280201

More. . . Copyright © 2012 by Therapeutic Research Center

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PL Detail-Document #280201

−This PL Detail-Document gives subscribers

additional insight related to the Recommendations published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER February 2012

H. Pylori Treatment: An Update

Background Helicobacter pylori infection plays a major

role in the pathogenesis of gastric and duodenal

ulcers, gastric cancer, and gastric mucosa-

associated lymphoid tissue (MALT) lymphomas.1

A triple therapy regimen with clarithromycin,

amoxicillin or metronidazole, and a PPI is often

used as a first-line therapy; however, resistance to

such a regimen is on the rise. Due the recent

shortages of clarithromycin and tetracycline and

the increased resistance rate, clinicians are

seeking effective alternatives to the standard triple

therapy regimen. Several alternative regimens

(e.g., quadruple therapy, sequential therapy, four-

drug nonbismuth-based concomitant therapy,

fluoroquinolone-based therapy, etc) have been

tried for H. pylori treatment. This document

reviews the efficacy and place in therapy for the

various treatment regimens for H. pylori. A chart

comparing the efficacy of the commonly

recommended H. pylori treatment regimens and

newer regimens is included.

Triple Therapy The 2007 American College of

Gastroenterology (ACG), the Canadian

Helicobacter Study Group (2004), and the

Canadian Dyspepsia Working Group (2005)

recommend proton pump inhibitor (PPI)-based

triple therapy (standard PPI dose BID +

clarithromycin 500 mg BID + amoxicillin

1000 mg BID [or metronidazole 500 mg BID if

penicillin allergic]) as first-line treatment of H.

pylori infection.2-4

The ACG recommends 14

days of treatment duration whereas the Canadian

guidelines recommend at least seven days of

treatment.4 The optimal duration of PPI-based

triple therapy with amoxicillin and clarithromycin

is an ongoing debate. A prospective, randomized

trial found no therapeutic gain from extending

standard triple therapy from seven to 14 days.5 A

meta-analysis of 21 randomized trials showed that

the eradication rate differences among the

different treatment durations (seven vs ten vs 14

days of triple therapy) to be statistically

significant with longer duration of therapy

yielding better eradication rates; however, the

clinical significance is marginal.6

Several studies and meta-analyses have shown

that triple therapy works better if the PPI is dosed

twice daily and when clarithromycin 500 mg,

rather than 250 mg, BID is used.7 The different

PPIs seem to have similar efficacy. Although

recommended as an alternative to patients who are

penicillin allergic, the combination of

clarithromycin and metronidazole should be

discouraged as there is currently no effective

salvage therapy if such a combination fails.7

Despite ongoing debate on the optimal

duration of therapy and antibiotic dosages, experts

recommend treating with higher dosages of

antibiotics (e.g., clarithromycin 500 mg BID) for

14 days unless shorter duration has been shown to

be equally effective per local susceptibility data.8

Recent data have shown the resistance rates to

metronidazole and clarithromycin are on the rise

up to 42% and 20%, respectively.9,10

In addition,

several meta-analyses have shown the cure rates

of standard triple therapy have fallen below the

acceptable rate of >80% (intention-to-treat [IT]

analysis) in many regions.8,11-13

Experts are now

discouraging the use of triple therapy as first-line

empiric therapy unless local susceptibility patterns

indicate such a treatment regimen to be highly

effective (>90% eradication rate per protocol [PP]

analysis).8,11

Based on the ACG and Canadian

Helicobacter Study Group Consensus criteria for

H. pylori protocol studies, the range for the 95%

confidence interval should remain above 80% (IT)

and above 90% (PP) for an effective regimen.2,4

Prevpac (Hp-Pac in Canada), a combo pack

containing a 14-day supply of lansoprazole 30 mg,

clarithromycin 500 mg, and amoxicillin 1 gram

dosed twice daily is available and can be used for

triple therapy in light of the current clarithromycin

shortage. In light of the current clarithromycin

(PL Detail-Document #280201: Page 2 of 6)



shortage, substituting clarithromycin extended-

release for clarithromycin immediate-release may

also be considered, but is not preferred.

Theoretically, clarithromycin extended release

should be effective in the treatment of H. pylori

since clarithromycin is a time-dependent

antibiotic, where the increased exposure to the

drug may help its antimicrobial effect.14,15

However, there are no data on the use of

clarithromycin extended release in the treatment

of H. pylori.

Substitution with other macrolides (e.g.,

erythromycin or azithromycin) for clarithromycin

in triple therapy regimens is not recommended

due to low efficacy.16

Quadruple Therapy An alternative to the triple therapy treatment

regimen is the bismuth quadruple therapy. U.S.

and Canadian guidelines both recommend the

bismuth quadruple therapy of PPI or H2-blocker

(U.S. guidelines only) + bismuth + metronidazole

+ tetracycline for ten to 14 days as a first-line

therapy for H. pylori eradication.2,4

The ACG also

recommends such quadruple therapy as a salvage

therapy in those who have failed clarithromycin-

based triple therapy.2 Quadruple therapy was

previously considered a rescue regimen rather

than first-line treatment regimen due to the

perception that the dosing was too complex and

less well tolerated than PPI triple therapies.4

However, two meta-analyses concluded that the

efficacy, tolerability, and patient compliance were

similar between PPI triple therapies and quadruple

therapy.17,18

Due to the increase in clarithromycin

resistance rate, quadruple therapy regimens are

increasingly being recommended as first-line

empiric therapy.8,11

Pylera (each capsule contains bismuth

subcitrate 140 mg, metronidazole 125 mg, and

tetracycline 125 mg [three capsules per dose]) or

Helidac (bismuth subsalicylate 525 mg,

metronidazole 250 mg, tetracycline 500 mg per

dose) combo packs (doses for both given four

times daily) plus a PPI can be used for quadruple

therapy in light of the current tetracycline

shortage. However, due to concerns about

metronidazole resistance, additional

metronidazole should be added to Helidac

treatment, aiming for at least 1500 mg of

metronidazole per day. Total daily dose of

metronidazole 1400 mg to 1600 mg in bismuth-

based quadruple therapy has been shown to

overcome metronidazole resistance.11

Due to the lack of data, the substitution of

doxycycline for tetracycline in standard quadruple

therapy is not recommended.

