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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

Background

Malaria continues to represent a significant risk for some travelers and malaria chemoprophylaxis has remained an important countermeasure. Trends in antimalarial use may be influenced by a number of factors, including the availability of antimalarials, increasing resistance, the issuing of updated guidelines for malaria chemoprophylaxis, and continuing education. The aim of this study was to investigate the trends in prescription of antimalarial drugs, particularly those recommended for chemoprophylaxis in Australia, from 2005 to 2009.

Methods

In 2011, data were extracted from the online Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Committee, on antimalarials used in Australia for the period 2005 to 2009.

Results

Among the drugs solely used as antimalarial drugs from 2005 to 2009, atovaquone plus proguanil and melfloquine were the most commonly prescribed antimalarials. Mefloquine prescriptions increased by 38% from 2005 to 2008 before decreasing by 17% from 2008 to 2009. The number of prescriptions for atovaquone plus proguanil has trebled during the period. Prescriptions for proguanil have dropped over 90% from 2005 to 2009. The diaminopyrimidines, pyrimethamine-containing antimalarials, have mostly been removed from the prescription drug list. Prescriptions for chloroquine have reduced by 66% from 2005 to 2008 and chloroquine was only available on special access from 2009. Artemether plus lumefantrine combination has been used in relatively small quantities and only on special authority from 2007 to 2009. Quinine prescriptions have fallen by 60%. Although a considerable quantity of doxycycline was prescribed, it was unknown how much was intended for malaria chemoprophylaxis.

Conclusions

The prescription of antimalarials in Australia was consistent with the national guidelines with the most commonly prescribed antimalarials being atovaquone plus proguanil, mefloquine, and most likely doxycycline. Other antimalarials previously used for chemoprophylaxis have continued to be removed from the prescriber list between 2005 and 2009. The prescriptions of quinine may be becoming displaced by newer antimalarial drugs for treatment, but this needs further investigation.

It was reported that there were 216 million cases of malaria worldwide in 2011, resulting in approximately 655,000 deaths.[1] Australia has been declared malaria-free since 1981; however, during the period 2005 to 2009, 3,411 cases of imported malaria (average = 682/y) were notified in Australia (Figure 1).[2-6] Malaria due to Plasmodium falciparum accounted for nearly half of recorded cases in Australia during this period.[2-6] Fortunately, deaths due to malaria in Australia are relatively rare with only one death reported in a study of 482 cases of imported malaria in Western Australia from 1990 to 2001,[7] and none were reported for the period 2005 to 2009.[2-6] It is known that taking chemoprophylaxis decreases the severity and frequency of death from malaria due to P falciparum compared to those who take no prophylaxis.[8] A comprehensive review of malaria in Australia has been published elsewhere.[9]

image

Figure 1. Cases of malaria notified in Australia 2005 to 2009.[2-6]

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Therapeutic Guidelines-Antibiotic, updated every few years in Australia, provide recommendations on the selection of malaria chemoprophylaxis and treatment.[10, 11] Previous studies in Australia have suggested that trends in the prescription of antimalarials are influenced by various factors, including the prevailing malaria chemoprophylaxis guidelines in Australia.[12, 13] Recent guidelines have recommended a number of options for malaria chemoprophylaxis, including chloroquine, doxycycline, melfoquine, and atovaquone plus proguanil, depending on the resistance patterns of the malaria likely to be encountered by the traveler.[10, 11] With a steady increase from 2005 to a record 6.3 million Australian resident short-term departures in 2009,[14] it is important that Australians traveling to malaria-endemic areas are prescribed malaria chemoprophylaxis, where appropriate.

The aim of this study was to investigate the trends in use of antimalarial drugs, particularly those prescribed for malaria prophylaxis in Australia, from 2005 to 2009.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

In 2011, data were extracted from the Australian Statistics on Medicines reports published by the Pharmaceutical Benefits Advisory Committee, Drug Utilization Committee, on antimalarials used in Australia for the period 2005 to 2009.[15-19] During 2005 to 2009, 12 drugs/drug combinations could have potentially been prescribed for malaria. Six drugs (chloroquine, primaquine, mefloquine, proguanil, atovaquone/proguanil, and artemether/lumefantrine) were most likely, almost solely used as antimalarials. The remaining six drugs (hydroxychloroquine, quinine bisulfate, quinine sulfate, pyrimethamine, pyrimethamine/sulfadoxine, and doxycycline) had additional indications. The former group of drugs would be expected to be an accurate indicator of trends in antimalarial use, while the latter group would be a less accurate indicator of trends as other uses potentially confound prescriptions for antimalarial use. Data were obtained on the number of prescriptions for each of these antimalarials. Trends in use were descriptively analyzed.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

