Rational Drug Selection Tool For Formulary Management Biology Essay

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The main goals of developing a Drug Formulary are to develop and implement policies on drug selection, evaluation, procurement, use of safe drugs and to disseminate reliable drug information to optimize patient care through rational selection and use of drugs and at the same time to ensure quality drug use and cost effective prescribing among physicians (Savelli et al., 1996). Too long and confusing - rewrite, restructure

The rapidly rising cost of drug therapy is a concern to healthcare provider in developing countries such as Malaysia. At least RM 1,510 million was spent annually in the procurement of drugs alone for the public hospitals throughout Malaysia (MOH, 2008). The government is finding it hard to subsidize this large spending. The introduction of new drugs which frequently offer only marginal improvements over existing therapies but at substantially increased cost does contribute to the heavy spending on drugs (Kessler et al., 1994). One means of controlling the overall drug expenditure is through the development of drug formulary. Rational selection of drugs through a structured and stringent selection process will only allow medications which are listed to be prescribed. Reducing the number of drug entities of the same therapeutic class with only slight differences in terms of clinical effectiveness and adverse effect can further help in containing cost (WHO, 2003).

2.1 Therapeutic substitution

A study on preferential listing of a single drug within a drug class was done in the Canada Forces (CF) in 2003 to control drug procurement cost. An observational cohort study was performed using the database in the Canadian Forces Pharmacy and a total number of 4738 PPI users who receive more than 1 PPIs between 1 January 2004 - 31 December 2004 were evaluated to explain the usage pattern of PPIs. The study selected pantoprazole as the most preferred agent in the PPI class based on clinical evidence, availability of dosage forms and costs while removing esomeprazole, lansoprazole, omeprazole and rabeprazole from the CF Drug Benefit List. Studies showed that very marginal difference in efficacy exist between PPIs when prescribed at equivalent doses (Amidon et al., 2000; Gearson et al., 2000). About 87% (n=4112) were prescribed pantoprazole english while 13.2% (n=626) received other PPIs. The reasons for those prescribed with other PPI drugs other than pantoprazole were 'failure to respond', and side effects with pantoprazole. The CF Pharmacy spent Can$ 214,451.98 for the year from 2003 to 2004 for pantoprazole alone, taking over 50% of cost associated with the PPI class of Can$431,504.42 which includes PPI drugs other than pantoprazole and the stocking up of intravenous pantoprazole in standardized military medical kits for use during deployment (Ma et al., 2008). Therefore, cost savings with therapeutic substitution will only be achieved with stringent policies and full compliance from physicians.

2.2 Drug Formulary

The conventional way of developing a formulary system usually involve a process whereby the medical staff of an institution, working through a Formulary and Therapeutics Committee, manages and evaluates, and selects from the numerous available drug products that are considered most efficacious, safe, and cost effective. It is a mechanism to streamline procurement activities, minimize costs and optimize patient care (Savelli et al., 1996).

The MOH Drug Formulary is one example of drug formulary developed using the conventional method. The MOH Drug Review Panel which comprise of the Director General of Health Malaysia (chairman), the Deputy Director General of Health (Medical Services), the Director of Pharmaceutical Services, 8 Consultants in Public Service, 2 Pharmacists in Public Service and a Senior Pharmacist in Public Service (secretary) will review and update the drug listed in the formulary from time to time to ensure that a comprehensive, evidence-based and dynamic list of drugs is available for prevention and treatment of patients. The MOH Drug List Review Panel will meet two to three times per year to consider proposals received from the States/Institution Drug Committees. The panel is assisted by 17 Technical Drug Working Committees from various specialised disciplines (MOH Drug Formulary Manual, 2008). The existing formulary system employs a disadvantageously very time consuming and not so transparent procedure to complete an approval and/or disapproval application.

In order to make the existing process more objective and transparent, a flexible and rational tool that exclude emotional factors, advertising influence or even cost interest can be developed. This tool can also be able to be used for any evaluation that requires re-assessment with time or provides ease of updating to accommodate changes in the context in which selection decisions are being made. This tool will be of great help to the Formulary and Therapeutic Committee especially in decision process as it becomes clear on which criteria the decisions are based on.

