Presence of excipients with potential for induction of adverse reactions to medicinal products marketed in Brazil

The presence of pharmaceutical excipients As Possible causes of adverse drug reactions (ADR) - situation in Brazil
Vinicios Antonio Alves da Silva; Said Gonalves da Cruz Fonseca, Paulo Srgio Golden Arrais; Eudiana Valley Francelino * Department of Pharmacy, School of Pharmacy, Federal University of Cear

ABSTRACT Pharmaceutical excipients may be responsible for numerous Adverse Drug Reactions (ADRs). The objective was to identify the presence of potential inducers of RAM excipients in medicines marketed in Brazil. We listed the 12 top selling products in the Brazilian market for analysis. The detection of excipients occurred from the appointment to the composition of pharmaceutical formulation products, held August to September/04, in Dictionary of Pharmaceutical Specialties, SAC sites from the manufacturer, and factsheet available on the ANVISA. The identification of excipients, possible causes of RAM, was held from consulting the literature. We identified 35 pharmaceutical presentations, 26 classified as prescription medicines (71.4%) and 15 pediatric use (42.8%). Among the excipients identified (n = 100), nine possible causes of RAM: methylparaben, propylparaben, tartrazine yellow dye, sodium bisulfite, sodium benzoate, lactose, benzalkonium chloride, and benzyl alcohol sorbitol, identified in seven presentations pediatric use (18.9%) and twelvecounter (32.4%). The results demonstrate the need for greater attention from health professionals, users of drugs and evaluation by pharmacovigilance systems, the presence of excipients as potential inducers of RAM. Key Words: Drug / adverse reaction; Excipient pharmacist; Pharmacovigilance, Pharmaceutical Preservatives

ABSTRACT Pharmaceutical excipients Can Be Responsible for many ADR. The Objectives of this study were to Identify the presence of the excipients Possible causes of ADR in drugs commercialized in Brazil. Twelve medicines with high indices of sales in Brazil, were selected to analysis. The bibliographic research about the Pharmaceutical Preparations (PP) was Carried from August to September/04. The sources of information were used Pharmaceutical Specialties Dictionary, web sites and customer services from the manufacturers and technical files of the National Agency of Sanitary Vigilance. The excipients were detected as a whole and Also the compounds That may cause adverse reactions and Its Risks to the health. They were Identified 35 PP. Of these, 26 were classified the Over-The-Counter medicines (OTC) (71.4%) and 15 of pediatric use (42.8%). Identified Between the excipients (n = 100), 9 were Possible causes of ADR: metylparaben, Propylparaben, yellow dye tartrazine, bissulfit sodium, sodium benzoate, lactose, benzalkonium chloride, sorbitol and benzlic alcohol, being Identified in 7 use in pediatric (19.0 %)

and 12 of OTC (32.4%). The results show the need of more attention from the health professionals, the patient and the development of evaluation by the pharmacovigilance systems, of the presence of excipients As Possible inductors of ADR. Uniterms: Drugs / adverse reactions. Pharmaceutical excipients. Pharmacovigilance. Pharmaceutical preservatives.

INTRODUCTION
Drugs are rarely administered alone, they form part of a formulation combined with one or more non-medicinal agents with functions to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, coloring, flavorizar and enable the obtaining of stable dosage forms , effective and attractive. With the use of such selective non-medicinal agents, pharmaceutical excipients known, result dosage forms of various types (Ansel et al. 2000). Pharmaceutical excipients were appointed by Napke (2004) as being responsible for numerous adverse reactions related to drugs, a major problem which according to the author is not being addressed adequately at the time of the evaluations of suspected Adverse Drug Reactions (ADRs ). The ratio between excipients and adverse reactions has been described by Buck (1996), Kumar et al. (1996, 1993) and Yang (1985), who identified some of these excipients risk. This fact and the absence of the Country justify the need to know that excipients are present in pharmaceutical formulations available in the national pharmaceutical market. The aim of this study was to identify the possible presence of excipients inducing backlash present in medicinal products marketed in Brazil.

