Mucocutaneous side-effects of isotretinoin and their management.
Article Type: Reprint
Author: Cunliffe, W.J.
Pub Date: 12/01/2009
Publication: Name: Clinical Dermatology Publisher: Mediscript Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Mediscript Ltd. ISSN: 1750-306X
Issue: Date: Dec, 2009 Source Volume: 25 Source Issue: 4
Accession Number: 218606445
Full Text: Introduction Cheilitis

Isotretinoin is an extremely effective drug for the treatment of otherwise therapy-resistant acne. Side-effects can be divided into two groups mucocutaneous and systemic. The major systemic side-effect is that of teratogenicity. Systemic side-effects and their management will be discussed in a future issue of this journal.

The emphasis for much of this article is on the pictorial presentation of the physical signs, with a didactic text to help the practising physician treat such patients. Tables 1 and 2 summarize the most common and uncommon mucocutaneous side-effects associated with isotretinoin. Many of the mucocutaneous side-effects are dose related and dose reduction may be appropriate if the side-effects are troublesome.

Cheilitis occurs in virtually all patients treated with isotretinoin and can vary from mild to very severe dryness with cracking of the lips (Figure 1). Secondary infection with Staphylococcus aureus may occur, producing more erythema and soreness (Figure 2). Classical impetigo is rare.

Prevention

It is important to use a good-quality lipsalve regularly from the day of starting isotretinoin therapy. Several applications a day are necessary.

Treatment

All cases will require regular use of a simple moisturizing ointment, such as an emulsifying ointment, petroleum jelly or one of the many commercial prescribable emollients. The greasier the ointment the more effective it will be. Soap may aggravate cheilitis so the use of one of the many bath additives for facial washing (for example, Oilatum Emollient[R], Balneum[R], Emulsiderm[R] or Alpha Keri[R]) should be considered.

In moderate cases, often associated with a low-grade peri-oral inflammation, an intermediate-strength steroid, often combined with an antiseptic, such as Haelan-C[R] ointment twice daily, is useful.

In more severe case, a swab should be taken to exclude colonization with S. aureus. Such patients may require mupirocin ointment (Bactroban[R]) or Naseptin[R] ointment twice daily. Not infrequently, a five-day course of oral flucloxacillin or 250mg erythromycin four times daily is essential to bring the symptoms and signs under control.

Blepharo-conjunctivitis

Blepharo-conjunctivitis may range in severity from mild dryness to very sore, inflamed conjunctivae (Figure 3).

Prevention

This complaint is more of a problem if patients wear contact lenses and even more so if the lenses are hard. More recently there has been an increased use of gas permeable soft lenses, which has reduced the degree of blepharo-conjunctivitis. Therefore, it is necessary to ask your patient whether they are wearing contact lenses.

Treatment

In mild cases a commercially available eyelid moisturizer may be all that is necessary. Ointments are preferred to creams and are usually applied at night rather than during the day (for example, Lacri-Lube[R]). A gritty sensation during the day may be eased with polyvinyl alcohol eye drops, such as Liquifilm Tears[R]. In moderate cases, hydrocortisone ointment applied at night will often resolve the problem.

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In more severe cases the presence of S. aureus infection should be considered and a swab obtained for culture and sensitivity. Prescribe chloramphenicol eye ointment twice daily and add a five-day course of an antibiotic if the symptoms are not resolved.

Nasal vestibulitis

This is not as frequently seen as cheilitis. It is often characterized by dryness of the nostril and at times cracking. Most humans have a predilection for picking their nose (usually privately), which may exacerbate the disorder and result in a crusty formation in the anterior nares. Frank nose bleeds are rare. These symptoms are exaggerated at the time of an upper respiratory tract infection.

Prevention

Petroleum jelly or a commercially available emollient should be applied to the anterior nares. The patient should be told not to apply the ointment too far into the nostril.

Treatment

In mild cases petroleum jelly or a commercial emollient should be used. Ointments are preferred and several applications a day will be required. In moderate cases, mupirocin ointment (Bactroban[R] nasal ointment) could be used twice daily. In severe cases, swab the nares and consider the addition of oral antibiotics, for example a five-day course of flucloxacillin or erythromycin. An extremely rare side-effect is nasal cellulitis (Figure 4). This is very painful and may necessitate hospital admission. Severe nose bleeds normally occur only in individuals who are already very prone to nose bleeds. The help of an ear, nose and throat specialist to cauterize the affected vessels may be required.

