can
become an example of the therapeutic group.
6.
INFORMATION SUPPORTING THE PUBLIC HEALTH RELEVANCE
6.1.
Genital Chlamydia burden
Incidence: 92 million infections worldwide per year (WHO/CDS/CSR/EDC/2001.10).
6.2.
Trachoma burden
Trachoma, caused by Chlamydia Trachomatis infection, is the world’s leading cause of
preventable blindness. WHO estimates that there are 146 million cases of active disease, in
need of treatment to prevent blindness. 590 million people worldwide are at risk of acquiring the
infection. 6 million people are irreversibly blinded by trachoma or at immediate risk of blindness.
Trachoma is responsible for at least 15.5% of blindness worldwide.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
7.
TREATMENT DETAILS
7.1.
General infections
Azithromycin is effective in treating uncomplicated skin infections, upper and lower urinary tract
infections, atypical and community acquired pneumonia. A major advantage over erythromycin is
the clinical efficacy of single-dose azithromycin in uncomplicated urethritis or cervicitis due to
Chlamydia trachomatis. An additional advantage includes a well-tolerated adverse-effect profile.
Azithromycin is also effective for primary prophylaxis and treatment of Mycobacterium avium
complex infection in patients with HIV infection.
Azithromycin is active against the following organisms as demonstrated by in vitro and clinical
studies: Gram-positive: Staphylococcus aureus, Streptococcus agalactiae, Streptococcus
pneumoniae, and Streptococcus pyogenes; Gram-negative: Haemophilus ducreyi, Haemophilus
influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae; Chlamydia pneumoniae, Chlamydia
trachomatis, Mycoplasma pneumoniae
Comprehensive reviews on azithromycin have been published1,2,3, including specific reviews on
paediatric patients4,5. Other review articles discuss the selection of the right macrolide antibiotic6.
The above information is for reference only; listing of azithromycin is not requested for general
infections.
7.2.
Genital Chlamydia infection
7.2.1. WHO Guideline
The current WHO/STI guideline7 recommends either:
-
doxycycline 100mg orally, twice daily, for 7 days, OR
azithromycin 1 g orally, in a single dose for adults >45kg, and 20 mg/kg single dose for
<45kg.
Alternative regimens are:
-
amoxicillin, 3 x 500mg for 7 days
erythromycin 4 x 500mg, for 7 days
ofloxacin, 2 x 300mg, for 7 days
tetracycline, 4 x 500mg, for 7 days.
Azithromycin has the clear advantage that it is easy to administer (just 1 single dose); all other
antibiotics need a 7-day course with 2-4 doses per day, which might reduce effectiveness
through poor compliance.
For genital chlamydial infections in pregnancy, WHO recommends erythromycin or amoxicillin,
as the safety of Azithromycin in pregnancy has not yet been established.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
7.2.2. Diagnostic tests for Chlamydia
There are often no obvious clinical manifestations of genital Chlamydia infection. If infection with
chlamydia is not properly diagnosed, it can result in sterility in some women or in mother-to-child
infection during childbirth, leading to conjunctivitis or eye inflammation in the baby. In men it can
cause urethritis with possible infection of the ductus deferens and the testicles (epididymitis).
Existing rapid diagnostic tests for gonorrhoea and chlamydial infection are based on antigen
detection, and are in the form of IC strips or cassettes. However, they are not simple because
they require a number of steps to obtain results and their cost is high at approximately US$7 per
test. Their sensitivity is 60% to 70% compared to amplification tests. Research on alternative
tests is ongoing.
WHO is developing a model as a tool for estimating the required sensitivity for a rapid test.
Different scenarios are considered depending on the population (sex workers, women with
multiple casual partners, women with long term regular partnerships), number of sex acts and
partners, prevalence of gonorrhoea and chlamydial infections and consistency of condom use.
The major variable in the model is the return rate and delay of return of the patients. Cost
analysis indicate that a strategy including a rapid test could be half as expensive as a strategy
using a gold standard (slow) test.
For symptomatic patients with urethral discharge, WHO recommends a syndromic approach with
a treatment for both gonorrhoea and Chlamydia infection, as determining the exact cause
requires expensive tests and takes time. Patients with urethral discharge should be treated
immediately.
