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Assessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia

2006; King Faisal Specialist Hospital and Research Centre; Volume: 26; Issue: 3 Linguagem: Inglês

10.5144/0256-4947.2006.192

0975-4466

Nicole Gebran, Khaled Al Haidari,

Pharmaceutical studies and practices

Original ArticleAssessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia Nicole Gebran and Khaled Al Haidari Nicole Gebran and Khaled Al Haidari Published Online:1 Jun 2006https://doi.org/10.5144/0256-4947.2006.192SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractBACKGROUND: Little research has assessed the quality of manufacturer-provided prescribing information or documented differences in key aspects of drug information among different marketed generic products of the same drug, particularly in the Middle East and Arabian Gulf. We assessed the quality of written prescribing information for selected generic drugs marketed in Saudi Arabia and manufactured in various countries of the Middle East.METHODS: We assessed the correctness and completeness of information pertaining to indications, dosage, cautions/contraindications, side effects and drug interactions in 37 package inserts for generic products registered in Saudi Arabia and manufactured in the Middle East, including atenolol (6 inserts), fluoxetine (4 inserts), ciprofloxacin (11 inserts), metformin (7 inserts), and omeprazole (9 inserts). We also described deficiencies in the quality and quantity of manufacturer-provided information that could be misleading to patients and prescribers.RESULTS: We found substantial disagreement in information between generic package inserts versus the British National Formulary and the package insert of the brand product marketed in Saudi Arabia. A cumulative average of 63±16% of drug information indicators were in agreement with these standard references. Section headings with the least conformity with study references were those related to dosage (57± 28%) and side effects (54±30%).CONCLUSION: Our results indicate that national authorities should implement appropriate measures aimed at removing misleading and incorrect information in generic package inserts and incorporating crucial prescribing information that is missing. National authorities in the Middle East and Arabian Gulf should strengthen collaboration and information interchange among each other and with international agencies to maintain common quality standards for delivering information through package inserts.IntroductionStudies have shown that including an information leaflet in the drug package may help bridge the information gap between healthcare professionals and patients and improve patient knowledge about drugs.1–4 Pharmacists and physicians also consider these inserts as handy references for drug information, especially when standard information resources are not accessible.5 There is published data addressing drug information in general6–9 and the readability of patient information provided in package inserts.2,10– 11 Very little research, however, especially in the Middle East and Arabian Gulf, has addressed the issue of documenting differences in key aspects of drug information among different marketed generic products of the same drug. In addition, little research has assessed the quality of manufacturer-provided prescribing information. Over 5500 pharmaceutical products are registered in the Kingdom of Saudi Arabia.12 The Regulation of Registration Act, last amended in 1989, sets requirements for manufacturer package inserts of pharmaceutical products registered in the Kingdom.13This report describes the methods and findings of an observational study that assessed the quality of written prescribing information for selected generic drugs that are marketed in Saudi Arabia and manufactured in various countries of the Middle East. The primary objective of this study was to assess the correctness and completeness of information pertaining to indications, dosage, cautions/contraindications, side effects and drug interactions presented in package inserts as compared to a world-renowned reference in drug information. Secondary objectives included pointing out the deficiencies in the quality and quantity of manufacturer-provided information that could be misleading to patients, patient caregivers and prescribers, as well as providing recommendations based on study observations to key regulatory agencies in Saudi Arabia.MethodsFive drugs were selected for the study from among those meeting the following criteria: 1) the drug is widely used and well known, 2) has several indications, 3) has at least 4 generics registered in Saudi Arabia that are manufactured in the Middle East, 4) ranked in the top 30 drugs in terms of global sales in 2004 and 5) covered therapeutic areas of high worldwide relevance in terms of mortality and morbidity.14 The selected drugs were atenolol, fluoxetine, ciprofloxacin, metformin