MATERIAL AND METHODS

This is a descriptive study conducted at the Centre for Pharmacovigilance of Cear (CEFACE) belonging to the Group for the Prevention of Drug Abuse (GPUIM) Department of Pharmacy, Federal University of Cear. Initially, we carried out survey on national and international literature to identify the excipients in general and the possible causes of undesirable effects and risks to public health. At the national pharmaceutical market, there are a number of registered products, so we decided to centralize research among the biggest selling. Therefore, it was used as a reference, the list of drugs with highest sales in Brazil, in the period novembro/02 November/03, according to the International Market Service (IMS, Brazil, 2003), from which we selected the 12 best sellers. The respective sample of medicinal represented 5.75% of the total monetary value of sales (U.S. $ 273,563,312.00; dollar value at the time 2.54) and 9.37% of pharmaceutical units sold in the Brazilian market study period. The distribution of products 12 can be seen in Table 1 in descending order and sales by the generic name which has been associated with the code Laboratory manufacturer expressed by letters of the alphabet (A, B, C, D, E, F, G , H and I). This encoding is adopted to avoid professionals and consumers are given the suggestion of some change of use of the

product above, without consulting the prescriber and prevent companies feel aggrieved with the exposure of the name of the product. The 12 best-selling products accounted for 35 pharmaceutical presentations. The bibliographic to collect information on the forms and pharmaceutical compositions of selected products was conducted from August to September/04, being used for this step the following information sources: Dictionary of Pharmaceutical Specialties (2004), and sites Service Customer (SAC) and the manufacturers data sheet is available on the National Health Surveillance Agency (ANVISA). In Table II , one can observe some pharmaceutical excipients cited by Buck (1996) and related as possible causes of adverse reaction. They were selected for this research from the identification of their presence in the pharmaceutical formulations of the products surveyed.

RESULTS
The 12 had 35 products surveyed for pharmaceutical dosage forms distributed in the following ( Table I ): Tablets (n = 7) Oral Suspension (n = 2); tablets (n = 2); drops (n = 7), suppository (n = 1); ampoule (n = 2); emulgel (n = 1); aerosol (n = 1); effervescent tablets (n = 3); tube (n = 1); capsule (n = 1); tablet (n = 1); nasal solution (n = 2) ointment (n = 1); dispersible tablet (n = 1); chewable tablet (n = 1) and an oral solution (n = 1). These presentations, 25 are classified as prescription medicines (71.43%) and 15 pediatric use (42.8%), and 9 (60%) of the latter, free sale. As to the source researched, pharmaceutical formulation nine products was found only in sites and Services Customer Service (SAC) of the laboratories B and H. Of the 35 surveyed presentations, two could not be identified by the excipients sources of information about the drug in research proposals, but the rest of the presentations (N = 33), 100 excipients were identified. Nine of the excipients were considered as possible causes of adverse reaction in seven appearances pediatric use (18.9%) and twelve-counter (32.4%) ( Table III ). Its distribution was as follows: two contained methylparaben, propylparaben two, two tartrazine yellow dye, sodium bisulfite two, four sodium benzoate, lactose two, two benzalkonium chloride, sorbitol and a five benzyl alcohol. In some situations, the product showed the presence of two or three excipients risk.

Regarding the description of the concentrations of the components of the formula, no amount of excipients identified was described in the leaflets, websites, or SAC reported by informants of the producers, it is not possible to verify if they are within the range normally used and / or permitted.

DISCUSSION
The study detected the presence of nine excipients risk among the 35 pharmaceutical preparations analyzed. Among some products it was found that there are two or three excipients risk, which can increase the chance of occurrence of RA. This demonstrates that there is a real risk of public exposure to excipients with potential for induction of RAM. The concern is even greater if we consider that most of these products are pediatric formulations and OTC. This fact must be taken into account by prescribers in choosing the medicine to his patient, and those responsible for analyzing the causal relationship between the drug and the adverse reaction suspected in Pharmacovigilance Centers, they may fall into the error of attributing the because of the reaction to the drug rather than the excipient. In research conducted in the scientific literature can highlight the risk related to each of the excipients identified in products sold in the domestic pharmaceutical market. The main problems related to these excipients are described below. Preservatives - Methylparaben and Propylparaben In this study, we detected two pediatric formulations (dimethicone drops and potassium diclofenac suspension) containing the preservatives methylparaben and propylparaben. According to Jackson (1992), cited by Soni et al. (2001), the combination of methylparaben and propylparaben in pharmaceutical formulations is the most widely used form, which was identified by study in some situations. According to Soni et al. (2001), numerous cases of adverse reactions to parabens and benzoates, especially hypersensitivity reactions have been reported in the medical literature, due to the fact their chemical structures are very similar. Parabens after your metabolism is converted in part to the -hydroxybenzoic acid, structurally related to acetylsalicylic acid, a substance well known to cause hypersensitivity reactions. Many of these reactions are mild cases and generally involve reactions of contact associated with the use of parabens in cosmetic formulations. Preservative - Sodium benzoate Pediatric formulations paracetamol drops, dipyrone 50 mg (oral solution), baby paracetamol (drops) and paracetamol suspension formulations presented in their antifungal preservative sodium benzoate, which appears related to the appearance of rashes such as urticaria immune associated angioedema, eczema atopic and contact dermatitis cases of anaphylactic reactions (Vilaplana, Romaguera, 2003). Preservative - benzalkonium chloride In this study, we identified the presence of the antimicrobial preservative, benzalkonium chloride solution in nasal associated with naphazoline hydrochloride, sodium chloride (adult use) and sodium chloride (for pediatric use). This was pointed out by Buck (1996), as responsible for a significant decrease in pulmonary function and hypersensitivity reactions in asthmatics. According to a study by Scadding (2000) observed that in a number of 1,000 patients, 10 experienced hypersensitivity reactions to benzalkonium chloride, corresponding to a prevalence of 1%.