7.2.3. Syndromic treatment of urethral discharge
Azithromycin is effective in the empiric treatment of nongonococcal urethritis. A 1-gram dose has
been shown to be as effective as doxycycline given for 7 days. For patients where a single dose
regimen would be advantageous, azithromycin is an effective alternative to doxycycline.8
Single dose therapy with either azithromycin (1 gram) or ciprofloxacin (500 milligrams) was
effective in the treatment of urethral gonorrhea or cervical gonorrhea.9 However, WHO/STI
guidelines prefer a 2g single dose for gonococcal infections, as the 1g dose provides protracted
sub-therapeutic levels which may precipitate the emergence of resistance.
If a specific diagnosis is not possible, patients should be treated using the syndromic approach.
For urethral discharge, WHO recommends a syndromic treatment of gonorrhoea AND
Chlamydia.
WHO also recommends the following treatments for uncomplicated gonorrhoea:
-
ciprofloxacin 500mg orally, single dose (contraindicated in pregnancy and adolescents)
OR
azithromycin 2g orally, single dose, OR
ceftriaxone 125mg IM injection, single dose, OR
cefixime, 400mg orally, single dose, OR
spectinomycin 2g IM inj, single dose.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
This means that a 2g single dose would be sufficient treatment for the syndrome “urethral
discharge”. Alternatively, countries can choose another gonorrhoea treatment, and combine it
with a single dose of 1g azithromycin (or 7 days doxycycline twice daily 100mg) for Chlamydia.
7.2.4. Studies
Three groups of treatment were created to determine the efficacy of treating Chlamydia
trachomatis in pregnant women. Everyone in group 1 (n = 17 pairs) received azithromycin (1
gram single dose); in group 2 (n = 21 pairs) the patient received erythromycin (500 milligrams
(mg) three times daily for seven days) and the partner took tetracycline (500 mg four times daily
for seven days); in group 3 (n = 10 pairs) the woman took azithromycin (1 gram single dose) and
the partner received tetracycline as described in group 2. No pregnant women and/or their
partners in group 3 had a positive culture four weeks after therapy, compared to 20% of patients
and partners in group 2 and 7.1% of those in group 1. For all participants given azithromycin,
only 4.5% had positive cultures four weeks after starting therapy, compared to 21.1% of
participants given either erythromycin or tetracycline (P=0.018). Azithromycin produced
significantly less adverse effects and resulted in better compliance compared with erythromycin
or tetracycline10.
Single-dose azithromycin (1 gram) is as effective as multi-dose doxycycline (100 milligrams
twice daily) in the treatment of Chlamydia Trachomatis infection. At 1 month following treatment,
the incidence of persistence or recurrence of Chlamydia Trachomatis infection was 5.1% and
4.1% for those treated with single-dose and multi-dose therapy, respectively. According to
relative risk (RR) calculations (RR, 1.2, 95% confidence interval 0.35 to 4.5), the two dosing
regimens are similar in efficacy. Of the 73 women on the multi-dose regimen, 94.5% were
compliant, that is taking doxycycline for 5 or more days (7 days = 67; 5 days = 2). Similar
compliance was noted in the male partners. Since compliance is a limitation in multi-dose
treatment regimens, azithromycin may be favoured in the treatment of C trachomatis. However,
this study demonstrated that compliance was not a limitation and that doxycycline is still a viable
treatment option. In patients where compliance will be problematic, azithromycin is an
alternative11.
Azithromycin, as a single dose, is as effective as multiple dose regimens of tetracycline,
doxycycline and erythromycin in the treatment of C trachomatis infections. The azithromycin
regimen has an advantage because compliance is increased substantially by single-dose
therapy12,13.
Azithromycin administered as a single dose was effective in the empiric treatment of
nongonococcal urethritis associated with both Chlamydia trachomatis and Ureaplasma
urealyticum14. In this large study, involving 452 men, patients were randomized to either
azithromycin 1 gram as a single dose or doxycycline 100 milligrams twice daily for 7 days. Both
regimens were equally effective, regardless of the infecting organism. Though the cost of
azithromycin is substantially greater, the increased compliance with a single-dose regimen may
warrant its use.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
Single-dose azithromycin has been used in the treatment of sexually transmitted diseases
related to Neisseria gonorrhoeae, Chlamydia trachomatis, or Ureaplasma urealyticum. In this
randomized study, involving 182 patients, regimens of doxycycline 100 milligrams orally twice
daily for 7 days, azithromycin 500 milligrams orally twice daily for 1 day, azithromycin 1 gram as
a single oral dose, and azithromycin 500 milligrams on day 1 followed by 250 milligrams twice
daily for 2 further days (3 day course) were similarly effective. Failure rates were higher with all
regimens that were used to treat ureaplasma infections15.