Among the drugs solely used as antimalarial drugs from 2005 to 2009, atovaquone plus proguanil and melfloquine are now the most commonly prescribed antimalarials (Table 1). Mefloquine prescriptions had increased by 38% from 2005 to 2008, but then dropped 17% from 2008 to 2009. The numbers of prescriptions for atovaquone plus proguanil have trebled (306%). Prescriptions for proguanil have dropped over 90% from 2005 to 2009. The diaminopyrimidines, pyrimethamine-containing antimalarials, have mostly been removed from the prescription drug list. Prescriptions for chloroquine have reduced by 66% from 2005 to 2008 and chloroquine was only available on special access from 2009. Artemether plus lumefantrine combination had been used in relatively small quantities and was available only on special authority from 2007 to 2009. Quinine prescriptions have also fallen by 60% from 2005 to 2009. Although a considerable quantity of doxycycline has been prescribed, it was unknown how much was intended for malaria chemoprophylaxis.

Table 1. Number of prescriptions of antimalarials by year in Australia, 2005 to 2009
Antimalarial20052006200720082009
  • SA, drug available through Special Authority only from the Therapeutic Goods Administration and no data were available; NA, drug not available during this period.

  • *

    These drugs are used for indications other than malaria.

  • Breakdown to bisulfate and sulfate not reported in 2009.

  • Where specified, prescriptions for doxycycline 100 mg as HCl salt were 914,303, 834,714, and 760,333, and for doxycycline as monohydrate were 39,088, 146.448, and 152,875 in 2007, 2008, and 2009, respectively.

Quinoline derivatives
Chloroquine5,1793,7414,4901,769SA
Hydroxychloroquine sulfate122,633134,050147,464161,047173,578
Primaquine phosphateSA159SASASA
Biguanides
Atovaquone plus proguanil8,41810,41823,27824,95325,841
Proguanil1,921805451NA125
Methanolquinolines
Mefloquine11,65412,40115,57216,03313,324
Quinine bisulfate*112,86970,47055,03841,263144,461
Quinine sulfate*252,650140,780134,983123,562 
Diaminopyrimidines
Pyrimethamine349269305194147
Pyrimethamine plus sulfadoxine*210NANANANA
Artemisinin and derivatives
Artemether plus lumefantrine22150SASASA
Tetracyclines
Doxycycline 100 mg *, ‡847,607830,333959,859986,983916,281

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

Trends in the use of antimalarial drugs for treatment and chemoprophylaxis have been found to be greatly influenced by availability of antimalarials, prevailing guidelines, and other factors, in several countries;[12, 13, 20, 21] however, this study was not designed to investigate factors that might impact on these trends. It has been suggested that doxycycline remained a commonly prescribed malaria chemoprophyaxis,[12, 13] although it was impossible from these data to determine the precise extent of its use as an antimalarial agent. Nonetheless, it remained a lead option in the prevailing malaria chemoprophylaxis guidelines.[10, 11]

A combination of atovaquone plus proguanil became available in Australia in 2000 and, since becoming incorporated into the Australian malaria guidelines in 2003,[10] has become widely adopted as the mainstay of malaria chemoprophylaxis and an important option for treatment among those antimalarial drugs with a sole indication for malaria. The main reasons for this are the high user adherence among travelers, especially as adverse effects are viewed as minimal.[22] The combination of atovaquone and proguanil has synergistic activity against blood stages and causal activity against liver schizonts of P falciparum.[23] Like many drugs developed previously, the longevity of the combination of atovaquone and proguanil as an antimalarial may be limited by the development of resistance, but it has become a suitable alternative as a daily dose antimalarial to doxycycline.