The use of doxycycline in an alternative

quadruple therapy (omeprazole 20 mg +

amoxicillin 1000 mg + doxycycline 100 mg +

bismuth subcitrate 420 mg all given BID) based

on sensitivity data has been tried in the Italian

population. This alternative quadruple therapy

regimen was shown to have eradication rates of

92% (PP) and 91% (IT).34

Preliminary data from

a randomized, open-label Chinese trial (n=160)

also suggest the addition of bismuth to standard

triple therapy regimen (omeprazole 20 mg +

amoxicillin 1000 mg + clarithromycin 500 mg +

bismuth potassium citrate 220 mg all taken BID)

for 14 days to be a promising treatment regimen

to overcome clarithromycin resistance.9 The

results of this study showed that 14-day treatment

with bismuth, in addition to standard triple

therapy, yielded higher eradication rates compared

to seven-day treatment.

Results of these preliminary findings need to

be validated in the North American population

before such regimens can be routinely

recommended.

Sequential Therapy A 10-day sequential therapy, combining a 5-

day course of PPI BID with amoxicillin

1000 mg BID immediately followed by a second

course of clarithromycin 500 mg BID,

metronidazole 500 mg or tinidazole 500 mg BID,

and a PPI BID for five additional days, is another

promising regimen.1,11,12

Cure rates of such

sequential therapy has been shown to be as high

as 92% in Europe.19

Two pooled analyses of European studies

support the efficacy of sequential therapy,

especially in those infected with macrolide-

resistant H. pylori.20-22

Another meta-analysis

found comparable efficacy of sequential therapy

vs triple therapy.22

Trials conducted in the Asian population also

show promising results with sequential therapy.

In one study conducted in Thailand, treatment

with lansoprazole 30 mg + amoxicillin 1000 mg

BID for five days, then lansoprazole 30 mg +

metronidazole 500 mg BID + clarithromycin




1000 mg once daily for another five consecutive

days yielded a 95% eradication rate.23

In a Chinese trial comparing standard triple

therapy, bismuth quadruple therapy, and

sequential therapy, the treatment with omeprazole

20 mg BID + amoxicillin 1000 mg BID for five

days followed by omeprazole 20 mg BID +

tinidazole 500 mg BID + clarithromycin 500 mg

BID for another five days yielded a higher

eradication rate compared to standard triple

therapy (omeprazole 20 mg BID + amoxicillin

1000 mg BID + clarithromycin 500 mg BID) and

quadruple therapy consisting of rabeprazole

20 mg BID + amoxicillin 1000 mg BID +

levofloxacin 500 mg daily + bismuth pectin

100 mg QID.24

In contrast to these positive findings, a trial

conducted in Spain, showed an eradication rate of

only 84% in patients treated with sequential

therapy.25

The web edition of Sanford Guide to

Antimicrobial Therapy recommends such

sequential treatment regimens as a first-line

treatment for H. pylori infection in patients with

gastric or duodenal ulcer.26

While sequential

therapy has been shown to be effective in the

European and Asian population, some clinicians

feel more experience with a North American

population is needed before recommending it as a

treatment option. The 2007 ACG guidelines state

that sequential therapy cannot be widely accepted

as first-line therapy in the U.S. until efficacy has

been validated in the North American population.2

A recent presentation at the Canadian Digestive

Disease Week 2010 also concluded that more data

are needed in the North American population

before sequential therapy can be widely accepted

as a treatment option in the Canadian

population.27

Four-drug Nonbismuth “Concomitant

Therapy” Sequential therapy can be a complex regimen,

requiring the patient to switch from a double to

triple therapy at mid point. As an alternative to

sequential therapy, researchers proposed the same

four drugs used in sequential therapy (PPI,

clarithromycin, metronidazole, and amoxicillin) to

be given concomitantly as a nonsequential four-

drug, three-antibiotic nonbismuth containing

quadruple therapy (aka “concomitant therapy”).