7.3.
Trachoma
In 1996, a WHO Expert Committee concluded that Azithromycin 20mg/kg was as effective as 67 weeks of topical tetracycline eye ointment, and that it was well tolerated with good patient
compliance. The only problem was its high cost, and the committee urged the manufacturer to
“consider all possible means of making azithromycin available on a sustainable basis to all those
in need, to prevent blindness from trachoma.”16
A single oral dose (1g stat or 20mg/kg if <45kg) is as effective as 6-week course of daily
tetracycline ointment in clearing ocular chlamydial infection and in resolving the signs of
trachoma17. The protocol is simple to follow due to its particular pharmacokinetics: the oral dose
is rapidly absorbed, time to peak plasma level is 2-3 hours, and the bioavailability of 37% is not
affected by co-administration of food. Azithromycin levels in the tissues are up to 50 times higher
than in plasma, and the terminal elimination T1/2 is > 40 hours after a single dose.18,19
For control of trachoma in entire communities, a short course of oral azithromycin is more
effective than the standard 6-weeks course of daily tetracycline ointment. Community-wide
treatment with oral azithromycin markedly reduces C Trachomatis infection and clinical trachoma
in endemic areas and may be an important approach to control of trachoma.20
The formulation is well accepted by the population and easier to administer than the topical
tetracycline eye ointment, specially to small children21.
Oral azithromycin therefore appears to offer a means for controlling blinding trachoma. It is easy
to administer and higher coverages may be possible than have been achieved hitherto.22
7.3.1. WHO guideline
WHO Guideline: Primary Health Care Management of Trachoma, HSC/PBD PBL/93.33, 1993.
WHO recommends the 'SAFE' strategy: surgery, antibiotics, facial cleanliness and
environmental improvement. The antibiotic is thus only 1 of the 4 components needed for
trachoma control.
Azithromycin is also mentioned in the 1994 FCH/HIS sexually transmitted diseases Management
of sexually transmitted diseases, GPA/TEM/94.1
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
7.3.2.
Studies
Single dose azithromycin (20 milligrams/kilogram) was 100% effective in 13 school-age children
with active trachoma. This study suggest that azithromycin tear concentrations are adequate to
eradicate Chlamydia trachomatis, the causative organisms of trachoma. A follow-up
ophthalmologic examination at 6 months demonstrated all patients were disease free23.
Single dose azithromycin (20 milligram/kilogram) was as effective as a six-week course of
topical tetracycline opthalmic ointment in the treatment of conjunctivitis caused by Chlamydia
trachomatis in a group of children (aged 6 to 14 years). Infection was resolved in 63.3% and
65.4% of patients treated with azithromycin and tetracycline, respectively24.
Single dose azithromycin was comparable to oxytetracycline/polymyxin eye ointment in the
treatment of active endemic trachoma. This study was conducted in 168 rural Egyptian children.
Azithromycin suspension was administered in 1 of the following 3 dosing regimens: a single 20
milligrams/kilogram (mg/kg) dose (n=40); one dose (20 mg/kg) weekly for 3 weeks (n=43); one
dose (20 mg/kg) every 4 weeks for a total of 6 doses (n=42). The eye ointment (1%
oxytetracycline with 10000 units/gram polymyxin) was administered once daily for 5 consecutive
days every 28 days for a total of six 5-day periods (n=43). After 1 year, the clinical cure rate was
not statistically different between any of the treatment groups and was approximately 47%.
Azithromycin may represent a treatment alternative for endemic trachoma25.
8.
SUMMARY OF COMPARATIVE EFFECTIVENESS IN A VARIETY OF CLINICAL SETTINGS
Drugs that have been proposed by WHO for the treatment of C Trachomatis include:
Genital infections:
doxycycline 100mg orally, twice daily for 7 days (recommended)
amoxycillin 500mg orally, 3 times daily for 7 days (alternative)
erythromycin 500mg orally, 4 times daily for 7 days (alternative)
ofloxacin 300mg orally twice daily, for 7 days (alternative)
tetracycline 500mg orally, four times daily for 7 days (alternative)
Trachoma:
tetracycline eye ointment
An advantage with azithromycin is its activity against Chlamydia trachomatis and proven efficacy
when administered as a single 1 gram dose26. Azithromycin only needs to be taken once (single
dose) which improves patient compliance, compared to all other antibiotics which require
multiple dosages for 7 days.
