Objective: Package inserts (PIs) provide information for the safe and effective use of a medication. PIs are among the most frequently used sources of medication information. There is no study on the evaluation of PIs in Iran. The purpose of this study was to evaluate the completeness of package inserts supplied with the 100 top-selling oral medications in Iran.
Methods: One hundred medications were chosen from a list supplied by the Iran Food and Drug Administration (IFDA). The PIs were assessed for the presentation and completeness of quality criteria.
Results: Thirty-seven out of 100 medications included no PIs. None of the PIs met all the criteria required by IFDA. The highest score for completeness was 18 out of 21 (85.7%). Only two medications listed physical signs of deterioration in dosage form, while 44 listed the way of medication administration with/without regard to meal.
Conclusion: PIs have improved in recent years in Iran, but there is an absolute need for more accurate and up-to-date information. The IFDA should supervise pharmaceutical companies more strictly in this regard and should revise its regulations requiring PIs to conform to the FDA regulations.
Keyword: package insert, oral medication, Prescription-only, OTC medications
Package inserts (PIs) are folded printed documents accompanying medications, over-the-counter (OTC) or prescribed, and contain information for patients on how to safely use medications. Therefore, they have a substantial impact on patients’ compliance (1). PIs instructions can help to safe medication use, successful treatment and protection from side effects. They are of great importance because self-medication is common in Iran (2); patients have little knowledge about medicines (3) and the most available source of information for patients are PIs. PIs not only help patients but also give healthcare professionals essential information (4); therefore every medication package must include a PI.
Most of the medications have printed information on the primary packages and package insert accompanied with the medication. The Information inside PIs vary between packages, some of them have very accurate and complete information and some, unfortunately, have incomplete and sometimes false information.
In Iran, during the drug registration process, pharmaceutical companies submit product information and labeling information to Iran Food and Drug Administration (IFDA). A study in India showed that PIs failed to adhere to the guidelines of the regulatory authorities(5).
To the best of our knowledge, no study has evaluated PIs in Iran. The aim of the present study was to evaluate adherence to guidelines criteria and the quality and completeness of PIs supplied with the one hundred top-selling oral medications in Iran, according to the evaluation criteria in this study.
This cross-sectional observational study was conducted in January 2017. As the first step in this study, a set of 21 criteria (table 1) was developed. The evaluation criteria consist of two parts. The first part is the criteria required by IFDA, mentioned in Chapter 16 of the pharmaceutical regulations and instructions provided by IFDA. The second part of the criteria was defined according to the critical comments of clinical and industrial pharmacists.
The list of top-selling medications(6) in Iran was obtained from the IFDA website. The first one hundred oral medications were chosen from the list.
The PIs were collected over a three-week period from pharmacies located in Rasht, Gilan, Iran, January 2017. When all required information on an item was present, it was scored as one; otherwise, a score of zero was assigned. Each item has one score and total score was 21. The total score (21) was calculated by adding the scores of all 21 items for an individual PI. For each medication, the presence or absence of criteria was expressed as percentages, by comparing PIs information with the IFDA and FDA Criteria and their completeness was presented as a percentage.
Listed medications were categorized based on their Martindale indication(7) as shown in figure 1.
Data were divided into four groups, group A (OTC medications), group B (prescribed only medication), group C (licensed medication) and group D (Local medication).
The PIs were analyzed twice to reduce the chance of missing information. Descriptive statistical analysis and appropriate tests were performed using SPSS software, version 14. P values less than 0.05 were considered statistically significant.
Thirty-seven out of 100 top-selling oral medications included no PIs. None of the PIs met all the criteria required by IFDA and quality criteria (figure 2). The highest score for completeness was 18 out of 21 (85.7%).
As shown in Table 2, items which included in all package inserts were medication name, description, and adverse reaction. Other items such as patient counseling information (98%), warnings (95.2%), precautions (95.2%), pregnancy/lactation (95%) and storage condition (90.5%) have been mentioned in a high percentage of PIs. Pediatric and geriatric considerations were available in 62% and 1.7% of PIs, respectively.
Only two medications listed physical signs of deterioration in the dosage form and 44 listed medication administration with/without regard to meal.
Nine medications on the list were mentioned in the gluten-free list of IFDA and three mentioned G6PD deficiency consideration in their PIs.
52% of PIs did not provide any information about over dosage toxicity and management.
Group A and C (or B????) consisted of 12 and 52 PIs, respectively. Group C and D consisted of PIs of the following licensed medications and local medications: Fexofenadine 120 mg, metformin 500 mg, sertraline 50 mg, glyceryl trinitrate 2.6 mg (modified release), valproate sodium 200 mg and atorvastatin 20 mg.