and omeprazole.Written information material, approved by the Saudi Ministry of Health and by the respective regulatory authorities of the countries of manufacture, were collected from pharmacies in Saudi Arabia in May 2005 for the different generics. Written materials were obtained in the form of package inserts prepared by the company holding the marketing authorization.A total of 37 package inserts for generic products registered in Saudi Arabia and manufactured in the Middle East for atenolol (6 inserts), fluoxetine (4 inserts), ciprofloxacin(11 inserts), metformin(7 inserts), and omeprazole(9 inserts) were collected. Information contained under the following section headings: indications, dosage, cautions/contraindications, side effects, and drug interactions, was compared to that presented in the British National Formulary (BNF 49, March 2005) and the package insert of the brand product marketed in Saudi Arabia. The BNF was used as a reference as it has a worldwide reputation for being complete, independent, reliable, and practice-oriented as a source of drug information. Though not contemporary to the package inserts' publication dates, which ranged between 1996 and 2003, this recent BNF edition served the purpose of identifying requirements for updating prescribing information of products currently on the market. We developed a checklist for each drug, each of which had a varying number of drug information indicators: atenolol (55 indicators) ciprofloxacin (88 indicators), fluoxetine (63 indicators), metformin (32 indicators), and omeprazole (54 indicators) (Table 1). The drug information indicators, detailed in Table 2, were selected based on the presence of the information statements in both the BNF and brand product label. For the side effects section heading, only those side effects that were frequent and severe were included. To be considered frequent, side effects had to be reported as appearing in at least 1% of patients, according to the American Hospital Formulary Service 2005.15 To be considered severe, side effects had to fit the criteria published by the WHO Collaborating Center for International Drug Monitoring, Uppsala, Sweden.16 Caution and contraindications section headings were combined under one entity in the statistical analysis. Statements found in the collected materials that were not documented in the BNF or brand package insert were disregarded from a statistical perspective, but incorrect statements are pointed out in the results and discussion sections. The statistical analysis was done in terms of frequencies.Table 2 Detailed drug information indicators for five studied drugs based on statements in the British National Formulary (BNF) and brand package inserts.Atenolol (55 indicators)Indications and DosageHypertension: 50 to 100 mg dailyAngina pectoris: 100 mg daily or divided twice dailyArrhythmia: 50 to 100 mg dailyEarly intervention within 12 hours of myocardial infarction: intravenous over 5 minutes, 5 mg, then oral, 50 mg after 15 minutes, 50 mg after 12 hours, then 100 mg dailyCautionsRenal impairment (moderate/severe): reduce dose; pregnancy: may cause intra-uterine growth restriction, neonatal hypoglycemia, and bradycardia; breast feeding: monitor infant, possible toxicity; stable/unstable heart failure/poor cardiac reserve; asthma; diabetes: modifies tachycardia of hypoglycemia; do not discontinue abruptly in patients with ischemic heart disease; risk of precipitating heart failure when beta-blockers and verapamil are used together in established ischemic heart disease; first-degree AV block; portal hypertension; history of obstructive airways disease; myasthenia gravis; history of hypersensitivity—may increase sensitivity to allergens; may reduce response to adrenaline; Prinzmetal's angina; masks signs of thyrotoxicosisContraindicationsUncontrolled heart failure; marked bradycardia; hypotension; sick sinus syndrome; second- or third- degree AV block; cardiogenic shock; metabolic acidosis; severe peripheral arterial disease; pheochromocytoma (apart from specific use with alpha-blockers)Side EffectsBradycardia; deterioration of heart failure; postural hypotension; conduction disorders; bronchospasm; peripheral vasoconstriction; gastrointestinal effects; fatigue; sleep disturbances; rashes/dry eyes; nightmares/psychosis/hallucinations; visual disturbances; exacerbation of psoriasisDrug InteractionsVerapamil; diltiazem; nifedipine; digoxin; sympathomimetics; disopyramide; NSAIDs; anesthetics; clonidineCiprofloxacin (88 indicators)Indications and Dosagerespiratory-tract infections: 250–750 mg twice dailyUrinary-tract infections: 250–500 mg twice daily (100 mg twice daily for 3 days in acute uncomplicated cystitis in women)Chronic prostatitis: 500 mg twice daily for 28 daysGonorrhea: 250mg or 500 mg as a single dosePseudomonal lower respiratory-tract infection in cystic fibrosis: 750 mg twice dailyChild 5–17 years: up to 20 mg/kg twice