Azthromycin can be used in pregnancy, but the safety of amoxicillin and erythromycin has been
better established. Erythromycin and amoxicillin are therefore preferred treatments in pregnant
women.
Doxycycline is equally effective and more affordable in the treatment of genital CT, but must be
taken twice daily for 7 days. Doxycycline is contraindicated in pregnancy.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
Azithromycin has several distinct advantages over erythromycin: it is better tolerated; there is
better tissue penetration; and there are favourable pharmacokinetics.
Ofloxacin is expensive, and often reserved for MDR/TB programmes?
Oral tetracycline is as effective, but has more side-effects than azithromycin. It is also contraindicated in pregnancy and children.
Azithromycin is equally effective to tetracycline eye ointment, but can be given in a single dose,
whereas tetracycline eye ointment needs to be given for 6weeks, causes visibility problems and
may suffer from stability problems in tropical climates.
The short duration of treatment used, once daily dosing, and the acceptable taste to most
children make azithromycin a good first choice in paediatric infections.
The price of Azithromycin may be a stumbling block, especially in countries where the patent is
still valid. However, generics are available at acceptable prices, and could be imported under
compulsory licenses.
8.1.
Identification of clinical evidence
8.1.1. Genital chlamydia infection
The BMJ Clinical Evidence rates single dose Azithromycin as “likely to be beneficial” in men,
non-pregnant women and pregnant women.27
A meta-analysis of short term RCTs has found that a single dose of Azithromycin may be as
effective in achieving microbiological cure of C Trachomatis as a 7 day course of doxycycline.
Rates of adverse effects were similar28.
One systematic review of RCTs has found that a single dose of Azithromycin is as effective in
achieving microbiological cure of C Trachomatis as a 7 day course of erythromycin in pregnant
women29.
8.1.2. Trachoma
Trachoma is a public health problem which requires more than drugs alone: WHO recommends
the integrated “SAFE” strategy: Surgery, Antibiotics, Face-washing and Environmental change.
The existing Cochrane Review searched The Cochrane Controlled Trials Register CENTRAL/CCTR, which contains the Cochrane Eyes and Vision Group specialised register
(Cochrane Library Issue 3, 2001), MEDLINE (1966 to August 2001), and EMBASE (1980 to
September 2001). They used the Science Citation Index to look for articles that cited the
included studies, searched the reference lists of identified articles and contacted authors and
experts for details of further relevant studies
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
The systematic review found 15 studies that randomised a total of 8678 participants. For both
outcomes (active trachoma and laboratory evidence of infection) the results of the chi-square
tests suggested that there was significant statistical heterogeneity among the trials. There was
also marked clinical heterogeneity. No summary statistics were calculated and we therefore
present a narrative summary of the results. For the comparisons of oral or topical antibiotic
against placebo/no treatment, the data are consistent with there being no effect of antibiotics but
are suggestive of a lowering of the point prevalence of relative risk of both active disease and
laboratory evidence of infection at three and 12 months after treatment. For the comparison of
oral against topical antibiotics the results suggest that oral treatment is neither more nor less
effective than topical treatment..30
8.2.
Summary of available data
Azithromycin is an effective treatment for genital Chlamydia infection and trachoma.
8.3.
Summary of available estimates of comparative effectiveness
Active trachoma has been treated with antibiotics since the 1950s and a variety of regimens
have been used. The antibiotic can be applied directly to the conjunctiva (topically) or taken
orally (systemic antibiotics). Antibiotics applied topically are usually in the form of an ointment
and a variable amount is squeezed onto the inner surface of the lower eyelid. This route gives a
high concentration of the antibiotic to the conjunctiva but low doses to the nasopharynx, which is
also a reservoir for the organism. Ointments may cause stinging eyes and temporary blurred
vision and they are difficult to apply to small children. The World Health Organization (WHO)
recommended topical treatment is 1% tetracycline ointment twice daily for six weeks, or on five
consecutive days each month for six months. Compliance with this treatment is poor due to the
side effects of the ointment and the length of the treatment programme. 31
Oral treatment gives a higher dose of antibiotic to sites of infection outside of the eye, but
systemic antibiotics can have various adverse effects in the person taking them, and other
pathological bacteria may develop resistance to the antibiotics. The full course of oral treatment
has a higher compliance rate than a directly supervised course of topical antibiotic. 32
The WHO recommended oral antibiotic is azithromycin, as a single dose of one gram in adults
and 20 milligrams/kilogram of body weight (mg/kg) in children. Azithromycin has low plasma
levels but high intracellular concentrations and a long half-life and has been shown to be an
effective treatment of genital chlamydial infections.