Mefloquine has remained as one of the primary recommendations for chemoprophylaxis of travelers entering chloroquine-resistant areas throughout the study period.[10, 11] It has also been recommended as one of the drugs of choice for standby treatment and treatment during this period.[10, 11] The turnaround in flagging mefloquine prescriptions seen in 2002 to 2005[13] has been demonstrated with mefloquine prescriptions having steadily risen for the period 2005 to 2008, although there was a small drop in prescriptions in 2009 (Table 1). Recent evidence suggesting that the reports of neuropsychiatric side-effects may have been overstated[24] may help contribute to the continuing judicious use for what is otherwise a highly effective antimalarial. Because of the perceived risks of neuropsychiatric side-effects, it is important that guidelines concerning its selection and use as a malaria chemoprophylaxis are closely followed, including discussion of alternatives and several trial doses of mefloquine, where appropriate.[25]

Proguanil was recommended as a second line chemoprophylaxis for malaria in the 2003 and 2006 guidelines, but only in combination with chloroquine;[9, 10] hence it was not widely prescribed. The demise of pyrimethamine plus sulfadoxine has also occurred, as neither of these drugs has been recommended for many years, and pyrimethamine itself has all but disappeared from reported antimalarial prescriptions. The number of prescriptions of chloroquine has also decreased fairly dramatically, while the number of prescriptions for hydroxychloroquine has continued to increase during 2005 to 2009 from previous years.[12, 13] However, as hydroxychloroquine may have other uses apart from antimalarial use, especially in rheumatoid conditions, interpretation was difficult for this particular drug. Like chloroquine, its use as an antimalarial was undoubtedly mainly directed at treatment of patients with Plasmodium vivax infection, as there are few areas of the world where it could be used for malaria chemoprophylaxis owing to increasing resistance.[26] Travelers may also be selecting alternative antimalarials for prophylaxis in chloroquine-sensitive areas, which would need further investigation. Chloroquine registration was not renewed by the sole manufacturer in Australia in 2008 and this may have affected the number of prescriptions of chloroquine and resulted in a switch to hydroxycloroquine, which would need further investigation.

By 2003, artemether plus lumefantrine became available in Australia and was recommended in the 2003 and 2006 guidelines for the treatment of uncomplicated malaria due to P falicparum.[10, 11] Although there was no prescription data for the last 2 years of this study, artemether plus lumefantrine gained “Orphan Drug” status from the Therapeutic Goods Administration in Australia in 1999,[27] but has become available on prescription by special authority. The “Orphan Drugs” program was aimed at “encouraging sponsors of prescription medicines for treatment of rare diseases.”[27] Artemisinin-based combination therapies have become central to malaria treatment globally.[28]

This study has a number of limitations. Among the group of drugs used for other purposes, the extrapolation to antimalarial use is difficult to make accurately. It also could not be determined from the data to what extent antimalarials were used for treatment as opposed to chemoprophylaxis; however, it was expected that the many imported cases of malaria reported each year in Australia were treated with quinine and tetracycline derivatives, as per the prevailing Australian guidelines.[10, 11] Nevertheless, quinine use has dropped by two thirds over the period, which may reflect uptake of alternative antimalarial drugs for treatment. Travel health advisers may also use only some drugs for treatment or standby treatment, such as artemether plus lumefantrine. Primaquine's evaluation was limited by the non-availability of data for most of the period 2005 to 2009; however, its reported use was minimal for the only year reported, 2006. Primaquine has been used primarily for eradication treatment of relapsing cases of P vivax malaria,[28] as it is not recommended for chemoprophylaxis in the prevailing guidelines.[9, 10] As destination data were not available with prescription data, only general trends in antimalarial use could be studied here. In addition, prescription data may not include some sources of antimalarial use outside of prescription data, such as in hospitals and perhaps some travel clinics that maintain their own dispensaries; however, this was thought not to greatly affect those antimalarials primarily prescribed for chemoprophylaxis.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

The prescription of antimalarials in Australia was consistent with the national guidelines, with the most commonly prescribed antimalarials being atovaquone plus proguanil, mefloquine, and most likely doxycycline. Other antimalarials previously used for chemoprophylaxis have continued to be removed from the prescriber list between 2005 and 2009. The prescriptions of quinine may be becoming displaced by newer antimalarial drugs for treatment, but this needs further investigation, as artemether plus lumefantrine was available only through special access from 2007 to 2009.

Declaration of Interests

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References

The author states that he has received conference travel scholarship support from GlaxoSmithKline, Australia.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Declaration of Interests
  8. References
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