Isotretinoin Treatment in Patients with Known Peanut Allergies: To Give or Not to Give?

Isotretinoin can prevent the permanent scarring evolving from untreated severe acne vulgaris, it is considered a gold standard treatment. The main side effects include dryness, mood changes and muscle and joint pain. Medicines containing soya in the UK and Europe come with a warning advising against their use by patients with soya or peanut allergies due to the risk of an allergic reaction. This is mirroring the recommendation of European Medicines Agency (EMA) which applies to isotretinoin, even though the capsules lack peanut protein, which could lead to an undertreatment of this group of patients. However, Allergy experts in the UK, representing the British Association of Dermatologists, have assessed the risk and advised that individuals with a peanut allergy, but no soya allergy, can safely use isotretinoin. The current evidence for the link between peanut-allergic patients and potential cross-reactivity with soybean oil is quite poor. Manufacturers have different insights and provide in depth response upon enquiring. The aim of this paper is to help illuminate the treatment of acne vulgaris in patients with peanut allergies and provoke discussion on isotretinoin as a potential management option in these patients.

Introduction

In the United Kingdom, approximately over 20% of the population is affected by one or more allergic disorders [1]. With a growing rate in our younger population documented by the increase in hospital admission rates due to food-induced anaphylaxis [2]. In the context of dermatology, there are 3.5 million visits to primary care in the United Kingdom due to acne vulgaris, a chronic inflammatory skin condition that, if not treated appropriately, can lead to permanent scarring and psychosocial effects [3]. The most effective and mainstay treatment prescribed by dermatologists is oral isotretinoin, a drug that should be closely monitored and, if done correctly, is a safe drug to administer [4].

The presence of highly processed soya oil in isotretinoin capsules raises concerns for patients with peanut or soya allergies in Europe and the UK. Such individuals are typically cautioned against consuming medications containing soya due to the potential threat of an allergic reaction. While both peanuts and soya belong to related food groups, it is important to note that isotretinoin does not contain peanut protein [5].

However, a thorough assessment of this risk has been conducted by allergy specialists in the United Kingdom on behalf of the British Association of Dermatologists, who have concluded that individuals with a peanut allergy can safely consume isotretinoin, provided they do not have a soya allergy. This guidance is in line with advice from the European Medicines Agency (EMA), which recommends not consuming a medical product containing soya oil if the patient is allergic to peanuts or soya [6]. This has led clinicians to avoid prescribing isotretinoin for peanut-allergic patients to avoid any adverse reaction, limiting the options to treat those with a peanut allergy and acne vulgaris. Previous iterations of isotretinoin used to contain arachis oil, a peanut-derived oil, which is why the peanut allergy cautions were initially given; however, since this ingredient has been removed, a review of excipients on the Summary of Product Characteristics, there are no peanut ingredients used in the formulation of isotretinoin [7].

Aims

This paper aims to help shed more light on the management of acne vulgaris in peanut-allergic patients and generate further conversation on whether isotretinoin is a viable resource in the management of these patients. In doing so, this can hopefully eventually guide clinicians further on prescribing to help deliver the best management for patients, reducing the extent to which the condition can develop and limiting the effects of scarring and the implications this may have.

Methodology

The report draws upon several resources to help gain an understanding of the current guidance. We investigated the safety of isotretinoin use in patients with peanut allergy by looking at the current literature. We also aimed to reach out to companies that provide isotretinoin through email to seek their guidance. We will then use our research to offer our opinion on what we think should be done in these situations based on the literature and personal experience.

Discussion

Existing Literature

A case report from Humphrey et al. highlights the barriers to this limited cross-reactivity in patients receiving the best treatment for their condition [8]. As highlighted, the package insert in the United States makes no mention of allergy for peanut users. However, many healthcare professionals have it built in to not give isotretinoin without performing any allergy tests [8]. Barring patients from the best possible solution to their condition is something we should be wary of and work towards countering this. Referring patients to an allergist before prescribing isotretinoin is a potential solution. Humphrey et al. point out further how the cross-reactivity between peanut and soybean is due to protein content; therefore, as isotretinoin contains ‘hydrogenated soybean oil’ and ‘soybean oil,’ if prepared correctly, should pose minimal risk to peanut-allergic patients. Denorme et al. have proposed similar conclusion [9]. Moreover, Ruth et al. [10] focussed on a larger sample size of 67 male children, of which 90% were allergic to peanuts; however, when testing for IgE sensitization to isotretinoin, there were 0 positive results. Hourihane et al. [11] conducted an allergy test with 60 individuals being subjected to refined peanut oil, resulting in 0 reactions, which further supports that fully refined oils, including peanut and soybean oil, do not induce allergic reactions in susceptible individuals [9], [10]. These trials further reinforce evidence and advice that the use of isotretinoin is safe in peanut-allergic patients and that soybean and peanut oil-containing products should be harmless to consume in soya and peanut-allergic patients.

