>> Clinical Guidelines

Advice on the safe introduction and continued use of isotretinoin in acne

Since its introduction into clinical trials in the mid 1970's and its widespread use since the early 1980's, isotretinoin has proved a very effective therapy for severe and persistent acne. Initially only used for severe cystic acne, its use has been gradually extended for those with significant but milder disease that has been persistent despite the use of conventional topical and oral therapies¹. The profile of side effects has been well described, and the need for appropriate care in its use, particularly in women at risk of pregnancy, is well understood². More recent concerns over the potential development of mood change, and particularly depression^3,4, have led to further re-evaluation both of its use and the necessary pre-treatment evaluation and further monitoring. The American Food and Drug Administration has recently expressed its opinion on the use of isotretinoin⁵. The current document expresses the view of the BAD on this issue on the basis of current knowledge. It does not discuss the indications for use of isotretinoin that are the subject of a BAD Guideline which is currently in production, but considers the precautions necessary before and during therapy. Members should be aware that the European Medicines Control Agency is reviewing the registration of isotretinoin as a consequence of the application by Schering for a European license. It is possible, or even likely, that the recommendations made in this document will have to be revised when the results of the review are known.

Overview

The majority of the potential adverse effects of isotretinoin are well documented^1,2,3,4, have been reviewed⁶ and are discussed in the manufacturers' product documentation.

Briefly

The drug is contra-indicated in patients with hypervitaminosis A, uncontrolled hyperlipidaemia, and during pregnancy or lactation. It should be used with caution in patients with renal and liver disease.

The majority of the adverse events are dose related and predictable in terms of the known pharmacological and physiological effects of the drug.

• Variable dryness of skin and mucous membranes including nose, eyes and lips. These symptoms are dose related, and may lead to active inflammation eg cheilitis.
• facial erythema, eczema, hair loss, photosensitivity, skin fragility, paronychia and pyogenic granuloma
• myalgia and arthralgia
• photophobia, impaired night vision, keratitis
• nausea, colitis, pancreatitis (in those with hypertriglyceridaemia)
• abnormalities of liver function including hepatitis:
• elevation of triglyceride and cholesterol levels: these are rare, and there are data suggesting that routine screening during treatment is not worthwhile^7,8, although they are still recommended by the manufacturers. There are also recent data indicating that the development of hyperlipidaemia during treatment may be a marker for the development of significant hyperlipidaemia in later life⁹.
• bacterial overgrowth, particularly Staphylococcus aureus
• cutaneous vasculitis
• benign intracranial hypertension

Whilst these side effects are generally mild and reversible, occasional severe reactions occur. A full and appropriate history should be taken and recorded before isotretinoin is prescribed.

There are two specific areas for concern and care that require more specific advice

1. Risk of teratogenicity

The consequences of taking isotretinoin while pregnant are well described². Every action should be taken to ensure that the risks and consequences are fully understood by all female patients being considered for treatment. It is suggested that:

1. A current sexual history in all females of childbearing potential is taken. No assumptions should be made on the basis of age, race or religious beliefs, although clinicians should be sensitive to such issues. It may be necessary to conduct some of this enquiry with the patient alone, in the absence of parents and partners. A patient's sexual behaviour may change during therapy, so a discussion of the risks of teratogenicity should not be limited to those who are sexually active before treatment starts.
2. A menstrual history should be taken: patients with irregular menses present a difficult management problem that may require specialist advice.
3. All female patients at risk of pregnancy should have a pregnancy test, preferably, but not essentially, performed on blood since it is more accurate at an earlier stage, in the 2 weeks before starting treatment.
4. An appropriately trained clinician should give advice on adequate contraception: this will not necessarily be the dermatologist. Ideally contraception should be hormonal - either the combined contraceptive pill, or injectable or implantable hormonal therapy should be used. The progesterone-only pill may be less reliable in those taking isotretinoin.
5. All female patients who are at risk of pregnancy should sign a form indicating that they fully understand the risks of pregnancy, that they are not currently pregnant and have been using appropriate contraception for one month before starting treatment, and that the responsibilities of the patient and physician have been discussed. This should include the responsibility of the patient to consult their GP, dermatologist or pharmacist if they have knowingly had unprotected intercourse so that the possibility of using emergency contraception can be considered.
6. Treatment should begin on day 3 of the patient's next menstrual cycle following a negative pregnancy test.