Table 4 3 shows that PIs of licensed medications got a better score on average than local PIs. 66.6% of licensed medication PIs had instruction on over dosage toxicity and management, but only 16.6% of local PIs mentioned over dosage toxicity and management. 66.6% and 83.3% of licensed medication PIs provided information on pediatric consideration and dosage/administration respectively, while 33.3% and 50% of local PIs provided information on these topics. The data in figure 3 indicate that 23% of OTC medications did not have PIs; on average, the PIs of prescribed medication scored better than OTC medications. Nearly half of the PIs pointed out over dosage toxicity and management. The missed dose was mentioned less than desired, 8.3% in OTC and 65% in prescribed medication. Significant differences between groups A and B was seen in G6PD deficiency consideration, signs of deterioration and missed a dose. As evident in Table 3, a significant difference between group C and D was only seen in the address, phone number and website items, because of the small sample size.
After scoring, PIs were categorized into poor (score 0-7), good (score 8-14) and very good (score 15-21). Figure 4 shows that none of the PIs were graded as poor, most of them (40) were graded as good and 22 were graded as very good. (???? ???????? ?? ???? ???? ??? ??????? ????? ??? 62 ?? ?? ?????? ????? ????? ????)(?????? ?? ???? ?????? ??? ????? ?????)
The most commonly used medication categories based on Martindale indication in the list were cardiovascular drugs (21%), analgesics/anti-inflammatory drugs/antipyretics (20%) and gastrointestinal drugs (13%).
Table 1 showed the differences between US FDA labeling guidelines and IFDA criteria. There are certain deficiencies in IFDA guidelines such as Boxed warning, Recent major changes, Use in specific population, Drug abuse and dependence, Clinical pharmacology, Nonclinical toxicology and Clinical studies.
According to the results of this study, the highest score for PIs completeness was 18 out of 21 (85.7%), and about two thirds of medications (63%) had PIs. medication name, description, and adverse reaction were mentioned in all PIs, it is promising because sufficient information on adverse reaction helps patients during treatment. However, information on geriatrics, g6pd deficiency and physical sign of deterioration and date of last revision were most frequently missing in the studied PIs. Excipients that could be harmful to some patients were mentioned less than desired.
PIs play an important role in patients’ health through improving patient’s knowledge (8, 9) and helping them in adherence to treatment(10). This was the reason why many studies were conducted in different countries.
A study showed that most of the patients fail to understand the information on PIs, specifically in contraindications and interactions sections(11). In this study, about half of the PIs did not refer to drug interactions and it is undesirable because patients with comorbidities take multiple medications (polypharmacy) and as such, the probability of interactions between OTC or prescription medication increases (12).
As shown in Figure 3, 34% of the listed medications were OTC. Of this 34 %, only 11% had PIs. Patients who buy OTC medications no longer refer to the doctor and do not benefit from their guidance, and most often patients do not receive counseling for their OTC medications in the pharmacy, therefore there is a need for correct and complete PIs. (?????? ?? ???? ?????? ??????)
Special populations such as pregnant women, pediatrics, geriatrics, require special considerations. Drug pharmacokinetics and pharmacodynamics, dosing and toxicity vary among these populations. FDA obligates companies to provide a recommendation for dosing in special populations (13). The result of a present study in pediatric and geriatric consideration is somewhat similar to a study conducted in India, in which pediatric and geriatric use was present in 44% and 13% of the PIs, respectively (14).
Sticking to medication routines or medication adherence is important (15). Miss dosing and non-adherence has multiple complications such as reduction in anticoagulation (16), hospital admission and ketoacidosis in diabetic patients (17), failure in controlling blood pressure (15)and can reduce patients quality of life. Appropriate guidance in this matter can reduce many of these problems. One of the most important causes of death in Iranian population is a cardiovascular disease(18), and it is worth mentioning that most of these patients receive medication therapy (19). In this study, 4 out of 23 (or 21 ????) drugs cardiovascular medications did not have PIs. Non-adherence to cardiovascular medications is one of the risk factors for treatment failures and poor outcomes. Considering the importance of this issue, it is suggested that the regulation regarding cardiovascular drugs be stricter and the overall quality will be higher than average (20). Providing appropriate information in PIs can be an impressive factor in reducing non-adherence to medications.
Six out of nine of the antibiotics did not have PIs due to the high prevalence of antibiotic self-medication in Iran and not completing the course of therapy (21); these can lead to microbial resistance, hospital admissions and additional costs to the healthcare system (22). It is highly recommended not to forget the importance of antibiotics PIs.