Yildirim et al. [12] performed a retro-perspective review of patients who had a confirmed peanut allergy and subsequently used isotretinoin to manage their acne. They utilized Epic, a medical record software that holds the records of 2.5% of patients internationally. From the patients identified, Isotretinoin use did not result in allergic eruptions in patients with a known peanut allergy. The mean patient age was 19, using isotretinoin for 3–6 months, with one patient reaching a maximum cumulative dose of 24,300 mg 11. This supports the poor link between peanut allergy and the use of isotretinoin. Moreover, Laing et al. [13] performed a study 25 years after the licensed use of isotretinoin in the United Kingdom and found only three reports of isotretinoin-associated anaphylaxis reactions in patients with a peanut allergy. Recent research has concluded that higher risk is imposed in patients who have a cashew nut allergy as opposed to a peanut allergy [14]. Interestingly, peanut allergy does not fall under the pre-treatment checklist when dispensing isotretinoin [15].

Alden et al. [14] suggest the use of a testing protocol to at least allow cross-reactivity to be confirmed on an individual basis so we can offer a safe and effective treatment to as many patients as possible. Even once done, Walsh and Holmes [16] reported two cases where severely peanut-allergic patients were treated successfully with isotretinoin and, to take caution of the theoretical risk of cross-reactivity, administered the first two doses of isotretinoin in a hospital setting to allow for rapid access to resuscitation equipment if required. Spierings et al. [17] build upon this and combine the prior testing and hospital setting administration to further protect the patients. They reported 0 cases of anaphylactic reaction in the six young patients who were successfully treated. Their suggested solution was for patients in the clinic to take a single 20 mg tablet of isotretinoin followed by monitoring for at least one-hour post-ingestion and see what sequelae occur. This may seem like a time and cost-effective approach to the solution. However, as McCarthy et al. [18] point out, this can thin out already sparse resources and limit how many patients can benefit from this life-changing treatment. They conclude that as since Roaccutane preparations (Roche Brand name for isotretinoin) contain no arachis oil, there is no risk in the cross-reactivity between soya and peanut. Thus, particular precautions when prescribed Roaccutane^® are unnecessary [18].

Most recently, there have been statements by various governing bodies. The Medicines and Healthcare Products Regulatory Agency (MHRA), in October 2023, released the introduction of additional oversight of the initiation of isotretinoin in patients under the age of 18 and [19]. Looking through their advice and protocols, there seem to be updates concerning the adverse effects for the child-bearing population and the mental health of patients; however, there is no update on advice regarding peanut-allergic, or even soya-allergic, patients suffering from acne. A month prior, in September 2023, the British Association of Dermatologists released their position on soya-allergic patients taking isotretinoin [5]. They concluded that isotretinoin is safe to take in peanut-allergic patients and even soya-allergic patients. Allergy specialists as the link to soy allergy is through the protein contained, which is removed when refining the oil.

Additionally, the point is made that many foods containing soya oil do not have an allergy warning [5]. This is correct both in Europe and in the United States, where the Food and Drug Administration (FDA) follows a similar approach to their food market and doesn’t declare refined soya oil as an allergic ingredient [20]. Similarly, the package inserts in oral isotretinoin in the US do not list peanut allergy as a contraindication [21]. This very much contradicts Europe where we still follow EMA guidance that states if a medical product contains soya oil and the patient is allergic to peanut or soya, do not use this medicinal product [6]. This contradicts our food authority, the EU Food Safety Authority (EFSA) who, do not require fully refined soya oil to even be listed as an ingredient in foods because it does not contain any detectable soya protein, and allergists do not advise peanut-allergic subjects to avoid soya in any form [22]. This contradiction between the two approaches raises questions as to which is the right one. Looking at what we have already discussed, we would argue that the FDA has the correct approach on this matter.

With bodies such as the BAD making statements like this, it is crucial to recognize the expertise and evaluation conducted by these authorities in considering the safety of isotretinoin for patients with peanut allergies, and this is to be reflected by manufacturers. Further research and collaboration between medical professionals and regulatory bodies may contribute to refining guidelines and recommendations for patients with specific allergies. In doing so, we can help reduce the detrimental decrease in quality of life in patients suffering from acne. With the amount of literature on the matter, we wanted to reach out to manufacturers of isotretinoin to ask the manufacturers directly about their stance on the matter.

Statements from the Manufacturers

We reached out to manufacturers of Isotretinoin to ask their opinion. These included Sunpharm, Roche, and Ennogen. Two of the manufacturers responded to our inquiry.

Roche

Roch manufactures Roaccutane, a version of isotretinoin commonly prescribed by the National Health Service. We asked whether isotretinoin should be prescribed in peanut-allergic patients, and the response we received is below.