2. Mood Change

Whilst the evidence for the problems due to retinoids in pregnancy is clear-cut, the situation for the suggested link to mood change is much less certain. Changes in mood have been reported in patients taking Vitamin A¹⁰, etretinate¹¹ and isotretinoin. Such symptoms have been reported in the treatment of patients with acne, disorders of keratinisation and in patients with cancer given isotretinoin¹².  Vitamin A and its metabolites do cross the blood/brain barrier, can induce benign intracranial hypertension and cause headache, and so there are no theoretical reasons why mood alteration could not occur¹³.  However, the data supporting such a link are either anecdotal or based on small inconclusive studies, often with significant design faults. In particular it has not been possible to distinguish accurately between mood change due to the drug and to the acne itself.

The problem is not a new one. Beginning in 1983, there have been a number of case reports^3,14,15, some well publicised, as well as small case studies^16,17.  These suggest that mood change, and particularly depression, can occur during or soon after the use of isotretinoin. Hard evidence is not available, but the small number of studies in which patients with apparent mood change were rechallenged with isotretinoin and had a relapse of mood alteration is the most compelling. Seven of 700 isotretinoin-treated patients were described to have psychiatric symptoms in a case series by Scheinman et al¹⁶.  The most common symptoms reported have been fatigue, irritability, poor concentration, sadness, crying spells, loss of motivation and forgetfulness. The time course of onset of mood alteration is variable, but is often later in treatment, and in some cases, depressive symptoms have only occurred in second or even third courses of therapy. Resolution of symptoms is usually rapid - within days to weeks of discontinuing the drug -, although there are instances of prolonged illness requiring anti-depressive therapy¹⁴.  Not all patients have stopped therapy on developing depressive symptoms: some have elected to continue with isotretinoin and have improved psychologically without additional antidepressive therapy, and others have received psychological support and/or antidepressant medication. The frequency of suicidal behaviour appears to be very small - 37 suicides in 5 million individuals exposed in the USA between 1982 and 2000¹⁸.  This figure may be an under-estimate because of under-reporting since the numbers increased after the FDA warning in 1998, but if true it is lower than the estimated suicide rate for individuals of comparable age and sex distribution¹⁸.  It is important to be aware that suicidal behaviour can occur with psychotic conditions other than depression.

On a similar more positive note, there is a larger study of 7195 patients treated with isotretinoin compared with 13,700 treated with antibiotics drawn from Canadian and UK databases¹⁹ examining the risk of depression and suicide in these patients with acne. The UK data are unreliable because they relied upon the recording of isotretinoin therapy by GPs who are not responsible for prescribing it, and there was selection bias in the ascertainment of mental disorders. This study concluded that neither depression nor suicide were more common in patients treated with isotretinoin, but was not sufficiently large to confirm this reliably for suicide, nor for depression if the UK data is excluded. It was not designed to answer the question of whether there was an effect of acne itself on the development of psychiatric or psychological symptoms, although other studies have indicated this to be the case^20,21.

From the available data, it is unclear whether those patients with a pre-treatment history of depression may be more at risk. The frequency of pre-treatment anxiety and associated psychological traits both in the individual affected and their family is strikingly high (60 -70%) in those cases reported to the American FDA¹⁸. There are also reports of apparently spontaneous and idiosyncratic mood alteration in individuals without a preceding history of psychiatric disease²². Conversely, there are data indicating an improvement in psychiatric well being in patients with acne as their skin disease has improved after receiving isotretinoin^20,21.

In summary, there are unproven suggestions that isotretinoin can produce mood change: this has been reported in patients with or without preceding psychiatric illness, and thus far there are no predictive tests that allow the level of risk (if any) to be quantified.