A meta-analysis of five randomized controlled

trials (four European, one Japanese) showed that

concomitant therapy for three to five days

achieved higher eradication rate compared to

standard triple therapy of five to seven days (93%

vs 83%, respectively).28

A recent study in Taiwan comparing sequential

therapy vs concomitant therapy found both

therapies to be equally effective and safe for

eradication of H. pylori (92.3% vs 93%,

respectively).29

More studies comparing concomitant and

sequential therapies are needed to determine

whether the simplicity of concomitant therapy is

more effective than sequential therapy. Despite

limited clinical data in the U.S. and Canadian

population, experts now consider concomitant

therapy an option for patients who have not been

previously treated with clarithromycin or

metronidazole. However, there is concern of dual

resistance to clarithromycin and metronidazole as

such dual-resistant H. pylori strains are difficult to

eradicate.8,11,12

Salvage Therapy For salvage therapy, a regimen that has been

studied besides quadruple therapy is the

levofloxacin-based triple therapy, which shows

eradication rates ranging from 63% to 94% in

Asian and European populations. A meta-analysis

including four randomized, controlled trials

showed that a 10-day levofloxacin-based triple

therapy regimen had a superior eradication rate

and was associated with fewer side effects

compared to a 7-day course of bismuth-based

quadruple therapy.2,30

However, these results

require validation in the North American

population. Furthermore, the optimal

levofloxacin dose (250 mg BID vs

500 mg daily vs 500 mg BID) and duration of

therapy has yet to be determined (seven day vs

ten day). However, another meta-analysis did

find a higher eradication rate with the 10-day over

7-day regimen.31

Unfortunately, resistance to

fluoroquinolones is rapidly increasing. Experts

now recommend using fluoroquinolone therapy

only when susceptibility data are available.11

Rifabutin-based salvage therapy (rifabutin

150 mg + amoxicillin 1000 mg + PPI BID for 14

days) has also been tried in patients who have

failed other therapies. Due to concerns of adverse

drug effects and increased mycobacterium




resistance to rifabutin, such therapy should be

reserved as a last resort for patients who have

failed at least two courses of first-line

therapy.7,8,11,12

LOAD Therapy An investigational four-drug regimen known

as LOAD therapy (levofloxacin 250 mg daily with

breakfast + omeprazole 40 mg daily before

breakfast + nitazoxanide 500 mg BID +

doxycycline 100 mg daily at dinner) was found to

be an effective regimen with eradiation rates of

88.9% (10-day therapy) and 89.4% (7-day

therapy) in an open-label study.32

A larger

randomized controlled trial is warranted to further

evaluate the efficacy of this treatment regimen.

Sequential-Concomitant Hybrid Therapy A hybrid of sequential and concomitant

therapy with seven days of PPI plus amoxicillin

treatment followed by amoxicillin, clarithromycin,

metronidazole or tinidazole, and PPI for an

additional seven days is currently being

investigated. Treatment success with such hybrid

therapy has been shown to be >95%.8 Some

experts consider such hybrid therapy a reasonable

alternative to quadruple therapy for patients who

have not recently been treated with clarithromycin

and/or metronidazole.8,11,12

Dual Therapy Although dual therapy (e.g., PPI + amoxicillin)

for ten to 14 days is an FDA–approved regimen,

such regimens should not be recommended since

the eradication rate falls below 80%.2

Commentary In treating H. pylori infection, it is important to

achieve a high eradication rate in order to reduce

symptoms and complications of the infection.2

The eradication rate of H. pylori is highly

dependent on patient compliance to the treatment

regimen. An ideal treatment regimen should be

simple, well tolerated, cost effective, encourage

patient compliance, and provide a bacterial

eradication rate of >80% (IT) or >90% (PP).2 See

our PL Chart, H. Pylori Treatment Regimens, for

regimens and their efficacy. To avoid repeated

treatments of dyspepsia symptoms not attributable

to H. pylori, follow-up testing with urea breath

test or fecal antigen test is recommended.1 For

both urea breath test and fecal antigen test, the

patient should stop taking proton pump inhibitors

two weeks before testing or stop H2-receptor

antagonists for 24 hours before testing. Patients

should also avoid taking antimicrobial agents for

four weeks before testing. These agents can

reduce the sensitivity of testing.1

The choice of regimen should be based on

local susceptibility patterns.8 Standard triple

therapy is considered the first-line therapy in areas

where the clarithromycin resistance rate is <20%

[Evidence level A, high quality RCTs].1-4

In areas

with high prevalence for clarithromycin-resistant

H. pylori (>20%) or in patients who have failed

standard triple therapy, consider quadruple

therapy with PPI + bismuth + metronidazole +

tetracycline for ten to 14 days [Evidence level A,

high quality RCTs].1,2,4

If the local H. pylori

antimicrobial resistance information is not readily

available, it is reasonable to consider bismuth-

based quadruple therapy with a PPI in individuals

who have previously been treated with either a

macrolide or metronidazole for any reason, since

prior exposure significantly increases the

likelihood of H. pylori resistance to these agents

[Evidence level C; Consensus].2 In patients who

have not been recently treated with clarithromycin

and/or metronidazole, concomitant therapy can be

considered an alternative, especially in those who

are not able to adhere to the QID dosing schedule

of quadruple therapy regimens [Evidence level C;

Expert opinion].8,11,12

There are data suggesting

concomitant therapy and sequential therapy are

equally effective; therefore, sequential therapy can

also be considered in areas where efficacy of

triple therapy has fallen below the acceptable

level [Evidence level C, expert opinion].8,11,12

Experts also consider hybrid therapy a reasonable

alternative to standard quadruple therapy in

patients who have not recently been treated with

clarithromycin and/or metronidazole [Evidence

level C, expert opinion].8,11,12

A 10-day course of

levofloxacin-based triple therapy has been shown

to be effective in treatment of persistent H. pylori

infections in non-North American populations

[Evidence level A; quantitative systematic

review].30

However, it should not be

recommended routinely as a first-line therapy.33

More data with a North American population are

needed for its routine use; however, it can be

considered as a salvage therapy [Evidence level C,

Consensus].2




In light of the current clarithromycin and

tetracycline shortages, quadruple therapy using

PPI + bismuth + metronidazole + tetracycline for

ten to 14 days or Helidac dose pack with

additional metronidazole dose aiming for at least

1500 mg metronidazole per day as first-line

empiric therapy can be considered.2-4

Pylera plus

a PPI is also an option. However, cost can be a

limiting factor when using the brand combo

products.