The findings reported by Graf (2002) also show that the use of benzalkonium chloride can aggravate rhinitis medicamentosa induced nasal decongestants which second Scadding (2000) is considered in addition to allergic rhinitis, an adverse effect caused by this excipient. Antioxidants - Sulfites in general The presence of sulfites was perceived in the medication-based dipyrone (oral solution) and paracetamol (compressed). In the case of sulfite, the most common symptom of an adverse reaction is difficulty breathing. Other signs / symptoms are diarrhea, nausea and vomiting, abdominal cramps, dizziness, wheezing, hives, itching, swelling, rash, difficulty swallowing, headache, fainting, changes in body temperature, chest pain, changes in heart rate, unconsciousness and coma (Ansel et al., 2000). Symptoms typically occur minutes after ingestion of foods or drugs which contain sulfite. Many people are sulfite-sensitive asthma or other allergic conditions. Buck (1996) also reports to sulphites, a significant decrease in pulmonary function and hypersensitivity reactions in asthmatics. Sweetener - Lactose Lactose was found excipient formulations analyzed in the study and available on the national market as formulation-based bromazepam and another based on the dipyrone butylscopolamine. The substance is commonly used as a diluent in solid dosage forms. The sensitivity of patients susceptible to ingestion of lactose can vary in severity, the patient getting diarrhea, flatulence, abdominal pain resulting in restriction of its intake after intake of 3 g or less (American Academy of Pediatrics Committee on Drugs, 1997 ). Dye - Yellow Tartrazine The dye tartrazine found in two products: dipyrone 500 mg (drops) and paracetamol (drops). In the study, it was identified that their presence is occurring primarily in products for pediatric use. According to Buck (1996), this carrier is responsible for hypersensitivity reactions in patients with allergic predisposition as anaphylaxis, bronchospasm, angioedema, urticaria, abdominal pain and vomiting, as well as contact dermatitis. Numerous dyes are also used in pharmaceutical products. Several have been associated with serious adverse reactions. One is the tartrazine yellow dye, known as high-risk individuals intolerant to aspirin (American Academy of Pediatrics Committee on Drugs, 1997). Approximately 2-20% of asthmatics are sensitive to aspirin. In studies conducted by Stevenson et al. (1986) and Simon (1984), the incidence of cross reaction to tartrazine has been less than 2.4%. Reactions may occur from the use of this dye (acute bronchospasm, hives non-immune, eosinophilia and angioedema) in subjects with or without a history of intolerance to aspirin. Rarely anaphylactoid reactions occurring non-immunological (American Academy of Pediatrics Committee on Drugs, 1997). Considering this risk, in Brazil, according to Board Resolution (RDC) 137/03 of ANVISA, the medicine that use the yellow dye tartrazine in their formulations, should bring the following warning in the package insert and labeling of secondary