Roche responded with the following: “Thank you for your recent enquiry about Roaccutane ^® ▼ (isotretinoin) and use in a patient with a soya or nut allergy. The Summary of Product Characteristics (SPC) for Roaccutane states [23] Roche: 4.3 Contraindications” “Isotretinoin is also contraindicated in patients with hypersensitivity to isotretinoin or to any of the excipients listed in section 6.1. Roaccutane 10 mg contains refined soya-bean oil, partially hydrogenated soya-bean oil, and hydrogenated soya-bean oil. Therefore, Roaccutane 10 mg is contraindicated in patients allergic to peanut or soya.” “I can confirm that Roche Roaccutane capsules (10 mg and 20 mg) do not contain peanut oil or peanut extract. The component of the capsule that did contain peanut extract (arachis oil) was removed from the formulation in March 2009” [23]. “However, Roaccutane capsules still contain soya oil and there is a potential for those that are allergic to peanuts to also have a similar allergic reaction to soya. Therefore, the contraindication for those allergic to peanuts or soya remains on the SPC” [23]. “This guidance is in line with the EMA guidance, which states that if a medicinal product contains soya oil patients with a peanut or soya allergy should not use it” [6].

SunPharma

We asked whether isotretinoin should be prescribed in peanut-allergic patients to manufacturer SunPharma and below is the response we received.

“We want to inform you that our product Isotretinoin contains soya oil, partially hydrogenated soya oil, and hydrogenated soya oil.

Peanut and soy are phylogenetically and antigenetically related and share several homologous proteins. Patients with severe peanut allergy are also at risk of developing severe reactions to soy. Soybean oil still contains soy proteins; therefore, isotretinoin, which contains soybean oil, is contraindicated in patients with known soybean or peanut allergy, owing to the risk of potential cross-reactivity.

As a Marketing Authorisation Holder for Isotretinoin and based on the detailed data, the administration of Isotretinoin at patients with peanut allergy is contraindicated. In regards to other nuts we cannot exclude accidental cross-contamination that can occur during production, transport or filling in packaging units.

Hopefully this is helpful.”

This information gained from the medical information personnel at Roche and SunPharma indicates the reasoning that peanut-allergic patients are not allowed to be prescribed isotretinoin is due to this potential cross-reactivity with soybean oil. As we have pointed out through the review of current literature, the current evidence for this link is quite poor. Furthermore, Roche mentions the key component, Arachis oil from peanut extract, hasn’t been involved in the ingredients of Roaccutane since March 2009–nearly 15 years ago. Despite this, we are still not allowing patients with a peanut allergy to be prescribed the medication, even that the existing case reports and research prove there is limited cross-reactivity. In our literature search, we found to believe that if soyabean oil has been refined efficiently, there should be little to no protein left. However, SunPharma indicates that their soybean oil still contains protein. This brings to question if the oil should be refined further so there is little to no protein left and whether a certain concentration of protein is required for a reaction to occur. The lack of soya and peanut protein within the oil further dismantles this weakly linked cross-reactivity. The EMA even mentioned in their guidance that the cross-reactivity is ‘In line with Arachis oil.’ That component has since been removed in Roaccutane; therefore, we ask that Roche, as well as SunPharma, review the literature and modify the information on their Summary of Product Characteristics to explicitly give guidance on whether their medication can be used in peanut allergy patients. Additionally, we call for the EMA to alter their guidance on soybean oil excipient medications in the review of what we have already discussed.

Author Opinions

Upon review of the literature and response from the manufacturer, it is unlikely that the small amount of refined soybean oil in oral isotretinoin would cause problems in people with a peanut allergy. This is due to the lack of protein content within the oil upon which this theoretical risk is based and the abundant number of cases where isotretinoin has been used successfully to treat acne vulgaris. Guidelines need to be altered as we believe that peanut-allergic patients can tolerate isotretinoin. There is no established method of administering isotretinoin to these patients; however, authors have recommended additional allergy tests and oral challenges under observation. We think these are appropriate but only to an extent as resources need to be weighed up; otherwise, this effective drug could very much be limitingly prescribed. Patients with peanut allergies will be able to tolerate oral isotretinoin and should not be limited in treatment options due to theoretical, low-risk cross-reactivity between soya and peanuts. Even soya-containing medicinal products should be reconsidered as to whether they should be contraindicated in soya-allergic patients due to the low protein content within refined soybean oil.

Conclusion

Acne Vulgaris is an inflammatory condition affecting many of the young people in our population and oral isotretinoin is the best way to combat it, prescribed only by dermatologists. The guidelines set in place, however, are more counterproductive than helpful. We believe that no precautions should be taken when prescribing isotretinoin to patients with peanut allergies and that reconsideration should be made concerning listing soybean oil as an allergen in medical products. We hope this paper can help push this existing notion forward to help improve the management of patients suffering from acne and peanut allergy, reduce further complications, and improve quality of life.