If necessary, H. pylori treatment can be

delayed until appropriate antibiotics are available.

In general, there is no urgency in treating H.

pylori since H. pylori is typically acquired in

childhood and most patients have been infected

for decades.8

Users of this PL Detail-Document are cautioned to use

their own professional judgment and consult any other

necessary or appropriate sources prior to making

clinical judgments based on the content of this

document. Our editors have researched the

information with input from experts, government

agencies, and national organizations. Information and

internet links in this article were current as of the date

of publication.

Project Leader in preparation of this PL Detail-Document: Wan-Chih Tom, Pharm.D.

Levels of Evidence In accordance with the trend towards Evidence-Based

Medicine, we are citing the LEVEL OF EVIDENCE

for the statements we publish.

Level Definition

A High-quality randomized controlled trial (RCT)

High-quality meta-analysis (quantitative

systematic review)

B Nonrandomized clinical trial

Nonquantitative systematic review

Lower quality RCT

Clinical cohort study

Case-control study

Historical control

Epidemiologic study

C Consensus

Expert opinion

D Anecdotal evidence

In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based

clinical review article. Am Fam Physician 2002;65:251-8.

References 1. McColl KE. Clinical practice. Helicobacter pylori

infection. N Engl J Med 2010;362:1597-604. 2. Chey WD, Wong BC; Practice Parameters

Committee of the American College of

Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808-25.

3. Veldhuyzen van Zanten SJ, Bradette M, Chiba N, et al. Evidence-based recommendations for short- and long-term management of uninvestigated dyspepsia in primary care: an update of the Canadian Dyspepsia Working Group (CanDys) clinical management tool. Can J Gastroenterol 2005;19:285-303.

4. Hunt R, Fallone C, Veldhuyzan van Zanten S, et al. Canadian Helicobacter Study Group consensus conference: update on the management of Helicobacter pylori--an evidence-based evaluation of six topics relevant to clinical outcomes in patients evaluated for H. pylori infection. Can J Gastroenterol 2004;18:547-54.

5. Zagari RM, Bianchi-Porro G, Fiocca R, et al. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER Study. Gut 2007;56:475-9.

6. Fuccio L, Minardi ME, Zagari RM, et al. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med 2007;147:553-62.

7. Calvet X. Helicobacter pylori infection: treatment options. Digestion 2006;73(Suppl1):119-28.

8. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010;59:1143-53.

9. Sun Q, Liang X, Zheng Q, et al. High efficacy of 14-day triple therapy-based, bismuth-containing quadruple therapy for initial Helicobacter pylori eradication. Helicobacter 2010;15:233-8.

10. Malfertheiner P. Infection: bismuth improves PPI-based triple therapy for H. pylori eradication. Nat Rev Gastroenterol Hepatol 2010;7:538-9.

11. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011;8:79-88.

12. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol 2011;17:3971-5.

13. Graham DY, Lu H, Yamaoka Y. A report card to grade Helicobacter pylori therapy. Helicobacter 2007;12:275-8.

14. Quintiliani R. Pharmacodynamics of antimicrobial agents: time-dependent vs concentration-dependent killing. http://www.antimicrobe.org/h04c.files/history/PK-PD%20Quint.pdf. (Accessed January 15, 2012).

15. Rapp RP, Nogid B, Goldberg T. Principles of treatment of CAP—Part2: implications of antimicrobial pharmacokinetics/pharmacodynamics. https://secure.pharmacytimes.com/lessons/200711-01.asp. (Accessed January 15, 2012).

16. Silva FM, Eisig JN, Teixeira AC, et al. Short-term triple therapy with azithromycin for Helicobacter pylori eradication: low cost, high compliance, but low efficacy. BMC Gastroenterol 2008;8:20.


17. Gene E, Calvet X, Azagra R, Gisbert JP. Triple vs. quadruple therapy for treating Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol Ther 2003;17:1137-43.

18. Luther J, Higgins PD, Schoenfeld PS, et al. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol 2010;105;65-73.

19. Vaira D, Zullo A, Hassan C, et al. Sequential therapy for Helicobacter pylori eradication; the time is now! Therap Adv Gastroenterol 2009;2:317-22.

20. Zullo A, De Francesco V, Hassan C, et al. The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis. Gut 2007;56:1353-7.

21. Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naïve to treatment. Ann Intern Med 2008;148:923-31.

22. Gatta L, Vakil N, Leandro G, et al. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009;104:3069-79.

23. Sirimontaporn N, Thong-Ngam D, Tumwasorn S, Mahachai V. Ten-day sequential therapy of Helicobacter pylori infection in Thailand. Am J Gastroenterol 2010;105:1071-5.

24. Gao XZ, Qiao XL, Song WC, et al. Standard triple, bismuth pectin quadruple and sequential therapies for Helicobacter pylori eradication. World J Gastroenterol 2010;16:4357-62.

25. Sanchez-Delgado J, Calvet X, Bujanda L, et al. Ten-day sequential treatment for Helicobacter pylori eradication in clinical practice. Am J Gastroenterol 2008;103:2220-3.

26. Chambers HF, Eiopoulos GM, Gilber DN, et al. The Sanford Guide to Antimicrobial Therapy. Web Edition. Sperryville, VA: Antimicrobial Therapy, Inc., 2012. http://webedition.sanfordguide.com/. (Accessed January 15, 2012).

