Review: UK medicines likely to be affected by the proposed European Medicines Agency’s guidelines on phthalates

Background Phthalates are excipients in drug formulations. However, concerns have been raised about the effects of particular phthalates on reproduction and development. As a result the EMA has introduced guidelines for permitted daily exposure (PDE) limits for certain phthalates. Therefore, the objective of this study was to identify UK licensed medicines that contain the relevant phthalates and determine if they fall within the recommended PDE. Methods The eMC was used to identify which UK licensed medicines contain the phthalates in question. Companies were then contacted for information on the phthalate levels in their products, which was compared with the PDE recommended by the EMA. Results The eMC search revealed that 54 medicines contained at least one of the phthalates in question. However, only six medicines, namely Asacol 800 mg MR (Warner Chilcott UK), Epilim 200 Gastro-resistant tablets (Sanofi), Prednisolone 2.5 mg and 5 mg Gastro-resistant tablets (Actavis UK), Vivotif (Crucell Italy S.r.l), and Zentiva 200 mg Gastro-resistant tablets (Winthrop Pharmaceuticals UK), were identified as containing levels that exceeded the recommended PDE. Conclusions These findings indicate that very few UK licensed medicines will be affected by the proposed EMA guidelines. For those medicines identified as exceeding recommendations, these findings highlight the need to instigate a risk-benefit review.

However, concerns have been raised regarding the effects of certain phthalates on reproduction and development. These worries predominantly stem from their endocrinedisrupting properties, and associated anti-androgen implications. They have been well documented pre-clinically, particularly in the rat, where prenatal exposure to particular phthalates has affected male and female offspring, with respect to numerous parameters including anogenital distance (AGD), gender ratio, nipple retention, ear and eye unfolding, vaginal opening and foetal weight and viability [2][3][4]. In addition, it has been demonstrated that their effects are additive when combined with each other, as well as, different classes of anti-androgen chemicals [5]. In fact the endocrine-disrupting effects of phthalates in the rat are so robust that within endocrinology laboratories, phthalates are often used as tools to induce testicular dysgenesis syndrome (TDS). By contrast to the preclinical arena, where there are vast studies evaluating the health implications of phthalates, too many to discuss within the scope of this article, clinical data are few and far between. Those that exist come from human association studies and suggest that prenatal exposure to certain phthalates reduces the AGD amongst male offspring, possibly indicative that it compromises virilisation [6,7]. There is also evidence to suggest that prenatal exposure reduces masculine-play behaviour amongst pre-school males [8]. Furthermore, evaluation of phthalate exposure during adulthood demonstrates that it may contribute to both a reduction in the levels of circulating steroid hormones and sperm quality in males, as well as reduced fertility, in both males and females [9][10][11][12].
Whilst it is acknowledged that clinical data are limited and, in some cases inconsistent, regulatory bodies affiliated with consumer goods that contain phthalates deemed it necessary to take precautionary measures. Consequently, guidelines have been developed aimed at reducing exposure to certain phthalates in cosmetics [13], childcare articles [14], plastics in contact with food [15] and medical devices [16][17][18]. Certain medicines represent a source of phthalate exposure, where they exist as excipients, that is, inactive components. Since phthalates are insoluble in acidic environments and soluble in neutral and alkaline conditions, they are commonly used as plasticizing agents in gastroresistant film coatings for tablets, capsules, beads and granules, thus enabling targeted delivery of active ingredient(s) to the more alkaline environment of the intestine. This is likely the reason that drugs for gastrointestinal indications have been identified as particularly high sources of phthalate exposure [19,20]. Furthermore, animal and human pharmacokinetic studies have shown that LMW phthalates, such as DBP and DEP, have near complete intestinal absorption, with 78-90 % of the administered dose excreted in the urine within 24 h [21][22][23]. However, for the HMW phthalates CAP, PVAP and HPMCP, there is currently no pharmacokinetic data available.
Accordingly in 2012, the Food and Drug Administration (FDA) also developed guidelines aimed at minimising phthalate exposure in products regulated by the Centre for Drug Evaluation and Research (CDER) [24]. Specifically, the Agency determined that there is evidence that exposure to DBP and DEHP from pharmaceuticals presents a potential risk of developmental and reproductive toxicity. While the Agency recognised that drug products may carry inherent risks, it stated that DBP and DEHP are used as excipients, and safer alternatives are available. Therefore, the Agency recommends that DBP and DEHP be avoided as excipients in CDER-regulated drug and biologic products [24]. In line with the FDA, the EMA's Committee for Medicinal Products for Human Use (CHMP) is currently drafting its own recommendations on the use of phthalates as excipients in human medicinal products [1]. Whilst these guidelines have yet to be finalised, they are expected to propose permitted daily exposures (PDE) of ≤ 0.01, 4 and 2 mg/kg for DBP, DEP and PVAP, respectively and are predicted to be enforced in 2015. For existing authorised medicinal products, the EMA is proposing to set a time limit of three years (after coming into force of the final guideline) for the implementation of formulation changes and consequential regulatory applications, as necessary. Ahead of their implementation, the authors of this study aimed to identify which United Kingdom (UK)-licensed drugs are likely to be affected by the proposed EMA guidelines, in order to help prepare for potential consequences.