2.3 Drug selection system

Many drugs selection tools such as the Pharmaceutical Product Drug Differential Evaluation (PPDEM), Comparative Utilization of Resource Evaluation Model (CURE), System of Objectified Judgement Analysis (SOJA) and Formulary Analysis have been developed and used for formulary purposes worldwide (Karr, 2000; Moore et al., 2002, Janknegt et al., 1997).

Drug selection methods should be able to aid in providing optimal drug therapy to all patients through the development of standard treatment guidelines, to objectively evaluate clinical data of new drugs proposed for use in hospitals, to prevent unnecessary duplication of drugs, to develop list of drugs accepted for procurement and use in the hospital, to recommend and approve additions and deletions from the formulary, to conduct ongoing drug use evaluation programs (Savelli et al., 1996).

PPDEM is an analytical tool to support evaluations on drug selection. PPDEM is usually used to distinguish selection criteria of drugs belonging to the same therapeutic class of drugs which were used to treat a particular prevalent disease (Karr, 1994; Rawlins, 1999).

CURE is a similar flexible model for drug evaluation and selection that can differentiate drugs within the same therapeutic class which includes criteria such as efficacy, safety, side effects and cost. The advantage of CURE over PPDEM is the inclusion of an additional criterion called climate for change. Climate for change includes the experience factor of the prescriber, hospital readiness to change to a new drug, patient acceptability of changing to new drugs when the current drugs works well on them, resource benefit where by changing to a new drugs with only marginal cost savings is gained and frequency of review especially when new drugs are launched at a fast pace, the susceptibility of the prescriber and patient to alter the prescribing practice. CURE model provides decision makers with an analytical tool to support evaluations on drug selection and also intended to stimulate discussion or debate by decision makers and may assist in providing a suitable mechanism for producing the decision itself. CURE model is auditable, flexible and accommodate changes.

A Formulary Analysis on angiotensin receptor blockers (ARBs) was done in the Sheffield Teaching Hospital Trust, England. Six ARBs which consist of candersartan, eprosartan, irbersartan, losartan, telmisartan and valsartan were reviewed and evaluated by a panel of cardiologists, a physician and a pharmacist. Nine selection criteria were developed as a comparison framework between these drugs. A relative weight was assigned to each criterion by the panel. Each ARB was systematically evaluated against each criterion and scores were calculated. Results obtained were presented and recognized by the hospital's P&T committee. Losartan was ranked the highest (707), followed by valsartan (611) and candersartan (610) (Moore et al., 2002).

Another structured approach to the selection of drugs for formulary inclusion was of System of Objectified Judgement Analysis (SOJA) which was first developed in The Netherlands for the evaluation of hypnotics, NSAIDs and ARBs. The criteria included in the method for hypnotics drugs selection were clinical efficacy (300 points), adverse effects (250 points), clinical documentation (150 points), cost (120 points), pharmacokinetic properties (80 points), toxicity (50 points), drug interactions (30 points) and the number of tablet strengths available (20 points).

A slight modification of the SOJA system was then developed which was tested on the selection of ACE Inhibitors (ACEIs) in Northern Ireland. ACEIs included in the study were captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinalapril and trandolapril. The relative weighting for each drug were assigned to each criterion for every drugs were determined by a panel of expert which consisted of a consultant cardiologists, a general practitioners, two pharmacists, a regional pharmaceutical procurement manager, a hospital pharmaceutical services manager and a health economist. The selection criteria for ACEI were based on evidence based pharmacotherapeutic evaluation for all the ACEIs, safety and cost impact. Relative weightings were then assigned to the criteria by the expert panel. The resultant scoring system containing the selection criteria as well as the weighting scores was validated by 103 key decision makers and secondary care consultants in Northern Ireland, the association of British Pharmaceutical Industry, the British General Manufacturing Association and the Parallel Pharmaceutical Distribution Industry. These prescribers were asked to comment on the allocation of the scores and to change the scores and give importance to the criteria by adding and removing criteria. The last step involved scoring of the individual ARBs by 33 expert panels (7 cardiologists, 6 nephrologists, 8 pharmacists 2 endocrinologists, 2 internal medicine consultants, 1 senior geriatrician and 7 decision makers) using published literature as well as from both proprietary and generic manufacturers within the class of ACEIs. Only 5 ACEIs i.e. trandolapril, lisinopril, ramipril, enalapril, fosinopril scored the highest and were included in the drug formulary. Modified SOJA allows drug selection within a drug class across a range of indications and confers clinical effectiveness primacy over cost (Alabbadi et al., 2006).