In the absence of a definitive study large enough to detect what all agree is at worst a very uncommon effect (requiring around 8000 subjects), for now, we suggest that:

i). A direct enquiry about previous psychiatric health should be made of all patients who are being considered for isotretinoin and the facts recorded fully in the notes. There may be a role for specific psychiatric questionnaires, but this remains a subject for research.

ii). All patients, and their parents in the case of minors and adolescents, should be made aware of the potential for mood change in a realistic, non-judgemental way, and should be advised to ask their family and friends to comment if such change should occur.

iii). Direct enquiry about psychological symptoms should be made at each clinic visit. Suggested screening questions might be²²:

For most of the last 2 weeks…

a) Have you been feeling unusually sad or fed up?

b) Have you lost interest in things that used to interest you, or gave you pleasure?

More extensive screening using a validated questionnaire may be helpful. The Beck questionnaire²³, the Baer HANDS²⁴ questionnaire, or the 6 question screening tool advocated in a recent BMJ review²⁵ may be useful.

iv). If symptoms of depression or mood change do occur, then ideally, isotretinoin treatment should be discontinued. However, some patients, after discussion, may wish to continue with the drug because of the benefit to their skin. In this case, specialist psychiatric support should be obtained.

v). If serious psychiatric disease is suspected, there should be an immediate referral to the psychiatric services.

Audit points

1. The frequency with which female patients sign the form indicating that they have received appropriate information.

2. The number of patients who have had serum lipids checked at least once during treatment.

References

1. Cunliffe WJ, Simpson N. Diseases of Sebaceous glands. in Rook's Textbook of Dermatology. Eds Champion, Burns, Breathnach, Burton. Fifth Edition, Blackwell Oxford, 1996, pps
2. Strauss JS, Cunningham WJ, Leyden JJ, Pochi PE, Shalita AR. Isotretinoin and teratogenicity. J Am Acad Dermatol. 1988;19:353-4
3. Hazen PG,Carney JF,Walker AE,Stewart JJ. Depression - a side effect of 13-cis-retinoic acid therapy. J Am Acad Dermatol. 1983;9:278-9
4. Hanson N, Leachman S. Safety issues in isotretinoin therapy. Semin Cutan Med Surg. 2001;20:166-83
5. Josefson D. Acne drug is linked to severe depression. BMJ. 1998;316:723
6. Cunliffe WJ,van de Kerkhof,Caputo R, et al. Roaccutane treatment guidelines: results of an international survey. Dermatology. 1997;194:351-7
7. Barth JH et al. Isotretinointherapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol. 1993;129:704-7
8. Alcalay J,Landau M,Zucker A. Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests. J Dermatol Treatment. 2001;12:9-12
9. Radandi N,Daniels R, Racorbelli A, et al. High Risk for hyperlipidaemia and the metabolic syndrome after an episode of hypertriglyceridaemia during 13 cis retinoic acid therapy for acne: a pharmacogenetic study. Ann Int Med. 2002;136:582-589
10. Restak RM. Pseudotumor cerebri, psychosis and hypervitaminosis A. J Nerv Ment Dis. 1972;155:72-5
11. Henderson CA, Highet AS. Depression induced by etretinate. Br J Dermatol. 1989;298:964
12. Meyskens FL Jr. Short clinical reports. J Am Acad Dermatol. 1982;6:732
13. Krezel W,Ghyyselinck N,Samad TA, et al. Impaired locomotion and dopamine signalling in retinoid receptor mutant mice. Science. 1998;279:863-7
14. Gatti S, Serri F. Acute depression from isotretinoin. J Am Acad Dermatol.1991;25:132
15. Byrne A,Hnatko G. Depression associated with isotretinoin therapy. Can J Psychiatry. 1995;40:567
16. Scheinman PL,Peck GL,Rubinow DR,DiGiovanna JJ,Abangan DL,Ravin PD. Acute depression from isotretinoin. J Am Acad Dermatol.1990;22:1112-4
17. Bruno NP, Beacham BE, Burnett JW. Adverse effects of isotretinoin therapy. Cutis. 1984;33:484-9
18. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol. 2001;45:515-9
19. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide and attempted suicide. Arch Dermatol. 2000;136:1231-6
20. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol.1999;140:273-82
21. Rubinow DR, Peck GL, Sqillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol. 1987;17:25-32
22. Millard LG. Depression in patients treated with isotretinoin. Br J Dermatol. 2001;142:S25
23. Jacobs DG, Deutsch NL, Brewer M. Suicide, depression and isotretinoin: Is there a causal link? J Am Acad Dermatol.2001;45:S168-75
24. Beck AT,Steer RA,Brown GK. Beck Depression Inventory Manual, ed 2. San Antonio, The Psychological Corporation, 1996
25. Baer L, Jacobs DG,Meszler-Reizes J, et al. Development of a brief screening instrument: the HANDS. Psychother Psychosom. 2000;69:35-41
26. Peveler R,Carson A,Rodin G. Depression in Medical Patients. Br Med J. 2002;325:149-152