Methods
The first step in this process was to identify which UK licensed medicines contain at least one of the three precautionary phthalates, DBP, DEP and PVAP, named in the draft EMA guidelines. The electronic Medicines Compendium (eMC) [25] was deemed an effective way to find these medicines, as it contains up to date information about most medicines licensed in the UK and is checked and approved by either the Medicines and Healthcare products Regulatory Agency (MHRA) or the EMA. The eMC was utilised via the algorithm depicted in Fig. 1.
The eMC provided the medical information email address associated with each medicine found to contain the precautionary phthalates. The next stage was to contact the companies affiliated with each of the medicines identified as containing the precautionary phthalates. In many cases, a single medical information address was affiliated with numerous products, thus it was only necessary to issue emails to 28 different medical information companies, requesting information about the maximum daily exposure of the relevant phthalate(s) in their product(s). Twenty-seven companies were contacted using the medical information email address provided by the eMC and one was contacted by an online enquiry form. The companies were made aware of the proposed EMA guidelines and their phthalate containing product(s) was identified together with a request for information on the maximum daily exposure of the affiliated phthalate(s).

Results
The eMC search to identify UK medicines containing at least one of the three precautionary phthalates, DBP, DEP and PVAP, named in the draft EMA guidelines, produced 50 hits (information correct as of 9 th June 2014), one of which was deemed a false positive because the drug was listed as discontinued (Maxolon SR 15 mg Capsules). The remaining 49 hits, consisted of 54 branded medicines, five of which contained DBP alone, 17 contained DEP alone, 27 contained PVAP alone, four contained DEP in combination with PVAP and one contained DBP in combination with DEP (Table 1). It should be noted that this list will only contain those drugs registered on the eMC.
Whilst some companies provided maximum daily exposure as requested, thus enabling direct comparison with those set out in the draft guidelines, others did not specify exposure levels but instead commented on how exposure compared with the guidelines. In some instances, companies stipulated the amount of phthalate present in a single unit of the medicine, thus requiring the authors to calculate the maximum daily exposure based on maximum indicated dose as per the 'summary of product characteristics' (SPC). There were five cases where companies stated that they were unable to quantify (UTQ) exposure and for 11 products, companies refused to declare (RTD). Remaining companies provided no response (NR) at all which amounted to 12 products. Responses are summarised in Table 1, however, we were unable to include the phthalate content for 23 products because either the licence holder refused to declare or provided no response.
The proposed permitted daily exposures (PDE) in the EMA guidance equates to < 0.7 mg for DBP, 280 mg for DEP and 140 mg for PVAP, for an individual with 70 kg body weight.

Phthalate in tablet/capsule logo ink
For some preparations, the phthalate was contained in the tablet/capsule logo ink on the surface of the dosage formulation. In all of these preparations, the phthalate was PVAP. For those companies who responded, the level of PVAP in the ink in each preparation was below proposed EMA PDE in all products. In some cases, the manufacturer declared that the phthalate content was so low per dosage form that it was negligible or too low to measure accurately.