27. Johnston C. Sequential therapy eradicates Helicobacter pylori better than triple therapy in Aklavik Natives: Presented at CDDW. March 2, 2010. Doctor’s Guide. http://canhelpworkinggroup.ca/Doctor's%20Guide%20Dispatch_2010-03-02.pdf. (Accessed January 15, 2012).

28. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four drug, three antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009;14:109-18.

29. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with four drugs is equally effective for eradication for H. pylori infection. Clin Gastroenterol Hepatol 2010;8:36-41.

30. Saad RJ, Schoenfeld P, Kim HM, Chey WD. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol 2006;101:488-96. [Abstract].

31. Jodlowski TZ, Lam S, Ashby CR Jr. Emerging therapies for the treatment of Helicobacter pylori infections. Ann Pharmacother 2008;42:1621-39.

32. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Am J Gastroenterol 2011;106;1970-5.

33. Liou JM, Lin JT, Chang CY, et al. Levofloxacin-based and clarithromycin-based triple therapies as first-line and second-line treatments for Helicobacter pylori infection: a randomised comparative trial with crossover design. Gut 2010;59:572-8.

34. Cammarota G, Martino A, Pirozzi G, et al. High efficacy of 1-week doxycycline- and amoxicillin-based quadruple regimen in a culture-guided, third-line treatment approach for Helicobacter pylori infection. Aliment Pharmacol Ther 2004;19:789-95.

Cite this document as follows: PL Detail-Document, H. Pylori Treatment: An Update. Pharmacist’s

Letter/Prescriber’s Letter. February 2012.

Evidence and Recommendations You Can Trust…

3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2012 by Therapeutic Research Center

Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com,

www.prescribersletter.com, or www.pharmacytechniciansletter.com

PL Detail-Document #280201 −This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER February 2012


Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com

H. Pylori Treatment Regimens for Adults

Abbreviations: ACG=American College of Gastroenterology; AMOX=amoxicillin; BID=twice daily; BIS=bismuth subcitrate potassium;

BSS=bismuth subsalicylate (Pepto-Bismol Regular Strength); CLAR=clarithromycin; DOX=doxycycline; DU=duodenal ulcer;

ESOMP=esomeprazole; GU=gastric ulcer; IT=intention-to-treat; LANS=lansoprazole; LEV=levofloxacin; MET=metronidazole; NIT=nitazoxanide;

OMP=omeprazole; PANT=pantoprazole; PP=per protocol; PPI=proton pump inhibitor; QID=four times daily; RAB=rabeprazole; RIF=rifabutin;

TCN=tetracycline; TID=three times daily; TIN=tinidazole; TPD=Therapeutic Products Directorate (Health Canada).

NOTE: Not all FDA- or TPD-approved regimens have maximum efficacy. Only Regimens with >80% (IT) or >90% (PP) are considered effective.1,2

PPI or

H2-Blockera,f,g

Antibiotic 1 Antibiotic 2 Bismuth

Compound

Duration1-3

Comments Efficacyb,c

FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Recommended Oral Regimens per ACG Guidelines (2007), Canadian Helicobacter Study Group Consensus (2004), or Dyspepsia Working Grp (2005)1-3

ESOMP 20 mg

BID2,3

or ESOMP 40 mg

once daily1

CLAR 500 mg

BID

AMOX 1 gm

BID

14 days1

U.S.

7 or 10

days3

Canada

10-day regimen is FDA

approved.

FDA-approved Nexium

40 mg once daily dosing

rather than 20 mg BID.4

7-day regimen is TPD

approved.

This regimen is known

as Nexium

1-2-3 A in Canada.

10-day

regimen4

84% (PP)

77% (IT)

7-day

regimen5

86% (PP)

89% (IT)

Yes

Yes

ESOMP 20 mg

BID2,3

or ESOMP 40 mg

once daily1

CLAR 500 mg

BID

MET 500 mg

BID

14 days1

U.S.

7 or 10

days3

Canada

-- No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


LANS 30 mg

BID1-3

CLAR 500 mg

BID

AMOX 1 gm

BID

14 days

U.S.

7 or 10

days

Canada

Both 10-day and 14-day

regimens are FDA

approved.6,7

7-day, 10-day, and 14-

day regimens are TPD

approved.8

Available as Prevpac in

U.S. and Hp-Pac in

Canada.

7-day

regimen

90% (PP)

85% (IT)

10-day

regimen6-8

84% (PP)

81% (IT)

14-day

regimen6,7

85-92%

(PP)

82-86%

(IT)

Yes

Yes

LANS 30 mg

BID1-3

CLAR 500 mg

BID

MET 500 mg

BID

14 days

U.S.

7 or 10

days

Canada

≥90%

(PP)1

≥80%

(IT)1

No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


OMP 20 mg

BID1-3

CLAR 500 mg

BID

AMOX 1 gm

BID

14 days

U.S.

7 or 10

days

Canada


approved.9


approved.10

Also known as Losec 1-

2-3 A in Canada.

Give additional 18 days

of OMP 20 mg daily for

ulcer healing and

symptom relief.9 Give

additional OMP 20 mg

daily for up to 3 wks for

active DU and OMP 20-

40 mg daily for up to 12

wks for active GU.10

10-day

regimen

77-90%

(PP)9

69-83%

(IT)9

7-day

regimen

95-98%

(PP)10

94%-96%

(IT)10

Yes Yes

OMP 20 mg

BID1-3

CLAR 250 mg or

500 mg BID

MET 500 mg

BID

14 days

U.S.