Declaration of Interest

The Retinoid Working Party consisted of:

Dr Mark Goodfield (Chair). Dr Goodfield has received no direct or indirect sponsorship from either of the companies that supply isotretinoin. The Department in which he works has received both specific and non-specific sponsorship for research from Roche in the past.

Dr Neil Cox. Dr Cox has received sponsorship from Roche to attend non-targeted educational meetings in the past.

Mrs Alison Dudley (Chief executive of the Acne Support Group). The Acne Support Group has received financial support from Roche. Mrs Dudley has received no direct sponsorship from either of the companies supplying isotretinoin.

Dr Clifford McMillan. Dr McMillan has received no direct or indirect sponsorship from either of the companies supplying isotretinoin.

Dr Leslie Millard. Dr Millard has received no direct or indirect sponsorship from either of the companies that supply isotretinoin.

Dr Nick Simpson. Dr Simpson has received honoraria and travel support for contributions to national and international meetings from Roche and Douglas Pharmaceuticals (who supply isotretinoin in Australasia). These meetings have been both targeted and non-targeted. He has contributed to medical advisory panels held on behalf of Roche.

Pre-treatment Checklist for Isotretinoin Treatment

This checklist suggests the steps that may be taken before patients are started on isotretinoin: as with all such lists, it may be modified for individual circumstances, and is not intended to represent essential practice.

Only medical staff trained in its clinical use should prescribe isotretinoin and before any treatment, the site, nature and severity of acne should be documented.

1) Take and record a full history appropriate to the known side effects of isotretinoin.

2) The outcome of previous treatment episodes with isotretinoin should be recorded.

3) General side effects should be discussed and written information given: for example, information leaflets produced by the manufacturers or by the Acne Support Group may be used.

4) In potentially child-bearing female patients of any age:

• Warn the patient of the risk of teratogenicity during treatment and for one month afterwards.
  Give appropriate written information
• Establish whether the patient is currently sexually active. Record the patient's current method of contraception, and stress the importance of using adequate contraception should they become sexually active during the period of risk.
• The patient's menstrual history should be established.
• Ensure a negative pregnancy test in those at risk within the 2 weeks before treatment, and record the result of this in the notes.
• If necessary, an appropriate GP/specialist may be involved to give advice on contraception. Inform the patient of the need to consult their GP, consultant or pharmacist immediately if there is a risk of pregnancy during treatment so that emergency contraception can be considered. Written information may be useful.
• Treatment should begin on day 3 of the patient's next menstrual cycle following a negative pregnancy test.

5) i). Make a direct enquiry about previous and current psychiatric health and record the

ii). Specifically discuss with patients, and their parents in the case of minors and adolescents, the potential for mood change in a realistic, non judgemental way.

iii). Advise that family and friends should comment if such change should occur.

6) Take blood for liver function tests and fasting lipids. Advise patient to start therapy once the tests have been reviewed.

7) Give the patient a telephone number to which they may report significant complications.

8). Arrange an appropriate follow-up appointment.