Patients with G6PD deficiency manifest different levels of enzymatic activity and because of this, a range of hematological complications can occur in these patients (23). Given the 6.7% prevalence of g6pd deficiency in Iran (24) and the importance of the disease, It is suggested that the necessary information for these patients be available in PIs. Unfortunately, 2 out of 5 medications with a high risk of hemolysis did not mention G6PD deficiency consideration in their PIs.
Patients with celiac disease try to get information on the presence of gluten in their medications through calling Drug and Poison Information Centers (DPICs) or drug companies or pharmacist in drug stores; this is very frustrating for these patients.Given the similar incidence of celiac disease in Iran with Europe and USA (25), it is recommended that the presence or absence of gluten be mentioned in PIs. This led us to distinguish which of the top-selling medications are gluten-free. Therefore, the list of gluten-free medications was taken from the IFDA website and compared with top-selling medications. Only nine medications were on the list, which means that the list of gluten-free medicines has not yet been completed and it is necessary to add celiac disease information to PIs.
After careful consideration, it was discovered that the licensed medication by another company from a foreign country has better quality. Similar findings regarding the superiority of information in both quality and quantity of imported over local medications which were found in a recent study in Palestine (26).
Consultation for patients on taking medications regularly and its administration with/without regard to meal are other issues that should be mentioned in the PIs. Another problem affecting patients is inappropriate dosage instruction (e.g. 1-3 capsules or take 2-3 times a day) in PIs. to solve this issue, Non-quantifiable statements should not be mentioned in PIs without appropriate instructions (27).
A study that compared patient information leaflets of the United Kingdom, the United States and Australia showed that the best PI was from Australia. The U.S PIs lack sufficient information such as drug interactions, contraindications and did not even get an acceptable score for readability and comprehensibility (28). Another study in Saudi Arabia (4) showed that many PIs defect vital information such as adverse reactions, dosage instruction and did not pass safety criteria.
One of the confusing problems that patients are struggling with, is information overload (29). There should be a balance between information overload and relevant and necessary information. The usability of PIs is a valuable factor, a study showed that PIs have usability problem particularly in finding relevant information. the usability of PIs improved after authors revision (30).
One of the pharmaceutical companies routinely has printed the leaflet information inside the box, although this approach reduces paper consumption, it can be a factor for confusing patients because it is unlikely that the printed information will be seen and as such can be missed.
A study in Germany (31) demonstrated that the PIs were not only incomprehensible but also did not pass all the quality criteria for interactions and maximum daily dose. Other aspects such as readability and comprehensibility were not analyzed in this study; further studies should consider evaluating the readability and comprehensibility of PIs because studies have shown that PIs are not patient-friendly enough (32, 33).
There are ways to reduce this problem such as designing the layout of PIs with bold headings and bullet points using suitable paper with a right transparency and choosing the appropriate font and size, using short sentences and understandable words for the public. Another way that comes to mind is to involve the non-academic people in the PI writing process(34).
The result of this study was compared with other researches done in different countries. As shown in table 4 the information on adverse reactions, Pregnancy/Lactation, and Storage condition in this study was similar to other studies. However, compared with other studies, it was found that information on over dosage, Drug interactions and contraindications were mentioned less than others.
Similarly to other studies, this results showed the most PIs were graded as good, that means the number of PIs in poor and very good groups are very low (35-37). So PIs quality should be improved in order to reach the best grade.
As evident in table 1, the US FDA labeling guidelines in comparison to IFDA are more complete, understandable, patient-oriented, helping the patients and healthcare professionals to access information easier from PIs. Lack of some items in PIs compared with US FDA labeling guidelines also reported in other investigations (38, 39).
In this study, the adherence to IFDA guidelines was evaluated besides other criteria. Until now, there are no standard criteria for evaluating PIs and this is one of the limitations of this study. Another limitation is that readability and comprehensibility of PIs were not evaluated. Finally, yet importantly, this study only evaluated the first one hundred medications in the IFDA list. Despite these limitations, this is the first study to our knowledge on evaluating PIs in Iran.
In this study, 100 PIs were evaluated for their completeness of information required for the patients’ best benefit. Clearly, as shown in the result, none of the PIs were complete and they did not provide satisfactory information. This study is a reliable source of information upon the quality of PIs in Iran. The findings can be a good guide for IFDA and companies for improving PIs.
Although PIs have improved in recent years in Iran, there is a need for more accurate and up-to-date information. In this regard, IFDA should supervise pharmaceutical companies more strictly and should revise its regulations and conform PIs to the FDA regulations.