For use in pregnancy, the recommended antibiotic is erythromycin at a dose of 250 mg four
times a day for four weeks.33
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
9.
SUMMARY OF COMPARATIVE EVIDENCE ON SAFETY
Initial studies in 4000 adults and 2000 children indicated that Azithromycin is well-tolerated34.
This has been confirmed in further use studies35.
9.1.
Estimate of total patient exposure to date
Global sales in first quarter of 1999 showed a turnover of USD 441m (for Zithromax alone36).
Assuming a price of USD 4 per tablet, one can estimate annual usage of at least 440 million
tablets. Assuming an average treatment of 1.5g (6 tablets), this would mean a global, annual
patient exposure of 73 million treatment episodes. This figure excludes all generics worldwide,
and branded products sold in Central and Eastern Europe.
Conclusion: experience with Azithromycin is substantial.
9.2.
Description of adverse effects/reactions
Azithromycin has similar side-effects as erythromycin, but at lower frequencies. A review of
safety issues is available37.
Common: gastro-intestinal disturbances, but usually mild and less frequent than with
erythromycin: anorexia, dyspepsia, constipation.
Reported: rashes, dizziness, headache, drowsiness; photosensitivity; hepatitis, transient
elevations of liver enzymes; interstitial nephritis, acute renal failure, asthenia, paresthesia,
convulsions and transient alternations in neutrophil counts.
Rarely: tinnitus, cholestatic jaundice, hepatic necrosis, hepatic failure, Stevens-Johnson
syndrome, toxic epidermal necrolysis and taste disturbances.
9.3.
Identification of variation in safety due to health systems and patient factors
Pregnancy:
U.S. Food and Drug Administration's Pregnancy Category B (risk not excluded; use only
when needed)
Australian Drug Evaluation Committee's (ADEC) Category B1
A Cochrane systematic review on the use of Azithromycin in pregnancy for Chlamydia genitalis
concludes:38
With the relatively small amount of data presented, azithromycin appears to be very well
tolerated.
The number of women included in these trials is too small to assess whether
azithromycin is safe for use in pregnancy, as rare adverse outcomes are unlikely to be
detected and clinical experience with their use is limited.
Clindamycin and azithromycin may be considered further alternatives if erythromycin and
amoxycillin are contra-indicated or not tolerated.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
Lactation: safe use of Azithromycin has not been established; use with caution
Renal failure: normal dosage can be used39 (only 10% excreted by kidneys)
Hepatic insuffiency: A study in 16 cirrhotic patients with mild or moderate hepatic impairment
suggests that no modification of azithromycin dosage is necessary, despite its hepatic
metabolism40. However, the manufacturer suggests it should not be used in hepatic insuffiency.
Porphyria: avoid.
Possible drug interactions with other essential drugs exist, but at lower frequencies than with
erythromycin41:
Antacids
Anticoagulants (warfarin)
Carbamazepine
Digoxin
Cimetidine
Ergot alkaloids
Rifabutin
Theophyllin
reduces absorption
may increase bleeding
may increase carbamezapine toxicity
may enhance effect of digoxin
may increase Azithromycin levels & toxicity
ergotism possible – avoid concomitant use
may increase rifabutin serum levels; risk of uveitis
reduces excretion of theophyllin – significant toxicity possible –
avoid
A review of drug interactions with Azithromycin is available42
Contra-indications:
known allergy against macrolides (erythromycin),
hepatic impairment.
9.4.
Summary of comparative safety against comparators
Compared to other macrolides: Azithromycin has fewer side-effects than erythromycin or other
macrolides.
Compared to doxycycline: doxycycline is contraindicated in pregnancy; Azithromycin can be
used if needed (class B).