SOJA, modified SOJA, Formulary Analysis, PPDEM and CURE are scoring systems that can be used to evaluate and then re-evaluate drugs in the same therapeutic class whenever there is new update on the drugs (Karr, 1994; Rawlins, 1999; Janknegt et al., 1997). The summary of each tools were demonstrated in Tables 2.1, 2.2 and 2.3.

Table 2.1: Comparison between drug selection methods in terms of criteria

Drug Selection Method



Efficacy, safety, cost


Efficacy, safety, cost, climate for changes

Formulary Analysis

Efficacy, safety, cost


Documentation, efficacy, safety, cost

MOH Drug Formulary

Efficacy, safety, cost

Table 2.2: Comparison between drug selection methods in terms of evaluator

Drug Selection Method



Expert panel which consists of consultants and healthcare providers


Expert panel which consists of consultants and healthcare providers

Formulary Analysis

Expert panel which consists of consultants and healthcare providers


Expert panel which consists of consultants and healthcare providers

MOH Drug Formulary

Expert panel which consists of consultants and healthcare providers

Table 2.3: Comparison between drug selection methods in terms of weightage

Drug Selection Method



Arbitrary; Depend on the degree of importance in the evaluation process. The more important criteria will assigned a higher score.

Total score:100


Arbitrary; Depend on the degree of importance in the evaluation process. The more important criteria will assigned a higher score.

Total score: 100

Formulary Analysis

Arbitrary; Depend on the degree of importance in the evaluation process. The more important criteria will assigned a higher score.

Total score:1000


Arbitrary; Depend on the degree of importance in the evaluation process. The more important criteria will assigned a higher score.

Total score: 1000

MOH Drug Formulary

Highly dependent on panelists' experiences, evidence-based information

No score points.

Gastroesophageal reflux disease (GERD) any numbering

Gastroesophageal reflux disease (GERD) is the retrograde movements of gastric contents from the stomach into the esophagus which can cause inflame and damage to the linng of the esophagus. The regurgitate liquid usually contains acid and pepsin. GERD symptoms can vary from mild to severe; from typical symptoms include heartburn, belching, hypersalivation, and regurgitation without endoscopically demonstrated esophagitis, to severe esophageal mucosal damage such as peptic stricture and Barrett's metaplasia (Devault & Castell, 1999).

The normal function of lower esophagus sphincter (LES) is to produce contraction and closing of the passage from the esophagus into the stomach. This closing prevents reflux. When food is swallowed, the LES relaxes foe a few seconds to allow the food to pass from the esophagus into the stomach, and then contracts and closes again. Weak contraction of the LES and transient LES relaxation which caused abnormal relaxation of LES are dysfunction of the LES that cause reflux. Other factors that may contribute to GERD are hiatal hernias, pregnancy and obesity (Devault & Castell, 2005).

The goals of treatment for GERD include:

relieving symptoms

healing of esophagitis

preventing further symptoms and complications.