Facial dermatitis

Facial dermatitis is a very common feature that ranges from mild exfoliation to extensive scaling and is often associated with erythema (Figure 5). More severe cases are associated with localized S. aureus infection, presenting as oozing and crusting. The typical golden-yellow crusts of impetigo are rare.

Prevention

A moisturizer should be used regularly--sooner rather than later.

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Treatment

In mild cases moisturizing ointments are preferable to creams. In moderate cases 1% hydrocortisone or a medium-strength steroid ointment should be considered. This would usually be required only for a few days before reverting back to an ordinary moisturizer. Often in severe cases there may be cracking and this usually signifies secondary impetiginization. Swab the skin and prescribe a five-day course of flucloxacillin, erythromycin or clindamycin.

Widespread or patchy eczematous changes

Isotretinoin may be associated with a whole range of eczematous changes on various parts of the body; these include widespread drying of the skin, palmar dermatitis, stickiness of the palms, follicular eczema, discoid eczema and peri-oral eczema.

Widespread drying of the skin

This usually affects the upper trunk.

Palmar dermatitis

This is particularly evident on the tips of the fingers and may masquerade as contact dermatitis--allergic or irritant (Figure 6).

Stickiness of the palms

This is a rare feature of isotretinoin treatment (Figure 7) and is more often observed with acitretin or etretinate. There is no way of preventing this disorder; treatment usually involves dose reduction.

Follicular eczema

This is rare, presenting as follicular lesions of eczema particularly on the limbs (Figure 8).

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Discoid eczema

Again an uncommon eczematous reaction to the drug, presenting as typical discoid eczema (Figure 9).

Peri-oral eczema

Peri-oral eczema is uncommon and probably drug related (Figure 10).

Treatment

For widespread drying of the skin preventative measures include bath oil substitutes, moisturizing ointments or oily creams, which should be applied two or three times a day. If the eczematous changes are more extensive, 1% hydrocortisone ointment should be considered in conjunction with bath oils. This is usually quite adequate.

Treatment of palmar dermatitis, stickiness of the palms, follicular eczema, discoid eczema and peri-oral eczema usually involves the use of an oilated bath substitute, a topical steroid twice daily--preferably an ointment--just for a few days and then reversion back to a moisturizing cream or ointment. Oral antihistamines are rarely required as the itch associated with this type of eczema is relatively mild.

Because of the infrequent nature of these side-effects, it is sometimes difficult to know whether they are drug related or not. The causal relationship between onset and improvement with dose reduction suggests that they are aetiologically related.

Pyogenic granulomata

This is an uncommon side-effect. Pyogenic granuloma may be single or multiple (Figure 11) and present as haemorrhagic or haemorrhagic and scaly papules. They may also ulcerate (Figure 12) and are not specific to isotretinoin therapy since they have been recorded uncommonly--in patients who have not received isotretinoin. They are, however, much more frequent in acne patients treated with isotretinoin.

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Prevention

There is no form of prevention.

Treatment

In isolated cases cautery and curettage should be performed under local anaesthetic. However, in extensive cases potent topical steroids, such as Dermovate-NN[R], should be applied twice daily.

Scalp folliculitis

Scalp folliculitis is an uncommon, but disturbing, feature of isotretinoin therapy (Figure 13). These lesions range from small papules or pustules to haemorrhagic crusting. The cause is not always identified In some patients scalp folliculitis is dose dependent and improves on dose reduction and in others S. aureus is identified and the patient will respond to an antiseptic shampoo and a five-day course of an appropriate antistaphylococcal therapy.

In some patients there appears to be an overgrowth of Pityrosporum ovale organisms and the patient may improve with an appropriate antifungal cream or shampoo, particularly ketoconazole.

In some patients the cause is unknown and the side-effect may persist on cessation of therapy. A small number of patients with acne have scalp folliculitis, ie scalp acne. Such patients have symptoms that precede therapy and are isotretinoin responsive.

Facial erythema

This is an uncommon side-effect. It is dose dependent and when severe may be very disturbing to the patient (Figure 14).

Prevention

Excessive sunshine should be avoided wherever possible.

Treatment

Reduce the dose. Consider cosmetic camouflage until the acne is brought under adequate control. Good sunblocks may be required.

Photosensitive dermatitis

Photosensitive dermatitis is unusual and is dose related

Prevention

Minimization of exposure to sunshine is often impractical, thus a very good sunblock should be recommended.

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Treatment

Advise the patient on sun protection and reduce the dose of isotretinoin. An intermediate-strength topical steroid ointment such as Haelan[R] should be applied twice daily for a few days.