10. SUMMARY OF AVAILABLE DATA ON COMPARATIVE COST AND COST-EFFECTIVENESS WITHIN THE
PHARMACOLOGICAL CLASS OR THERAPEUTIC GROUP
The cost of Azithromycin is heavily influenced by the patent status of Azithromycin. The original
products from Pliva (Sumamed, Central and Eastern Europe) and Pfizer (Zithromax, in USA and
Western Europe) are expensive, whereas generics are available at 3.5 – 40% of such prices.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
The MSH Price Indicator Guide 2001 does not list azithromycin. It is, however, listed in the May
2002 WHO / MSF / UNAIDS / UNICEF List of HIV-related medicines.
In developing countries, the generic price fluctuates from USD 0.12 – 0.64 per 250mg capsule
(see table 1 below).
Table 1: Manufacturer (orientative) price per 250 mg capsule, in US$
Price
200mg/5mL
Date/source
3.54a or 3.35d
7.47b
BNF 3/2001
Spain
2.17a or 2.91b or
3.35b or 1.02c
8.09b
www.cof.es
Pfizer
France
3.01b
Pfizer
Mali
2.50b
Vita
Spain
1.37a or 1.47b
Square
Bangladesh
0.64
median price
Unknown
0.61c
Wockhardt
India
0.59a or 0.175b
Farmoz
Portugal
0.54ab
Eskayef
Bangladesh
0.46a
Aurobindo
India
0.33b
Cipla
India
0.37a or 0.20b
lowest price
Unknown
0.12c
Manufacturer
Country
Price 250mg
Pfizer
Brazil
5.25
Pfizer
UK
Pfizer
Vidal 2000
6.58b
Jan 2000
WHO May 2002
0.95b
MSF visit
Nov 99
MSF visit
0.65b
MSF visit
WHO May 2002
Sources:
a) MSF Nov 99 report
b) Cecile Mace report on Mali; prices CIF Bamako
c) WHO/MSF May 2002 Sources and prices document
d) BNF March 2001
For purposes of calculating the cost of treatments, we will use a range: the lowest-average price
for the developing countries: USD 0.12 – USD 0.39 per 250mg caps Azithromycin.
The lowest 500mg Azithromycin price in the May 2002 survey is USD 0.18, and the median price
USD 0.83. Using 500mg capsules may lower the cost of 1g stat treatments even more.
The USA patent expires 14 October 2005, and the EU patent in 2008. However, generics are
marketed in Portugal and Spain.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
10.1.
Range of costs of the proposed medicine
Assuming a 1g adult single dose, the cost of treatment varies according to source, and whether
4 x 250mg or 2x500mg tablets are being used. The range given is the lowest available price to
the median price in developing countries.
4 x 250mg caps @ USD 0.12-0.39 = USD 0.48 - USD1.56 per treatment
2 x 500mg caps @ USD 0.18 – 0.83 = USD 0.36 – USD 1.66 per treatment
Paediatric dosages using suspension will cost USD 0.65-0.95.
Treatment will be substantially higher in countries where Azithromycin is still patented.
One option for those countries is to request participation in the donation programme of the
“International Trachoma Initiative” (see below); another option is to enable the public health
safeguards that were explicitly approved by the WTO Doha conference.
10.1.1. Donation programme
In November 1998, Pfizer founded, in collaboration with the Edna McConnell Clark Foundation,
the Conrad N. Hilton Foundation and the William H. Gates Foundation, the “International
Trachoma Initiative” (ITI), a non-profit, tax-exempt organization, to implement a donation
programme for trachoma using azithromycine.
ITI decided to pilot test the donation programme in 5 countries for 2 years. It claims the donation
programme is worth USD 66 million in cash and kind (Azithromycin).
Morocco field-tested single dose azithromycin treatment for trachoma among 10,000 families in
the early 1990’s. In October 1999 ITI announced a collaboration with the Moroccan MOH to
disburse 1.2 million azithromycin tablets for an estimated 600,000 people in the 5 most affected
provinces. ITI will provide another USD 750,000 over 2 years for running the non-drugs aspects
of the project. USAID, through Helen Keller Foundation, also donated USD 100,000. The
donation is being executed through the National Programme for Blindness Control. In 6 months,
more than 600,000 people received azithromycin, whereas the MOH held 31,547 health
education sessions, reaching some 1.17 million people.
Tanzania agreed in August 1999 to receive 1.4 million doses of azithromycin from ITI. ITI will
donate another USD 1.4 million to implement the other aspects of the SAFE strategy. The Helen
Keller Foundation donated another USD 400,000. After 8 months, 75% coverage in 36 villages
was achieved: a total of 65,000 patients.