Prevention and recurrence of the disease

There are two grading scheme that has been used in endoscopic assessment in comparative clinical studies. The Savary-Miller grading scale was the most commonly applied while the Los Angeles (LA) scale is the most often used grading scale for reflux esophagitis. Table 2.4 and Table 2.5 are the classifications of the grading scheme for the Savary-Miller grading scale and the LA scale:

Table 2.4: The Savary - Miller classification of reflux esophagitis




Single erosion above gastro-esophageal mucosal junction


Multiple, non- circumferential erosions above gastro-esophageal mucosal junction


Circumferential erosions above mucosal junction


Chronic change with esophageal ulceration and associated stricture


Barett's esophagus with histologically confirmed intestinal differentiation with columnar epithelium

Table 2.5: The LA classification of reflux esophagitis




One or more mucosal break not longer than 5 mm, that does not extend between the tops of two mucosal folds


One or more mucosal break more than 5 mm long that does not extend between the tops of two mucosal folds


One or more mucosal break that is continuous between the tops of two or more mucosal folds but involves less than 75% of the circumference


One or more mucosal break which involves at least 75% of the circumference

(Source: ????????Lundell et al., 1999)

2.4 Clinical Practice Guidelines

As stated in the 2004 Asia-Pacific Consensus on the management of GERD, lifestyle modifications are commonly used as first line of therapy in patients presenting with GERD-related symptoms. They include weight loss, smoking cessation, avoidance of postprandial recumbency for a period of at least 3 h, elevation of the head of the bed, avoidance of tight-fitting garments, and avoidance of large heavy meals as well as food and drink that exacerbate GERD symptoms (e.g. spicy foods, fatty meals, peppermint, chocolate, onions, citrus juices, and carbonated beverages) (DeVault & Castell, 2005)

H2RAs and antacids are commonly used for episodic heartburn, primarily for postprandial heartburn. The onset of action of antacids on esophageal acid concentration is 30 min after dosing and inhibition persists for 1 h, an expectation that the PPI are unlikely to provide.65????? However, studies reported that meaningful heartburn relief can already be achieved 19 min after consumption.66 In contrast, H2RAs have been shown to provide symptom relief within 30 min of dosing that can last up to 12 h.67 There is some evidence to suggest that simultaneous consumption of both an H2RA and an antacid provides better control of esophageal acid exposure and heartburn symptoms, when compared to the clinical effect of each one of theseproducts alone (Robinson et al., 2001). There are indications of plagiarism - cut and paste, right ?

PPIs are the most efficacious medical intervention for GERD. Studies have shown repeatedly and consistently that PPIs are superior to histamine 2 receptor antagonists (H2RAs) in healing the esophageal mucosa and relieving GERD-related symptoms of patients with ERD (Caro et al., 2001). In a meta-analysis, the authors demonstrated that after 12 weeks of treatment, healing rates were 83.6% with PPIs, 51.9% with H2RAs, 39.2% with sucralfate, and 28.2%with placebo (Chiba et al., 1997). In addition, treatment with PPIs resulted in healing rates of esophageal inflammation and relief of heartburn symptoms that were two-fold higher than what was observed in patients receiving H2RAs. Similarly, PPIs demonstrate superiority in relieving heartburn symptoms in patients with NERD when compared to H2RAs (Richter et al., 2000).

According to NICE guidance for dyspepsia (2004), patients who are present with typical GERD symptoms should be started on full dose PPI for 4 - 8 weeks. If patients have severe esophagitis and remain symptomatic, double-dose PPI for a further 4 weeks may increase the healing rate. PPIs appear more effective than H2RAs in endoscopy-negative reflux disease. For recurring symptoms, a PPI at the lowest dose possible should be given to control symptoms, with a minimum number of repeat prescriptions. PPIs are more effective than H2RAs at maintaining against relapse of esophagitis in trials of 6-12 months duration (NICE, 2004).

American Gastroenterology Association (AGA) drew the same guidelines and it was adopted by the National Guidelines Clearinghouse on GERD that lifestyle modifications should be recommended throughout the treatment of GERD. This is followed by pharmacological treatment such as H2-receptor antagonists (H2RAs), proton pump inhibitors (PPIs), and prokinetics. For non-erosive reflux disease (NERD), Step-up (H2RAs followed by a PPI if no improvement) and step-down (PPI followed by the lowest dose of acid suppression) therapy are equally effective for both acute treatment and maintenance. On-demand (patient-directed) therapy is the most cost-effective strategy. For erosive esophagitis, initial PPI therapy is the treatment of choice for acute and maintenance therapy for patients with documented erosive esophagitis. Antireflux surgery is an alternative modality in the treatment of GERD in patients who have documented chronic reflux with recalcitrant symptoms (DeVault & Castell, 2005).