Confirmation of Receipt of Information Concerning the Potential Harmful Effects on Pregnancy of Isotretinoin Treatment

I understand that I have been prescribed isotretinoin as treatment for acne. My doctor has discussed potential side effects of the medication with me. In particular, I understand that the drug may be harmful to unborn babies, and I confirm that:

a) I am not aware that I am currently pregnant

b) I have been using appropriate contraception for one month before starting treatment.

c) I understand the need for continued contraception throughout treatment and for one month afterwards. I am aware that if there is a risk of pregnancy during treatment, I should immediately consult my GP, specialist or pharmacist to discuss the need for emergency contraception.

d) I am aware that significant damage may occur to any baby conceived whilst I am taking isotretinoin, and that such potential damage would provide grounds for termination of the pregnancy.

Name:

Signature:

Date:

Review Checklist for Isotretinoin Treatment

This checklist may be used as a reminder of the steps that may be taken on return visits for patients taking isotretinoin: as with all such lists, it may be modified for individual circumstances, and is not intended to represent essential practice.

1. Check effectiveness of treatment.

2. Check compliance with both isotretinoin and contraception and ask about the risk of pregnancy.

Discontinue isotretinoin and arrange a repeat pregnancy test if necessary.
Remind the patient of the availability of emergency contraception.

3. Specifically enquire about common side effects, and particularly mood change.
Suggested questions might be:

For most of the last 2 weeks…..
e) Have you been feeling unusually sad or fed up?
f) Have you lost interest in things that used to interest you or gave you pleasure?

Consider the use of an extended questionnaire for additional screening.

If such symptoms have occurred, assess their severity and consider the need for expert psychiatric or psychological input.

Discuss the need to discontinue isotretinoin with the patient and their parents if appropriate.

4. Ask an open question about other side effects.

5. Arrange blood tests if necessary:
If they are abnormal, decide whether to stop or to reduce the dose of isotretinoin.

6. Arrange a follow up appointment as indicated by progress and the results of any investigations.
This may be an open appointment in many uncomplicated cases.

Final Visit Checklist

This checklist may be used as a reminder of the steps that may usefully be taken at the end of an isotretinoin treatment course: as with all such lists, it may be modified for individual circumstances, and is not intended to represent essential practice.

1). Check effectiveness of treatment.

2). Check compliance with both isotretinoin and contraception.
Arrange a repeat pregnancy test if necessary.
Ensure that contraception is continued for one month after discontinuing isotretinoin.

3). Specifically enquire about common side effects, and particularly mood change.
Suggested questions might be:
i) Have you been feeling unusually sad or fed up?
ii) Have you lost interest in things that used to interest you or gave you pleasure?

Consider the use of an extended questionnaire for additional screening

If symptoms of mood change have occurred, assess their severity and consider the need for expert psychiatric or psychological input.

4). Ask an open question about other side effects.

5). Arrange repeat blood tests if indicated and take any necessary action.

6). Remind the patient about the need to inform the supervising consultant of any late complications.

7). Ensure that any unused isotretinoin is returned.

Possible isotretinoin side-effect checklist to be completed by patients

Name

Hospital number

Date of appointment

Have you had any of the following side-effects? (circle appropriate choices)

Dry lips                                             No          Mild          Moderate           Severe

Joint or muscle pain                           No          Mild          Moderate           Severe

Nosebleed                                         No         Occasional            Frequent

Headache different from normal            No         Yes-mild               Yes-severe

In the last two weeks

Have you been feeling unusually sad or fed up?                            No                   Yes

Have you lost interest in things that used to interest you
or gave you pleasure?                                                                No                    Yes

Any other side effects? (please specify)

Female patients only:

Have you used reliable contraceptive measures whilst taking isotretinoin?

Yes             No             Not applicable

Have you any reason to believe you may have become pregnant whilst taking isotretinoin?

Yes             No              Not applicable

Reminder -female patients must take effective measures to avoid pregnancy during treatment and for a month afterwards.

Name (please print):

Signature:

Produced in 2003 by the British Association of Dermatologists