Ghana, Vietnam and Mali are the next countries to receive donations.
All countries have set up national Committees to handle the donation and organize the SAFE
campaign43.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
10.2. Comparative cost-effectiveness presented as range of cost per routine outcome
Cost per treatment episode:
USD 0.36c
USD 1.56b
USD 0.12a
USD 0.68a
USD 1.84a
USD 0.42c,d
USD 3.57b,d
USD 0.20a
Azithromycin: 1g stat (lowest price)
(median price)
Doxycycline: 2 x 100mg, for 7 days
Amoxicillin, 3 x 500mg for 7 days
Erythromycin 4 x 500mg, for 7 days
Ofloxacin, 2 x 300mg, for 7 days
Tetracycline, 4 x 500mg, for 7 days.
a)
b)
c)
d)
average price, International Price Indicator Guide 2001
median price, WHO May 2002
lowest price, WHO May 2002
based on 200mg tab. Calculated for 3 x 7 tabs.
The cheapest treatment is doxycycline (USD 0.12), followed by tetracycline (USD 0.20) and
Azithromycin (USD 0.36 – 1.56).
Azithromycin is not the cheapest, but it is affordable, and can be taken under health worker
supervision in a stat dose. This will ensure that treatment outcome is achieved.
For empirical treatment of uncomplicated chlamydial infection, doxycycline was more cost
effective than azithromycin when the compliance rate was more than 80%. The results were
unaffected if 1g of azithromycin cost less than US$544.
A 1995 study in the USA found that azithromycin is a cost-effective alternative to doxycycline.
However, the cost of azithromycin must decrease markedly for it to be less costly to a publicly
funded clinic. 45 The generic prices for a 1g course of azithromycin (USD 0.36- 1.56) have since
be heavily reduced.
11. SUMMARY OF REGULATORY STATUS OF THE MEDICINE
Registered in USA, UK, South Africa and most other developed countries (except Central
Eastern Europe): Azithromax, Pfizer.
Registered in Central Eastern Europe: Sumamed, Pliva (Croatia = country of origin).
Generics are produced in Spain (VITA), India (Aurobindo, EAS-Surg, Lyka, Strides), Portugal
(Farmoz), Guatemala (Laprin), Czech Republic (Leciva), China (Xian)46.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
12. AVAILABILITY OF PHARMACOPOEIAL STANDARDS
British Pharmacopoeia: no
International Pharmacopoeia: no
United States Pharmacopoeia: yes
13. PROPOSED TEXT FOR THE WHO MODEL FORMULARY
6.2.2.4 Macrolides
Azithromycin is an azalide, a subgroup of the macrolides;
it has an antibacterial spectrum that is similar to erythromycin.
It is effective in treating genital Chlamydia infection and trachoma.
Azithromycin
Azithromycin is a macrolide antibiotic.
Tablets, Azithromycin 250 mg; 500 mg
Powder for oral suspension, Azithromycin 200mg/5mL
WHO Model Formulary 2002
Uses: genital Chlamydia infection; trachoma.
Contraindications: hypersensitivity to erythromycin or other
macrolides; porphyria
Precautions: hepatic impairment (Appendix 5); pregnancy (not known to be harmful);
breastfeeding (Appendix 3);
Interactions: Appendix 1
Dosage:
Genital Chlamydia infection, trachoma, by mouth, ADULT and
CHILD over 45kg, 1g single dose; CHILDREN 20mg/kg single dose
PATIENT ADVICE. tablets should be swallowed whole
Adverse effects: gastro-intestinal disturbances, but usually mild and less frequent than with
erythromycin: anorexia, dyspepsia, constipation. Reported: rashes, dizziness, headache,
drowsiness; photosensitivity; hepatitis, transient elevations of liver enzymes; interstitial nephritis,
acute renal failure, asthenia, paresthesia, convulsions and transient alternations in neutrophil
counts.
Rarely: tinnitus, cholestatic jaundice, hepatic necrosis, hepatic failure, Stevens-Johnson
syndrome, toxic epidermal necrolysis and taste disturbances.
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APPLICATION FOR INCLUSION OF AZITHROMYCIN IN THE
WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
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WHO MODEL LIST OF ESSENTIAL MEDICINES
MEDECINS SANS FRONTIERES
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