2.5 Pharmacology of PPIs

All PPIs are substituted benzimidazoles that suppress the final step in gastric acid secretion by binding to the proton pump (H+/K+-ATPase enzyme system) on the gastric parietal cell. The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. The active form will covalently and irreversibly bind to the gastric proton pump, deactivating it. Minor differences exist among PPIs with respect to the mechanism of action within the parietal cell (Vanderhoff & Tahboub, 2002). Rabeprazole forms a partially reversible bond with the proton pump (Vanderhoff & Tahboub, 2002). Pantoprazole preferentially binds avidly to an additional acid inhibiting cycteine residue located deep within the membrane which greatly impairs the reversibility of bindings and prolongs duration of action (Welage & Berardi, 2000). Once inhibition occurs, recovery can only occur with regeneration or resynthesis of new ATPase. Recovery is therefore generally a relatively slow process compared with the initial inactivation (Fock et al., 2008).

2.6 Pharmacokinetics of PPIs

Table 2.7 showed the pharmacokinetics of the five PPI drugs. The absolute bioavailability ranges from 35% for a single dose of omeprazole to 90% with repeat administration of esomeprazole. Unlike other PPIs, the bioavailability of rabeprazole remains unchanged with repeated dosing. On the whole, the time to reach the peak plasma concentration (tmax) is about 2 hours. After absorption into the circulation, PPIs are taken up preferentially by gastric parietal cells, especially when they are actively secreting acid. Once inhibition occurs, recovery can only occur with regeneration or resynthesis of new ATPase. These mechanisms suggest that despite the short elimination half-lives, the biological effect persists for much longer (Fock et al., 2008).

All PPIs are extensively protein bound and undergo hepatic metabolism via the cytochrome (CYP) P450 pathways and the isoforms CYP2C19 and CYP3A4. Esomeprazole is the S-isomer of omeprazole, which is a racemic mixture of two optical isomers, the R- and S-isomers. However, esomeprazole and the omeprazole differ in the ratios in which they are metabolised by CYP2C19 and CYP3A4. Esomeprazole is metabolised to a greater extent by CYP3A4 than omeprazole and to a lesser extent by CYP2C19 (Abelo et al., 2000). CYP2C19 genotypes are classified into the three groups, i.e. extensive metabolisers (EMs), intermediate metabolisers (IMs) and poor metabolisers (PMs) (Lim et al., 2005). The metabolism of rabeprazole does not appear to be significantly affected by CYP2C19 where in one particular study on rabeprazole showed similar healing rates at 4 and 8 weeks were obtained in EMs, IMs and PMs (Ariizumi et al., 2004), whereas for omeprazole, lansoprazole and pantoprazole, a marked difference in metabolism exists between EMs and PMs (Ishizaki & Horai, 1999). At 4 weeks, the healing rates were 57.1%, 69.2% and 72.7% in EMs, IMs and PMs, respectively, while the healing rates at 8 weeks were 77.4%, 95.0% and 100%, respectively (Kawamura et al., 2003). These differences in polymorphisms affect the metabolic and pharmacokinetic profiles of PPIs and may influence the therapeutic effectiveness. Esomeprazole has a lower total intrinsic clearance than omeprazole, and its first-pass metabolism is decreased compared with omeprazole. The advantageous metabolism of esomeprazole results in higher area under the plasma concentration-time curve (AUC) values than those for omeprazole at the same dose, and hence may achieve better acid suppression than omeprazole in clinical practice (Fock et al., 2008).

Rabeprazole, lansoprazole and pantoprazole have similar bioavailability on days 1 and 5. The bioavailability of omeprazole increases 1.5 to 2 fold at day 5, while that of esomeprazole increases 3 fold at day 5 (Hellstrom & Vitols, 2004).