packaging: "This product contains the tartrazine yellow dye, which can cause allergic reactions in nature, including bronchial asthma, especially in those allergic to salicylates. " Sweetener - Sorbitol The presence of sweeteners like sorbitol in drug formulations as diclofenac potassium (suspension), vitamin C (and effervescent tablet) and paracetamol (drops and suspension), has been associated with reports of gastrointestinal disorders such as diarrhea and abdominal pain, as it is the large amount of sorbitol contained in these formulations the factors behind it (Buck, 1996). The sorbitol, and other sweeteners (saccharin, aspartame and fructose) are widely used in pharmaceutical formulations, particularly those intended for pediatrics. Preservative - Benzyl alcohol Diclofenac potassium in injectable form (Lab G) was the only drug adult use, which contained the excipient benzyl alcohol formulation. Benzyl alcohol is commonly used as a preservative in many solutions and injectable medications. According to the American Academy of Pediatrics Committee on Drugs (1997), a number of neonatal deaths and serious respiratory and metabolic complications in preterm low birth weight was associated with use of these agents in bacteriostatic saline for intravenous solutions and for washing tracheal tube. The mortality rate of premature infants, frame Kernicterus and intraventricular hemorrhage decreased markedly after discontinuation of solutions preservatives such as benzyl alcohol. In neonates survivors exposed to benzyl alcohol, was also found to be associated with morbidity, including paralysis and developmental delay. Cases involving the use of benzyl alcohol, present in injectable formulations as antimicrobial preservative, was responsible for cardiovascular collapse characterized by neonatal metabolic acidosis and hematologic abnormalities, and in elderly patients, reports of hypersensitivity reactions such as contact dermatitis, nausea and angioedema ( Buck, 1996). Benzyl alcohol is used as preservative in preparations intended for parenteral use in multiple doses, using as vehicle bacteriostatic water for injection (Ansel et al. 2000). Other important considerations The involvement of excipients as a risk factor for adverse drug reactions are associated with actions such as: prevention, modification of pharmaceutical formulations and continuous monitoring of their use in the general population. The identification of problematic excipients can lead to Pharmaceutical Industry to reevaluate their products, proposing modification of pharmaceutical formulations through requests from the regulatory agency, in the case of Brazil, ANVISA, a fact governed by Board Resolution (RDC) 140 / 03. With reference to Board Resolution (RDC) 210/04, which expressed the need for a statement of the concentrations of all components of the formula of a pharmaceutical product for the entry of his record, was not found in the study reported no concentration of excipients present analyzed in the presentations, but only "enough to" (qs), because the manufacturer is not required to express the concentrations on the labels, inserts and cartridges, probably as a way to ensure the secrecy of its industrial products (Balbani, Stelzer, Montovani , 2006).

In the case of the two products was not possible to identify the excipients in its composition, the omission of this information can generate an additional risk factor for patients with hypersensitivity. This is not an isolated situation, because studies by Auricchio, Batistic-Longatto and Nicoletti (2007), Balbani, Montovani and Stelzer (2006) and Barros (2000), have shown that information conveyed on labels, leaflets and DEF showed serious deficiencies. This explains the need for use of ANVISA sites and laboratories producing drugs for obtaining, among other things, information about the composition of the products. The consensus among the authors that lack of information may impair rational prescription and use the correct patient. Regarding the presence of excipients risk for prescription drugs, it was found that they are linked mainly to the self-medication products used in (Pereira et al. 2,007; Servidoni et al. 2,007; Arrais et al. 1997), as dipyrone, dimethicone, vitamin C, paracetamol, naphazoline hydrochloride associated benzalkonium chloride, sodium chloride combined with benzalkonium chloride and associations caffeine + + Dipyrone hydrochloride isometheptene; dipyrone + scopolamine butylbromide and camphor, menthol and eucalyptus oil. This is troubling, since this practice, widespread in Brazil, is considered by Honig (1995) a risk factor for the onset of adverse reaction that, coupled with the presence of these excipients, may further increase the likelihood of its occurrence. The risk of these products in pediatric patients Another determinant of risk is the fact that many of these products are for pediatric use. The incidence of adverse effects from drugs at the pediatric may range from 0.6% to 18.0% (Santos, 2004). Moreover, the RAM have been responsible for 0.6% to 4.3% of hospital admissions, putting at serious risk the lives of those (38%) or even leading to death. The pediatric risk generates additional care as evidenced greater supervision and guidance in the use of the drug by their caregivers and a rational prescription by the prescriber. The excipients and hospital environment Adverse reactions to excipients that make up the drug also constitute a serious health problem, since 10 to 20% of hospital admissions are due to adverse reactions without the possibility of excluding them from causality. According to Wong and Sandron (2001), the RAM can occur more frequently in Latin America than in other regions due to the high use of medicines, the existence of selfmedication and polypharmacy, the purchase of non-prescription drugs and the frequent use of medicines derived from medicinal plants. Still, in this region the ADR reports are scarce. According to the authors, this is due to misinformation from doctors on the subject, which consider that inform RAM consumes their time and commitment, as well as the belief that the drugs that are on the market are safe and that there A close link between the occurrence of adverse reaction to the active ingredient rather than with the excipient. In the process of informing and guiding the user on drug efficacy and safety, the pharmacist plays an important role. The Federal Council Resolution Pharmacy No 357/01, pursuant to Article 31, 32 and 33, calls the professional to assume his role as advisor in rational use, drug interactions, patient's own understanding about treatment and adherence as well as record all your actions during pharmaceutical consultation.

CONCLUSION

Excipients with risk of causing adverse reactions were detected between the pharmaceutical most consumed in Brazil, especially for pediatric use and free sale. Consider them as "inert" is a grave mistake. It is, therefore, necessary to make real awareness among health professionals about the subject, so they can make a preliminary identification of patients predisposed to hypersensitivity and alert the consumers about the risks, through the improvement of leaflets or packaging of medicines and the information contained in therapeutic guidelines and sources of information of a commercial nature, such as DEF.

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