daily (max. 1.5 g daily)Surgical prophylaxis: 750 mg 60–90 minutes before procedureAnthrax (treatment and post-exposure prophylaxis): 500 mg twice daily; child 30 mg/kg daily in 2 divided doses (max. 1g daily)Gastro-intestinal system (including typhoid fever)Bone and joint infectionSkin infectionSepsisCautionsEpilepsy or conditions that predispose to seizures; G6PD deficiency; myasthenia gravis (risk of exacerbation); children or adolescents (arthropathy has developed in weight-bearing joints in young animals); tendon damage: tendon rupture may occur within 48 hours of starting treatment; elderly patients are more prone to tendinitis; the risk of tendon rupture is increased by the concomitant use of corticosteroids; if tendinitis is suspected discontinue immediately; exposure to excessive sunlight should be avoided (discontinue if photosensitivity occurs); avoid excessive alkalinity of urine and ensure adequate fluid intake (risk of crystalluria); renal impairment: moderate: half normal dose; pregnancy: avoid; breast-feeding: avoid—high concentrations in breast milk; discontinue if psychiatric, neurological or hypersensitivity reactions occur; may impair performance of skilled tasks (e.g. driving)ContraindicationsHistory of tendon disorders related to quinolones use; hypersensitivitySide EffectsDysphagia; tachycardia; edema; hot flushes; sweating; movement disorders; tinnitus; vasculitis; tenosynovitis; erythema nodosum; hemorrhagic bulla; hyperglycemia; gastrointestinal effects; antibiotic-associated colitis; Stevens-Johnson syndrome/toxic epidermal necrolysis; anorexia; increase in blood urea and creatinine; drowsiness; restlessness; asthenia; depression; hallucinations; photosensitivity; hypersensitivity reactions; blood disorders; disturbances in vision, taste, hearing and smell; angioedema; arthralgia/myalgia; tendon inflammation and damage; hemolytic anemia; renal failure; interstitial nephritis; hepatic dysfunctionDrug InteractionsAntacids; calcium salts; coumarins; dairy products; glibenclamide; iron; opioid analgesics; phenytoin; probenecid; sucralfate; theophylline; cyclosporine; NSAIDs; zolmitriptan; estrogens; didanosine; diazepam; metoclopramideFluoxetine (63 indicators)Indications and DosageDepressive illness: 20–60 mg daily; (max. 80 mg daily)Bulimia nervosa: 60 mg dailyObsessive compulsive disorder: 20–60 mg dailyPremenstrual dysphoric syndrome: 20 mg dailyChild and adolescent 80 mg divide twice daily)GERD Treatment: 20–40 mg daily × 4–8 weeksGERD maintenance: 20 mg dailyAcid reflux disease -Reflux esophagitis (long-term management): 10–20 mg dailyAcid-related dyspepsia: 10–20 mg daily × 2–4 weeksH. Pylori: 20 mg twice daily or 40 mg daily × 1–2 weeksChild >2 yearsSevere ulcerating reflux esophagitis: 0.7–1.4 mg/kg daily × 4–12 weeks (max: 40 mg daily)CautionsLiver disease: not more than 20 mg daily should be needed; pregnancy: toxicity in animal studies; lactation: avoid—no information available; may mask the symptoms of gastric cancer; presence of 'alarm features' (dyspepsia/bleeding/dysphagia/recurrent vomiting/weight loss); rule out gastric malignancy before treatmentSide EffectsParesthesia; vertigo; alopecia; gynecomastia; stomatitis; encephalopathy in severe liver disease; hyponatremia; reversible confusion; agitation; hallucinations in the severely ill; increase the risk of gastro-intestinal infections; myalgia/arthralgia; skin reactions; gastro-intestinal disturbance; headache; dizziness; hematological: leucopenia/thrombocytopenia/agranulocytosisDrug InteractionsKetoconazole; diazepam; warfarin; phenytoinResultsResults are expressed in terms of the percentage of correct indicators present in the package inserts compared to the number of indicators that should be present as per the BNF and brand product label (Table 3). The results indicate substantial disagreement in information between generic package inserts and the comparator references. A cumulative average of 63±16% of drug information indicators were found to be correctly stated in package inserts of the study generics. Section headings with the least conformity with BNF data were those related to dosage (57±28%) and side effects (54±30%). An average of 70±22%, 70±20% and 63±30% of drug information indicators pertaining to indications, cautions/contraindications and drug interactions, respectively, were correctly documented in the package inserts of study generics.Table 3 Correctness and completion of information in generic package inserts vs. indicators based on the BNF and brand product label.1Generic formulationsIndications (%)Dosage (%)Cautions (%)Side Effects (%)Drug Interactions (%)Mean (%)±SDCompanyAtenolol Canar100257277857228Tabuk Glormin10010080661008916Global Pharma Hypoten50257938565020Hikma Normoten100505046335626Al Jazeera Tenol1001005885898617Saudi-Kuwait Tensotin7575888589827JulpharCiprofloxacin Ciflox91678297838411Saudi-Kuwait Ciprocin64224723393918EPICO Ciprodar5533354244429Dar Al Dawa