==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 1686187310.5144/0256-4947.2006.192asm-3-192Original ArticleAssessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia Gebran Nicole Al Haidari Khaled From the Pharmacy Department, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi ArabiaCorrespondence and Reprint Requests: Nicole Gebran, PharmD, Pharmacy Department King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia, Tel: +966-1-442 7604, Fax: +966-1-442 7608, nicolegebran@yahoo.comMay-Jun 2006 26 3 192 199 01 4 2006 Copyright © 2006, Annals of Saudi Medicine2006This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND 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. ==== Body Studies 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.13 This 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. Methods Five 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. Results Results 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. 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. Discussion An 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.18 Another 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.19 Key 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. Table 1 Number of drug information indicators for each of five selected drugs. Drug Indications Dosage Cautions/Contraindications Side Effects Drug Interactions Total Atenolol 4 4 25 13 9 55 Ciprofloxacin 11 9 17 33 18 88 Fluoxetine 4 7 14 27 11 63 Metformin 3 2 10 5 12 32 Omeprazole 13 14 6 17 4 54 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 Dosage Hypertension: 50 to 100 mg daily Angina pectoris: 100 mg daily or divided twice daily Arrhythmia: 50 to 100 mg daily Early 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 daily Cautions Renal 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 thyrotoxicosis Contraindications Uncontrolled 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 Effects Bradycardia; 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 psoriasis Drug Interactions Verapamil; diltiazem; nifedipine; digoxin; sympathomimetics; disopyramide; NSAIDs; anesthetics; clonidine Ciprofloxacin (88 indicators) Indications and Dosage respiratory-tract infections: 250–750 mg twice daily Urinary-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 days Gonorrhea: 250mg or 500 mg as a single dose Pseudomonal lower respiratory-tract infection in cystic fibrosis: 750 mg twice daily Child 5–17 years: up to 20 mg/kg twice daily (max. 1.5 g daily) Surgical prophylaxis: 750 mg 60–90 minutes before procedure Anthrax (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 infection Skin infection Sepsis Cautions Epilepsy 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) Contraindications History of tendon disorders related to quinolones use; hypersensitivity Side Effects Dysphagia; 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 dysfunction Drug Interactions Antacids; calcium salts; coumarins; dairy products; glibenclamide; iron; opioid analgesics; phenytoin; probenecid; sucralfate; theophylline; cyclosporine; NSAIDs; zolmitriptan; estrogens; didanosine; diazepam; metoclopramide Fluoxetine (63 indicators) Indications and Dosage Depressive illness: 20–60 mg daily; (max. 80 mg daily) Bulimia nervosa: 60 mg daily Obsessive compulsive disorder: 20–60 mg daily Premenstrual dysphoric syndrome: 20 mg daily Child and adolescent<18: not recommended Discontinue if no improvement after 10 weeks Cautions Renal impairment: (moderate): give on alternate days (severe): avoid; reduce dose or avoid in severe liver disease; pregnancy: use only when required; breast-feeding: avoid; patients with epilepsy; history of mania; cardiac disease; weight loss; diabetes mellitus; risk of suicidal behavior with young adults; hemorrhage; impair performance of skilled tasks Contraindications Use during the panic phase; use with MAOI Side Effect Anorexia with weight loss; gastro-intestinal effects; hypersensitivity reactions/anaphylaxis; angioedema; arthralgia/myalgia; photosensitivity; nervousness/anxiety/insomnia; tremor; drowsiness; urinary retention; sweating; hyponatremia/inappropriate ADH secretion; hypomania/mania; movement disorders/dyskinesia; visual disturbance; hallucinations; convulsion; galactorrhea; sexual dysfunction; blood sugar change; fever; serotonin syndrome; abnormal bleeding/vaginal bleeding on withdrawal/GI hemorrhage; ecchymoses; blood dyscrasias: pancytopenia/thrombocytopenia/anemia; violent behavior; hair loss Drug Interactions Should not be started until 2 weeks after stopping a MAOI; warfarin/St. John’s wort; tricyclic antidepressants; antiepileptics; lithium; serotonergics: sumatriptan, tramadol; tryptophan; electrocunvulsive therapy; flecainide; vinblastine; MAOI should not be started until at least 5 weeks after fluoxetine is stopped Metformin (32 indicators) Indications and Dosage Diabetes mellitus; with insulin; with sulfonylureas Initially 500 mg with breakfast × 1 week then 500 mg with breakfast/dinner x1 week then 500 mg with breakfast/lunch/dinner Maximum dose: 3g divided three times daily Caution Measure serum creatinine before treatment and once or twice annually during treatment Contraindications Renal impairment: (mild) avoid due to increased risk of lactic acidosis; ketoacidosis; hepatic impairment: withdraw if tissue hypoxia likely; use of iodine-containing X-ray contrast media (do not restart metformin until renal function returns to normal); use of general anesthesia/surgery (suspend metformin 2 days beforehand and restart when renal function returns to normal); pregnancy: avoid and substitute insulin; breast feeding: avoid; heart failure; respiratory insufficiency Side-effects Anorexia; gastrointestinal side effects; metallic taste; rarely lactic acidosis (withdraw treatment); decreased vitamin-B12 absorption Drug Interactions Angiotensin-converting enzyme inhibitors; alcohol; anabolic steroids; antidepressants; antihistamines; beta-blockers; corticosteroids; diazoxide; diuretics; hormone antagonists; estrogens/progesterone; testosterone Omeprazole (54 indicators) Indications and dose Adult Benign duodenal ulcer: 20 mg daily × 4 weeks Benign gastric ulcer: 20 mg daily × 8 weeks Maximum dose: 40 mg daily Ulcer Maintenance: 20 mg daily Prevention of relapse in duodenal ulcer: 10 mg-20 mg daily NSAID-associated ulcer treatment: 20 mg daily × 4–8weeks NSAID-associated ulcer prophylaxis in patients with history of ulcer/dyspeptic syndrome): 20 mg daily Zollinger-Ellison syndrome: Initial: 60 mg daily; usual: 20–120 mg daily (>80 mg divide twice daily) GERD Treatment: 20–40 mg daily × 4–8 weeks GERD maintenance: 20 mg daily Acid reflux disease -Reflux esophagitis (long-term management): 10–20 mg daily Acid-related dyspepsia: 10–20 mg daily × 2–4 weeks H. Pylori: 20 mg twice daily or 40 mg daily × 1–2 weeks Child >2 years Severe ulcerating reflux esophagitis: 0.7–1.4 mg/kg daily × 4–12 weeks (max: 40 mg daily) Cautions Liver 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 treatment Side Effects Paresthesia; 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/agranulocytosis Drug Interactions Ketoconazole; diazepam; warfarin; phenytoin Table 3 Correctness and completion of information in generic package inserts vs. indicators based on the BNF and brand product label.1 Generic formulations Indications (%) Dosage (%) Cautions (%) Side Effects (%) Drug Interactions (%) Mean (%) ±SD Company Atenolol  Canar 100 25 72 77 85 72 28 Tabuk  Glormin 100 100 80 66 100 89 16 Global Pharma  Hypoten 50 25 79 38 56 50 20 Hikma  Normoten 100 50 50 46 33 56 26 Al Jazeera  Tenol 100 100 58 85 89 86 17 Saudi-Kuwait  Tensotin 75 75 88 85 89 82 7 Julphar Ciprofloxacin  Ciflox 91 67 82 97 83 84 11 Saudi-Kuwait  Ciprocin 64 22 47 23 39 39 18 EPICO  Ciprodar 55 33 35 42 44 42 9 Dar Al Dawa  Ciproflacin 64 22 47 23 28 37 18 Ram Pharma  Ciproflox 64 44 41 42 22 43 15 Al Arabia  Ciprogen 91 89 53 87 56 75 19 Riyadh Pharma  Cipromax 73 33 35 94 28 53 29 Spimaco  Ciproxen 55 22 35 13 39 33 16 Jamjoom  Floxacin 73 33 65 35 61 53 18 SAJA  Quinox 64 44 29 35 56 46 14 Tabuk  Sarf 82 78 82 87 72 80 6 Julphar Fluoxetine  Evrex 100 85 75 37 45 68 27 Al Jazira  Flozak 100 71 88 44 73 75 21 Riyadh Pharma  Flutin 75 28 69 96 82 70 26 Julphar  Linz 75 71 69 37 64 63 15 Tabuk Metformin  Dialon 67 50 90 80 92 76 17 Julphar  Diaphage 67 50 80 100 75 74 18 UPM  Formit 67 50 80 80 8 57 30 Spimaco  Glucare 33 100 76 80 42 66 28 Al Jazira  Metaphage 33 100 60 40 33 53 28 Saudi-Kuwait  Metfor 33 50 70 20 42 43 19 Tabuk  Riyadhformin 100 100 100 60 25 77 34 Riyadh Pharma Omeprazole  Aciloc 69 71 67 87 100 79 14 Jamjoom  Gastrozole 62 64 83 33 100 68 25 Riyadh Pharma  Hyposec 30 36 83 7 100 51 39 Ram Pharma  Omedar 38 21 83 40 100 56 33 Dar Al Dawa  Omeprex 46 29 83 13 100 54 36 SAJA  Omeral 92 93 100 33 100 84 29 Al Jazeera  Omiz 54 14 67 40 75 50 24 Tabuk  Oprazole 77 79 100 7 0 53 46 Hikma  Rizek 85 86 100 100 100 94 8 Julphar Mean 70 57 70 54 63 63 SD(+/−) 22 28 20 30 30 16 SD= standard deviation. 1 Results calculated as % (observed number of correct indicators/actual number of indicators in Table 1) ==== Refs References 1 Regner J Hermann F Ried D Effectiveness of a printed leaflet for enabling patients 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