7 or 10

days

Canada

7-day regimen with

CLAR 250 mg BID is

TPD approved.10

Also known as Losec

1-2-3 M in Canada (with

CLAR 250 mg).

91–94%

(PP)10

87-95%

(IT)10

(with

CLAR

250 mg

BID)

No Yes

PANT 40 mg

BID1-3

CLAR 500 mg

BID

AMOX 1 gm

BID

14 days

U.S.

7 or 10

days

Canada


approved.11

86%-93%

(IT)11

No Yes




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


PANT 40 mg

BID1-3

CLAR 500 mg

BID

MET 500 mg

BID

14 days

U.S.

7 or 10

days

Canada


approved.11

83%-96%

(IT)11

No Yes

RAB 20 mg

BID1-3

CLAR 500 mg

BID

AMOX 1 gm

BID

14 days

U.S.

7 or 10

days

Canada


and TPD approved.12,13

7-day regimen is not

recommended per 2007

U.S. H. pylori treatment

guidelines due to lower

eradication rates

compared to 10- and 14-

day treatment regimens.1

7-day

regimen

84%

(PP)12

77%

(IT)12

10-day

regimen

86%

(PP)12

78%

(IT)12

Yes

Yes

RAB 20 mg

BID1-3

CLAR 500 mg

BID

MET 500 mg

BID

14 days

U.S.

7 or 10

days

Canada

-- No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


ESOMP 20 mg

BID or ESOMP

40 mg once daily

or LANS 30 mg

or OMP 20 mg or

PANT 40 mg or

RAB 20 mg BID1

TCN 500 mg

QID

MET 250 mg

QID

BSS 525 mg

QID

10 or 14

days1

BSS/MET/TCN

combination is available

in U.S. as Helidac.14

Experts recommend total

daily dose of MET to be

at least 1500 mg/day for

better efficacy and to

overcome MET

resistance.15

Consider

additional MET 250 mg

TID with meals when

using Helidac.

Considered a first-line

therapy per 2007 U.S.

H. pylori treatment

guidelines.1

-- No

No

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg BID3

TCN 500 mg

QID

MET 250 mg to

500 mg QID

BSS 525 mg

QID

10 or 14

days

Considered the

preferred therapy for

H. pylori treatment

failures per 2005

Canadian dyspepsia

treatment guidelines.3

--- No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


Ranitidine

150 mg BID or

standard dose

H2-blockers

(Famotidine

40 mg/day, or

Nizatidine

300 mg/day

[given as single

or divided

doses]).1

MET 250 mg

QID

TCN 500 mg

QID

BSS 525 mg

QID

10 or 14

days

BSS/MET/TCN combo

is available in U.S. as

Helidac.14





overcome MET

resistance.15

Consider

additional MET 250 mg

TID with meals when

using Helidac.

Ranitidine-based

regimen is considered a

first-line therapy per

2007 U.S. H. pylori

guidelines, but not listed

as an option in the

Canadian guidelines.1

Give BSS, antibiotics

and H2-blocker together

for 14 days. Then give

H2-blocker alone for an

additional 14 days. H2-

blocker may be given

QD at bedtime or in two

equally divided doses

BID. Avoid cimetidine

to reduce risk of drug-

drug interactions.14

71%

(PP)14

72%

(IT)14

Yes No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)


ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg BID2

MET 375 mg or

500 mg QID

TCN 375 or

500 mg QID

BSS 525 mg

QID

10 or 14

days2

Considered a first-line

therapy per 2004

Canadian Helicobacter

Study Group.2

>80%

(IT)2

No No

Other Oral Regimens

RAB 20 mg

BID16

(Days 1-10)

May use PPIs

other than

RAB.15

AMOX 1 gm

BID

(Days 1-5)

Followed by: CLAR 500 mg

BID

(Days 6-10)

TIN 500 mg

BID

(Days 6-10)

10 days Sequential therapy for

total of 10 days. Start

with RAB + AMOX for

5 days followed by RAB

+ CLAR + TIN for

another 5 days.16

Recommended as a

first-line therapy for H.

pylori infected patients

with DU or GU per

Sanford Guide to

Antimicrobial Therapy

web edition.16

Experts now consider

sequential therapy an

acceptable first-line

therapy in those who

have not been exposed

clarithromycin or

metronidazole

recently.15,19,20

92%

(PP)17

90%

(IT)16

(in

European

population)

No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Other Oral Regimens

AMOX 1 gm

BID (Days 1-5)

LAN 30 mg BID

(Days 1-10)18

CLAR 1 gm

Daily (Days 6-

10)

MET 500 mg

BID (Days 6-10)

10 days18

CLAR and MET

combination should not

be routinely

recommended as there

are no effective salvage

therapies if such

combination failed.1

95%18

(not

specified

PP or IT) (in Asian

population)

No No

OMP 20 mg

BID16

TCN 500 mg

QID

MET 250 mg

QID

BSS 525 mg

QID

14 days16

Considered an

alternative to sequential

therapy for H. pylori

infected patients with

DU or GU per Sanford

Guide to Antimicrobial

Therapy Web Edition.16

Experts now consider

sequential therapy an

acceptable first-line

therapy in those who

have not been exposed

to clarithromycin or

metronidazole

recently.15,19,20

90-99%17

(not

specified

PP or IT)

No No

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg BID

TCN 500 mg

QID

MET 500 mg

TID or

MET 400 mg

QID or

TIN 500 mg

TID

BSS 525 mg

QID

10 or 14

days15,19,

20





overcome MET

resistance.15

MET taken TID with

meals may cause

confusion while other

drugs are taken QID.