Ciproflacin64224723283718Ram Pharma Ciproflox64444142224315Al Arabia Ciprogen91895387567519Riyadh Pharma Cipromax73333594285329Spimaco Ciproxen55223513393316Jamjoom Floxacin73336535615318SAJA Quinox64442935564614Tabuk Sarf8278828772806JulpharFluoxetine Evrex100857537456827Al Jazira Flozak100718844737521Riyadh Pharma Flutin75286996827026Julphar Linz75716937646315TabukMetformin Dialon67509080927617Julphar Diaphage675080100757418UPM Formit6750808085730Spimaco Glucare331007680426628Al Jazira Metaphage331006040335328Saudi-Kuwait Metfor33507020424319Tabuk Riyadhformin10010010060257734Riyadh PharmaOmeprazole Aciloc697167871007914Jamjoom Gastrozole626483331006825Riyadh Pharma Hyposec30368371005139Ram Pharma Omedar382183401005633Dar Al Dawa Omeprex462983131005436SAJA Omeral9293100331008429Al Jazeera Omiz54146740755024Tabuk Oprazole7779100705346Hikma Rizek8586100100100948JulpharMean705770546363SD(+/−)222820303016SD= standard deviation.1Results calculated as % (observed number of correct indicators/actual number of indicators in Table 1)Particular deficiencies were noted in information related to doses in pediatrics and required dosage adjustments in patients with renal/liver impairment. Only two ciprofloxacin generics indicated the possibility of its use in children with cystic fibrosis and included the respective dosing. There was also inaccurate information pertaining to the dose range of fluoxetine in depression; in general, doses were not indication-specific (e.g., doses for bulimia and depression). Moreover, an incorrect maximum dose was indicated in one of the ciprofloxacin generics.There were deficiencies in the indications section related to both the quantity and quality of written information. Out of 11 ciprofloxacin generics, only one stated anthrax infection as an indication. Only one metformin generic indicated the possibility of its use in combination with insulin. None of the omeprazole generics indicated use and dosage of the drug in severe ulcerating reflux esophagitis in pediatric patients. Certain generics contained indications that were not approved; these included hyperkinetic heart syndrome with atenolol and treatment of atypical mycobacterium with ciprofloxacin.As for the cautions and contraindications section headings, certain cautions were stated under contraindications, and vice versa. This was observed in the ciprofloxacin package insert, where use in patients less than 18 years old was stated as a contraindication rather than a precaution. This may relate to the lack of updating of the prescribing information, which has been modified in recent years to utilize this drug in certain specific pediatric disease states (e.g. cystic fibrosis, anthrax infection) where benefits outweigh the risks of treatment. Moreover, recent safety data with regard to the risk of suicidal behaviour with fluoxetine was documented in only one of the reviewed package inserts. A serious drug interaction, metformin with contrast media, was not included in either the cautions or the drug interactions section of one of the metformin generics.Of the package inserts reviewed in the study, only 60% indicated a publication date.DiscussionAn international comparative study analysed the variability in 78 written drug information materials in 26 different countries for three drugs.17 The results showed substantial disagreement in the materials available to prescribers and patients in different countries. Disagreement was even found within a single country when written materials from different brands of the same drug were compared. The majority of the cases studied were related to products of the same mother company worldwide. That study suggested that there is an urgent need to increase information agreement between materials on drugs at the national level by measures such as requiring that prescribing information for all pharmaceutical equivalents be the same as that approved for a reference drug. A study conducted in Saudi Arabia in 1991 compared package inserts of 10 non-steroidal anti-inflammatory drugs marketed in Saudi Arabia by different companies with the US PDR reference. The comparison was based on the number of words, presence/absence of section headings, and other differences between the information in the package insert and the PDR as well as the Ministry of Health package insert requirements as required by the Registration Act in Saudi Arabia. The study showed variation in both the amount and type of information contained in Saudi-marketed products as compared with the US PDR. Moreover, section headings on possible adverse reactions or drug-drug interactions and the date of revision of the package insert were not mentioned in any of the Saudi-manufactured products.5 Bjerrum et al18 examined sources of inconsistency and diverging information in product information leaflets of different brands of generically identical drugs marketed in Denmark. Diverging information about indications for drug