Paronychia

This is uncommon, presenting as pain with redness and swelling of various intensities (Figure 15). The most common cause is S. aureus infection.

Prevention

There are no preventative measures

Treatment

For mild cases, mupirocin ointment or other antiseptics should be applied twice daily. In moderate cases oral antistaphylococcal therapy should be undertaken.

Impetigo

As discussed in earlier sections, impetiginization is a common complication of isotretinoin therapy in particular impetiginization of cheilitis, xeroderma and eczematous lesions.

Prevention

Some centres advocate the use of mupirocin ointment to the nose twice daily, but widespread use is probably unnecessary.

Treatment

When present, a five-day course of flucloxacillin, erythromycin or clindamycin should be undertaken with appropriate therapy of the eczematous or dry skin. The preferable treatment is combined antimicrobial/anti-inflammatory therapy with, for example, Haelan-C[R] ointment.

Skin fragility

This is an uncommon side-effect (Figure 16). It may occur due to rubbing of the skin or the application of a plaster to the skin.

Prevention

There are no preventative measures.

Treatment

Dose reduction is necessary. The skin should be treated with care, for example, gentle washing with an oilated soap substitute. The problem usually resolves after 7-10 days. It can be quite alarming to the physician and patient, but leaves no permanent marks on the skin.

Balanitis/vulvitis

This is not often seen by the dermatologist, but it is recognized by our genitourinary colleagues. On the whole, dermatologists tend to look at the top rather than the bottom half of the body, so they may underestimate these complications. Symptoms vary from mild dryness of the vulva or penis (Figure 17) through to severe dryness, cracking, oozing and impetiginization. Frequency of micturition may be a feature in severe cases. It is essential in such patients to exclude a sexually transmitted disease.

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Treatment

Obviously, the patient is concerned and so reassurance is essential. For mild cases petroleum jelly or other moisturizing ointments should be used several times a day. In moderate cases 1% hydrocortisone ointment should be applied twice daily and in severe cases an intermediate-strength steroid ointment should be used (this is often combined with an antiseptic, such as in Haelan-C[R] ointment).

Conclusion

Many mucocutaneous side-effects can be prevented by the regular use of good-quality emollients, ointment bases being preferred to creams. The use of oilated bath oil substitutes and the avoidance of soap (for facial washing and/or bathing) often helps. Mild cases frequently require an increased use of emollients, and moderate cases intermediate-strength steroid ointments, combined with an antiseptic. In a severe case a patient may be virtually impetiginized and will require oral antibiotics. A reduced dosage of isotretinoin may be required.

Oilatum Emollient is a registered trademark of Stiefel Laboratories Limited.

Balneum is a registered trademark of Merck E Pharmaceuticals Limited.

Emulsiderm is a registered trademark of Dermal Laboratories Limited.

Alpha Keri is a registered trademark of Westwood Pharmaceuticals.

Haelan-C is a registered trademark of Dista Products Limited.

Bactroban is a registered trademark of Smithkline Beecham Pharmaceuticals.

Naseptin is a registered trademark of Zeneca Pharma.

Lacri-Lube is a registered trademark of Allergan Limited.

Liquifilm Tears is a registered trademark of Allergan Limited.

Dermovate-NN is a registered trademark of Glaxo Laboratories Limited.

WJ Cunliffe

Formerly of The General Infirmary at Leeds, UK *

* Professor Cunliffe is now retired from all clinical practice, as from 2002. Leading Article reprinted from Cunliffe WJ. Mucocutaneous side-effects of isotretinoin and their management. Retinoids Today and Tomorrow, 1994, 36, 4-10
Table 1: Isotretinoin: mucocutaneous side-effects with an
incidence of greater than 30%.

                              Incidence %

Cheilitis                          95
Facial erythema                    67
Facial dermatitis                  65
Vestibulitis/epistaxis             55
Blepharo-conjunctivitis            30
Primary irritant dermatitis        30
Discoid eczema                     30
Follicular eczema                  30
Xeroderma                          30

Table 2: Isotretinoin: mucocutaneous side-effects with an
incidence of less than 10%.

                                  Incidence %

Staphylococcus aureus infection       7.5
Sun sensitivity                        1
Pyogenic granulomata                   1
Acne flare                             2
Paronychia                             2
Hair loss                             0.5
Curly hair                            0.5
Scalp folliculitis                     2
Eruptive xanthomata ([dagger])         0
Osteoma cutis ([dagger])               0
Erythema nodosum ([dagger])            0
Skin fragility                         2

([dagger]) Reported very uncommonly in other series
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