-- No No




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Other Oral Regimens OMP 20 mg BID AMOX 1 gm

BID

DOX 100 mg

BID

BIS 420 mg

BID

7 days Efficacy needs to be

validated in North

American population.28

92%

(PP)

91%

(IT)

No No

OMP 20 mg

BID21

BIS 140 mg MET 125 mg TCN 125 mg (Pylera)

3 capsules QID

10 days Each Pylera capsule

contains BIS 140 mg,

MET 125 mg, and TCN

125 mg.

93%

(PP)21

88%

(IT)21

Yes Yes (as

Helizide in

2003,

reapproved

as Pylera in

2011, but

not

marketed)

OMP 40 mg once

daily9

CLAR 500 mg

TID

14 days Give CLAR and OMP

together for 14 days.

Then give only OMP

20 mg daily for an

additional 14 days for

ulcer healing and

symptom relief.22

Regimens containing

clarithromycin as a

single antimicrobial

agent are more likely to

develop clarithromycin

resistance among

patients who fail

treatment.22

64-74%

(PP)22

55-60%

(IT)23

Yes Yes




PPI or

H2-Blockera,f,g


Compound

Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Other Oral Regimens

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg

BID21

RIF 150 mg BID AMOX 1 gm

BID

10 or 14

days

Reserve rifabutin based

therapy as salvage

therapy for patients who

have failed two different

first-line therapies.1

70-85%

(IT)24

No No

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg BID1

LEV 500 mg

once daily

AMOX 1 gm

BID

10 or 14

days15

May be considered as

salvage therapy for

patients with persistent

H. pylori who have

failed other treatment

regimens.1

The 2007 U.S. guideline

states that such regimen

requires efficacy

validation in the North

American population

before it can be accepted

as first-line therapy.1

10-day

regimen1

63-94%

(not

specified

PP or IT)1

No No

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg

BID19

LEV 500 mg

once daily

AMOX 500 mg

QID

BSS 525 mg

QID

10 days Efficacy of levofloxacin-

based quadruple therapy

needs to be validated.19

-- No No




PPI or

H2-Blockera,f,g

Antibiotic 1 Antibiotic 2 Antibiotic 3 Duration1-3


FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Other Oral Regimens

OMP 20 mg BID

or LANS 30 mg

BID25

CLAR 250 mg

BID

MET 400 mg

BID

AMOX 1gm

BID

5 days The efficacy of this

concomitant therapy for

5-day duration needs

further validation.25

90-96%

(PP)25

88-91%

(IT)25

No No

ESOMP 40 mg

BID26

CLAR 500 mg

BID

MET 500 mg

BID or

TIN 500 mg

BID

AMOX 1 gm

BID

10 days26

The efficacy of this four-

drug concomitant

therapy given for 10

days appears to be

equivalent to sequential

therapy of same four

drugs given in sequential

manner.26

10-day

regimen26

93% (PP

and IT)

(ESOMP

40 mg

BID)26

No No




PPI or H2 -

Blockera,f,g

Antibiotic 1 Antibiotic 2 Antibiotic 3 Duration Comments Efficacyb,c

FDA-

Approvedd

(U.S.)

TPD-

Approvede

(Canada)

Other Oral Regimens

AMOX 1 gm

BID (Days 1-7)

ESOMP 20 mg

BID or

LANS 30 mg

BID or

OMP 20 mg BID

or PANT 40 mg

BID or

RAB 20 mg

BID15

(Days 1-14)

AMOX 1 gm

BID (Days 8-14)

CLAR 500 mg

BID

(Days 8-14)

MET 500 mg

BID or

TIN 500 mg

BID

(Days 8-14)

14 days

Although there are

limited data, experts

now consider such

hybrid of concomitant

and sequential therapy

as acceptable for those

who have not been

exposed to

clarithromycin or

metronidazole

recently.15,19,20

99%

(PP)15

97%

(IT)15

No No

LANS 30 mg

TID6

AMOX 1 gm

TID

14 days Use only in

clarithromycin

allergy/intolerance or in

known/suspected

clarithromycin

resistance.6

77%

(PP)6

70%

(IT)6

Yes No

OME 40 mg or

LAN 30 mg QID

AMOX 500 mg

QID

14 days Considered a salvage

therapy. High dose PPI

can maintain intragastric

pH above 6, where H.

pylori is susceptible to

amoxicillin.20

Efficacy of this high

dose dual therapy needs

to be validated.20

-- No No

OME 40 mg once

daily

LEV 250 mg

once daily

NIT 500 mg

BID

DOX 100 mg

once daily

7 or 10

days

Efficacy of this regimen

needs to be validated.27

89% (IT)27

No No

a. The U.S. and Canadian guidelines were published prior to the approval of dexlansoprazole (Dexilant). There are limited data on the use of

dexlansoprazole for the treatment of H. pylori infection.29

However, it is the general consensus that PPIs are interchangeable (at equipotent




dose) for H. pylori regimens. Dexlansoprazole is not approved by the FDA or TPD for the treatment of H. pylori infection. To help with PPI

dose comparisons, see our PL Chart, Proton Pump Inhibitor Dose Comparison (U.S. subscribers #250801; Canadian subscribers #250820).

b. Efficacy reported as cure rate (eradication rate) by intention-to-treat (IT) analysis or by per protocol (PP) analysis. IT means that outcomes

were analyzed for all patients, based on the treatment to which they were randomized, regardless of whether they dropped out. PP means that

outcomes were analyzed for all patients who completed the study and complied with protocol. Based on the American College of