Phthalate in tablet/capsule/liquid formulation
Where the phthalate was contained as an excipient within the dosage form, the level of phthalate varied considerably. The EMA proposes that the presence in medicinal products of DBP, DEP or PVAP at levels giving rise to daily exposures above the PDEs may be accepted as exceptions, on a case-by-case basis taking into consideration the intended patient population, the disease seriousness and the presence (or not) of alternative treatment options. Furthermore, the EMA also proposes that in severe or terminal disease conditions, the strict application of the PDE may not be considered necessary for DBP, DEP or PVAP-containing medicinal products, where the risk of reproductive and developmental toxicity is outweighed by the benefits of treatment for patients.
Consequently, the drugs were assessed in terms of whether or not they are used acutely or chronically. Where a drug may be used in either an acute or a chronic condition, it was categorised as "chronic d ", due to the possibility that the drug may be prescribed on a long-term basis. Drugs were also categorised according to whether or not they are licensed for use in pregnancy. The SPC for some drugs advises caution in pregnancy or the drug may be used where the benefit outweighs the risk. For both of these categories, drugs were described as "benefit > risk" (Table 1).
Where the licence holder supplied information regarding DBP content, the level was above the proposed EMA PDE of 0.7 mg for 70 kg body weight in Asacol 800 mg MR (Warner Chilcott UK Ltd) and Vivotif (Crucell Italy S.r.l), the levels being 48 mg and 8 mg, respectively, at the maximum daily dose.
For DEP, the proposed EMA PDE is 280 mg per 70 kg body weight. Where the licence holder supplied information, this level was not exceeded at maximum daily dose in the DEP-containing products.
The proposed EMA PDE for PVAP is 140 mg per 70 kg body weight. There were two PVAP-containing products where the level exceeded this. These were Prednisolone 2.5 mg Gastro-resistant Tablets and Prednisolone 5 mg Gastro-resistant Tablets (Actavis UK Ltd), where the levels at the maximum licensed daily dose were 288 and 144 mg, respectively.
Four preparations contained a combination of DEP and PVAP. Of these, Epilim 200 Gastro-resistant Tablets

Summary
The aim of this study was to identify which UK licensed medicines are likely to be affected by proposed EMA guidelines on the use of phthalates as excipients in human medicinal products. Although we attempted to identify as many phthalate-containing preparations as possible by reviewing SPCs, this list cannot be considered exhaustive. For 23 products, the licence holder refused to declare the phthalate content or gave no response. At face value, it appeared that many medicines would be impacted by the recommendations as 54 medicines were identified as containing the precautionary phthalates DBP, DEP and PVAP, named in the guidelines. However, for those medicines where companies responded, once maximum daily phthalate exposures were established, only six branded medicines, namely Asacol 800 mg MR (Warner Chilcott UK Ltd), Epilim 200 Gastro-resistant Tablets (Sanofi), Prednisolone 2.5 and 5 mg Gastro-resistant Tablets (Actavis UK Ltd), Vivotif (Crucell Italy S.r.l), and Zentiva 200 mg Gastro-resistant Tablets (Winthrop Pharmaceuticals UK Limited), were identified as exceeding the EMA's proposed recommendations. Thus, this study will help to appease those concerned about the implications of enforcement of these guidelines.

Strengths and limitations
To the authors' knowledge, this study has provided the first review of the presence of phthalates in UK licenced medications. Furthermore, it has identified, where possible, which phthalate-containing medications will be affected by EMA guidance once it comes into practice. By virtue of the limited information in the public domain and the proprietary nature of drug formulations, information on the concentration of phthalates was limited to only 57 % of the drugs identified. This highlights the potential difficulty in clinical practice when undertaking a risk/benefit approach in the preceding 3 years before the enforcement of this guidance. In addition, not all SPC's are available on the eMC, further hindering the ability of making an informed decision in certain patient populations.

Conclusion
For those medicines identified as exceeding the EMA's recommendations, this study has highlighted the need to instigate a risk-benefit review, particularly in patients of childbearing age and/or with chronic conditions. To facilitate this process, the EMA, suggests taking into account factors such as the presence of non-phthalate containing alternatives, the intended patient population and the severity of the disease being treated.