use, adverse effects, drug-drug interactions and precautions, as well as considerations concerning pregnancy and breastfeeding resulted in patient confusion, which may have lead to reduced compliance, as measured by the number of inquiries to pharmacies. The study concluded that initiatives should be taken to coordinate information in patient leaflets covering the same generic product.18Another study conducted in Japan evaluated drug information in package inserts and interview forms according to necessity and importance for 324 generic drugs. Generics were found to have 25.3±18.7% to 46.1±14.2% of the information in the product labeling of brand name drugs when products were compared for quantity of information by formulation. Comparison according to manufacturer returned a larger range of variation, 14.4±8.6% to 64.3±14.2%. These data revealed that manufacturer differences play a large role in the provision of drug information. Generic drugs were found to have insufficient information on clinical data, pharmacokinetics, safety, side effects and non-clinical tests.19Key observations in our study include the inaccuracy and incompleteness of the provided prescribing information in reviewed package inserts. The main reason is that information is outdated in many package inserts, especially for some that were initially published years ago (publication dates ranged between 1996 and 2003). This finding indicates the need to enforce requirements for regular updating of drug information in package inserts and to indicate the last revision date through an amendment of the Saudi Regulation of Registration Act to address these issues.The incorrectness and lack of scientific reliability of the prescribing information, such as inappropriate doses or indications, is misleading to prescribers and pharmacists who consider package inserts as alternative references, especially in developing countries. Incompleteness of safety information whether it be side effects or cautions/contraindications is not acceptable. From a patient safety standing, the information should be complete to avoid any misadventures.The correctness and completeness of information varied among manufacturers, with some being more consistent in presenting reliable information than others (Table 3). Accordingly, manufacturers should be notified of the need to improve the quality of their products' package inserts and upgrade the presentation of their data, and national authorities are urged to be proactive in this regard and implement standards.This study, with its small sample size given the number of generics that have flooded the Saudi Arabian market, identifies key findings that may only be the tip of the iceberg. Our results indicate that national authorities should implement appropriate measures aimed at removing misleading and incorrect information in package inserts, which should be the same among generics, as well as incorporating crucial prescribing information, which was found to be missing. Package inserts should be rendered a reliable reference to promote patient safety and assist healthcare providers. Moreover, national authorities in the Middle East and Arabian Gulf should strengthen collaboration and information interchange among each other and with international agencies, such as the World Health Organization, to maintain common quality standards for delivering information through package inserts of generic products.ARTICLE REFERENCES:1. Regner J, Hermann F, Ried D. "Effectiveness of a printed leaflet for enabling patients to use digoxin side-effect information" . Drug Intell Clin Pharm. 1987; 21:200-204. Google Scholar2. Gibbs S, Waters E, George F. "The benefits of prescription information leaflets (2)" . Br J Clin Pharmacol. 1989; 28:345-351. Google Scholar3. European Commission Pharmaceutical committee. A guideline on the readability of the label and package leaflet of medical products for human use. 1998;1-26. Google Scholar4. Mottram R, Reed C. "Comparative evaluation of patient information leaflets by pharmacists, doctors and the general public" . 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Bjerrum L, Foged A. "Patient information leaflets-helpful guidance or a source of confusion?" Pharmacoepid Drug Safety. 2003; 12:55-59. Google Scholar19. Iijama H, Kamei M, Koshimizu T, et al. "Objective Evaluation of Generic Drug Information" . Yakugaku Zasshi. 2004; 124(6):341-347. Google ScholarTablesTable 1 Number of drug information indicators for each of five selected drugs.DrugIndicationsDosageCautions/ContraindicationsSide EffectsDrug InteractionsTotalAtenolol442513955Ciprofloxacin11917331888Fluoxetine4714271163Metformin321051232Omeprazole1314617454 Previous article Next article FiguresReferencesRelatedDetails Volume 26, Issue 3May-June 2006 Metrics History Accepted1 April 2006Published online1 June 2006 InformationCopyright © 2006, Annals of Saudi MedicineThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.