Gastroenterology and Canadian Helicobacter Study Group Consensus criteria, the range for the 95% confidence interval should remain above

80% (IT) and above 90% (PP) for an effective regimen.1,2

c. H. pylori resistance to clarithromycin is on the rise. Recent data suggest that cure rates for first-line triple therapy (PPI + CLAR + AMOX [or

MET]) fall below 80%.20

d. Treatment regimen is approved by the FDA.

e. Treatment regimen is approved by the Therapeutic Products Directorate (Health Canada).

f. For guideline recommendations, efficacy of all PPIs (excluding dexlansoprazole; see footnote “a”) appear comparable.1,3

For regimens with

only one PPI listed, the listed regimen is the specific regimen studied or listed in product labeling.

g. The 2007 U.S. guidelines provide specific dosing for PPIs.1 The Canadian guidelines do not provide specific PPI dosing,

2,3 but the 2005

Canadian guidelines state that all PPIs (excluding dexlansoprazole; see footnote “a”), dosed twice daily have similar efficacy in curing H.

pylori.3

Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making

clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national

organizations. Information and Internet links in this article were current as of the date of publication.

(Detail-Document #280201: Page 14 of 15)



Project Leader in preparation of this PL Detail-Document: Wan-Chih Tom, Pharm.D.

References 1. Chey WD, Wong BC; Practice Parameters

Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808-25.

2. Hunt R, Fallone C, Veldhuyzan van Zanten S, et al. Canadian Helicobacter Study Group consensus conference: update on the management of Helicobacter pylori—an evidence-based evaluation of six topics relevant to clinical outcomes in patients evaluated for H. pylori infection. Can J Gastroenterol 2004;18:547-54.

3. Veldhuyzen van Zanten SJ, Bradette M, Chiba N, et al. Evidence-based recommendations for short- and long-term management of uninvestigated dyspepsia in primary care: an update of the Canadian Dyspepsia Working Group (CanDys) clinical management tool. Can J Gastroenterol 2005;19:285-303.

4. Product information for Nexium. AstraZeneca. Wilmington, DE 19850. December 2011.

5. Product monograph for Nexium. AstraZeneca Canada Inc. Mississauga, ON L4Y 1M4. November 2011.

6. Product information for Prevacid. Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. October 2011.

7. Product information for Prevpac. Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015. October 2009.

8. Product monograph for Prevacid. Abbott Laboratories Canada. St. Laurent, QC H4S 1Z1. November 2010.

9. Product information for Prilosec. AstraZeneca LP. Wilmington, DE 19850. June 2011.

10. Product monograph for Losec Capsules. AstraZeneca Canada Inc. Mississauga, ON L4Y 1M4. November 2011.

11. Product monograph for Pantoloc. Nycomed Canada, Inc. Oakville, ON L6M 4X8. September 2010.

12. Product information for Aciphex. Eisai Inc. Teaneck, NJ 07666. May 2011.

13. eCPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2012. Pariet monograph [Dec 2010]. http://www.e-therapeutics.ca. (Accessed January 24, 2012).

14. Product information for Helidac. Prometheus Laboratories Inc. San Diego, CA 92121. November 2009.

15. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011;8:79-88.

16. Chambers, HF, Eliopoulos GM, Gilber DN, et al. The Sanford Guide to Antimicrobial Therapy. Web Edition. Sperryville, VA: Antimicrobial Therapy, Inc., 2012. http://webedition.sanfordguide.com/. (Accessed January 15, 2012).

17. Gilbert DN, Moellering RC Jr, Eliopoulos GM, Sande MA. The Sanford Guide to Antimicrobial Therapy. 37

th ed. Sperryville, VA: Antimicrobial Therapy, Inc.,

2007. 18. Sirimontaporn N, Thong-Ngam D, Tumwasorn S,

Mahachai V. Ten-day sequential therapy of Helicobacter pylori infection in Thailand. Am J Gastroenterol 2010;105:1071-5.

19. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol 2011;17:3971-5.

20. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010;59:1143-53.

21. Product information for Pylera. Axcan Pharma Inc. Birmingham, AL 35242. January 2011.

22. Product information for Biaxin. Abbott Laboratories. North Chicago, IL 60064. November 2011.

23. Product monograph for Biaxin. Abbott Laboratories, Limited. Saint-Laurent, QC H4S 1Z1. July 2011.

24. Calvet X. Helicobacter pylori infection: treatment options. Digestion 2006;73(Suppl 1):119-28.

25. Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” vs. triple therapy for Helicobacter pylori eradication. Helicobacter 2009;14:109-18.

26. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with four drugs is equally effective for eradication of H. pylori infection. Clin Gastroenterol Hepatol 2010;8:36-41.

27. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Am J Gastroenterol 2011;106:1970-5.

28. Cammarota G, Martino A, Pirozzi G, et al. High efficacy of 1-week doxycycline- and amoxicillin-based quadruple regimen in a culture-guided, third-line treatment approach for Helicobacter pylori infection. Aliment Pharmacol Ther 2004;19:789-95.

29. Zullo A, Severi C, Vannella L, et al. Role of gastritis pattern on Helicobacter pylori eradication. Intern Emerg Med. November 22, 2011. [Epub ahead of print.]

Cite this document as follows: PL Detail-Document, H. Pylori Treatment Regimens for Adults. Pharmacist’s

Letter/Prescriber’s Letter. February 2012.


Evidence and Recommendations You Can Trust…

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