The currently available PPIs have short elimination half-lives ranging from 1 to 1.5 hours. A PPI with a longer elimination half-life may produce more prolonged blockade of proton pumps with the potential for greater acid suppression and, hence, a greater clinical effect, particularly for patients with significant postprandial evening and/or nocturnal symptoms (Fock et al, 2008)

Table 2.6: Pharmacokinetics of PPIs













Time to peak plasma concentration

1.5 hours

1.7 hours

0.5-3.5 hours

2.5 hours

2-5 hours

Half-life (plasma)

1.2-1.5 hours

1.5 hours

0.5-1 hour

1 hour

1-2 hours

Major cytochrome P450 pathway








Protein binding






2.7 Clinical Efficacy of PPI drugs

All double blind randomized studies that were published comparing two or more PPIs or doses for the treatment of acute gastroesophageal disease (GERD) were obtained. The prospective evaluations of measurable clinical efficacy such as healing of esophagitis or symptoms resolution were summarized in Appendix A.

In one study comparing esomeprazole 40 mg, esomeprazole 20 mg and omeprazole 20 mg once daily, pH>4 was maintained for 16.8 hours, 12.7 hours and 10.5 hours respectively (Lind et al., 2000). In another study involving 2425 patients with erosive esophagitis, esomeprazole 40 mg and omeprazole 20mg were compared at 4 and 8 weeks. At 4 weeks, 93.7% on those on esomeprazole and 84.3% of those on omeprazole were healed (Richter et al., 2001). One study with 1960 patients with erosive esophagitis, it was found that esomeprazole 40 mg, esomeprazole 20 mg and omeprazole 20 mg have healing rates of 94.1%, 89.9% and 86.9% respectively (Kahrilas et al., 2000). These studies were often cited as evidence of the superiority of esomeprazole in esophageal healing, but it should be noted that the dose is not comparable. A meta-analysis concluded that esomeprazole healed erosive esophagitis at significant higher rates than omeprazole (Edward et al., 2001). However, all the studies were funded by AstraZeneca and two out of the three authors are employed by AstraZeneca.

In the only study that use comparable dosages of esomepazole and omeprazole at 40 mg respectively, those taking esomeprazole maintained a gastric pH > 4 for a mean of 16.4 hours while those taking omeprazole maintained for 14.9 hours. However, its small sample size of 114 patients limits its validity (Rohss et al., 2002).

In another study, esomeprazole 40 mg were more effective than lansoprazole 30 mg for healing of esophagitis (Castell et al., 2002). In a randomized double blind study, more patients were healed following 8 weeks of treatment with esomeprazole 40 mg compared to pantoprazole 40 mg (Labenz et al., 2005). All the above studies showed a superior efficacy towards esomeprazole 40 mg because all studies used higher dose of esomeprazole for comparison, where the standard dose of esomeprazole that should be used was esomeprazole 20 mg. All the studies were not of true comparisons.

When comparing lansoprazole 30 mg with omeprazole 20 mg, there is no significant difference in healing rates at 4 weeks (RR 1.02; 95%CI: 0.97, 1.08) and 8 weeks (RR 1.01; 95%CI: 0.97, 1.06) (Hatlebakk et al., 1999; Castell et al., 1996; Mee & Rowley,1996). There is no significant difference with pantoprazole 40 mg (Corinaldesi et al., 1995; Mossner et al., 1995) or rabeprazole 20 mg when compared with omeprazole 20 mg (Dekkers et al., 1999).

Vakil and Fennerty reviewed 32 studies and stated that there are insufficient data to establish superiority of any one agent. The meta-analysis concluded that all PPIs have similar potency and the same inherent capacity to inhibit acid secretion.

A Cochrane Collaboration review concluded that there was no statistically significant difference in healing of reflux esophagitis of the different PPI medications when given in equivalent dosage (Khan et al., 2007). The American College of Gatroenterology has stated in their practice guidelines that all omeprazole, pantoprazole, rabeprazole, lansoprazole and esomeprazole have been demonstrated to control GERD symptoms and to heal esophagitis when used at prescription dosages (DeVault & Castell, 2005)

Add another paragraph to end this literature review. How can you conclude your literature review section? What information can you gather from this chapter? Any gap of information that make you conduct this study? Any information is lacking which you intend to fine out?