1.)  [Voriconazole: a new weapon against invasive fungal infections].

Rev Med Brux. 2004 Jun;25(3):166-71.

[Article in French]

Aoun M.

Laboratoire de Microbiologie et Departement des Maladies Infectieuses, Institut Jules Bordet, ULB, Bruxelles.

Voriconazole is a fluoropyrimidine derivative of fluconazole with an extended spectrum of activity, non-linear pharmacokinetic characteristics, available intravenously and orally with an excellent bioavailability, and a good penetration into tissues including the brain. It is metabolized in the liver by the cytochrome P450 and less than 1% is eliminated in the urine. Voriconazole has been studied extensively in numerous randomized clinical trials of invasive fungal infections and became the therapy of choice of invasive aspergillosis, fusariosis and scedosporiosis. Voriconazole is an alternative for invasive candidiasis refractory or resistant to fluconazole. Voriconazole has a good tolerability and acceptable safety profile and has added a new weapon to our therapeutic armamentarium against fungi.

2.) [New antifungal agents and bronchopulmonary mycoses]

Rev Pneumol Clin. 2004 Jun;60(3):139-44.
[Article in French]

Germaud P, Morin O.

Service de Pneumologie, CHRU Nantes, boulevard Jacques-Monod, 44093 Nantes Cedex 1. patrick.germaud@chu-nantes.fr

The frequency of respiratory mycosal infections has increased over recent Years. Diagnosis has been improved by recent epidemiological data and advances in radiological and mycological diagnostic methods. Two new antifungal agents have recently received marketing approval: voriconazole and caspofungine. Voriconazole belongs to the echinocandin family of antifungals. Sites of action of antifungals have become more diversified: amphotericins act on ergosterol directly, azolated agents act on the synthesis of ergosterol, flucytosine affects synthesis of nucleic acids, and echinocandins alter the fungal wall. Synergetic or additive combinations, such as amphotericin-caspofungine, or voriconazole-caspofungine, can be proposed for advanced disease. Thus both first intention and secondary treatments, particularly for systemic candidiasis and aspergillosis, have been modified. These new protocols take into consideration the severity of the mycosal infection, co-morbidity, and drug combinations as well as cost.

 

3.) Guillain-Barre syndrome seen in users of isotretinoin.

BMJ. 2004 June 26; 328 (7455): 1537

J Pritchard, neurology research registrar,1 R Appleton, consultant paediatric neurologist,2 R Howard, consultant neurologist,3 R A C Hughes, professor of neurology1


1 Department of Clinical Neurosciences, Guy's, King's, and St Thomas's School of Medicine, Guy's Hospital, London SE1 1UL 2 Royal Liverpool Children's NHS Trust, Liverpool 3 St Thomas's Hospital, London


Correspondence to: J Pritchard jane.pritchard@kcl.ac.uk

Top
References


We report Guillain-Barre syndrome in people taking oral isotretinoin, a retinoid drug used in secondary care for severe acne.1 The Committee on Safety of Medicines has received one other report of Guillain-Barre syndrome after oral isotretinoin (Committee on Safety of Medicines, private communication).

Case 1—A 31 year old man took 80 mg of oral isotretinoin a day for five weeks, during which he had epistaxis, dry lips, cough, and arthralgia before developing paraesthesiae in his feet and influenza-like symptoms. The next day he could not stand due to an areflexic tetraparesis and needed ventilatory support. Within four days he could only blink.

Case 2—A 13 year old boy took 50 mg of oral isotretinoin a day for two months, stopped for one week, and then took 30 mg a day for six weeks but had epistaxis, lethargy, and headaches. After stopping isotretinoin again for 10 days he developed a flaccid areflexic tetraparesis needing ventilatory support.

Both patients displayed cerebrospinal fluid albuminocytological dissociation. Nerve conduction studies in case 1 showed a motor axonal neuropathy with unrecordable sensory potentials and F waves, those in case 2, done after 21 months, showed borderline increased F wave latencies. Both patients received intravenous immunoglobulin IVIg 2 g/kg and left hospital within three months. Neither patient has been rechallenged with oral isotretinoin, although the first continued to use topical isotretinoin gel 0.05% which is not absorbed.

Retinoids affect the development, differentiation, and function of the central nervous system. Sensory neuropathy has been described in patients taking the retinoid drug acitretin.2 Over a 19 year period, an estimated 375 000 patients have been treated with oral isotretinoin in the United Kingdom (Roche, personal communication), and the annual incidence of Guillain-Barre syndrome is about 2 in 100 000. This is insufficient to establish a causal association between Guillain-Barre syndrome and isotretinoin. We hope to alert others to report similar cases

 

4.)  Isotretinoin-associated intracranial hypertension.
 

Isotretinoin-associated intracranial hypertension.
Ophthalmology. 2004 Jun;111(6):1248-50.

Fraunfelder FW, Fraunfelder FT, Corbett JJ.

University of Mississippi School of Medicine Neurology Department, Jackson, Mississippi, USA. eyedrug@ohsu.edu

PURPOSE: To evaluate the association between intracranial hypertension (IH) and isotretinoin use. DESIGN: Observational case series. METHODS: In this retrospective study, approximately 1950 case reports of adverse ocular side effects related to isotretinoin were received from spontaneous reporting systems. Reports were evaluated as to the occurrence of IH with isotretinoin use. A survey was mailed to all members of the North American Neuro-ophthalmology Society soliciting their opinions on whether isotretinoin caused IH. RESULTS: One hundred seventy-nine reports of IH were associated with isotretinoin use. The mean time from drug exposure to IH diagnosis was 2.3 months. There were 6 cases of positive rechallenge; 5 new cases are reported here, along with 1 previously published report. Of neuro-ophthalmologists surveyed (62% response rate), 6% believed an association between IH and isotretinoin use was certain; 32%, probable; 52%, possible; and 10%, unlikely. Twelve respondents (4%) had personally seen one or more cases of positive rechallenge with isotretinoin causing IH. CONCLUSIONS: Based on the number and pattern of rapid IH onsets after isotretinoin exposure and the 6 cases of positive rechallenge, along with the probable similarity in metabolic pathways of this agent and vitamin A (a known cause of IH), it seems certain that there is a direct correlation between IH and isotretinoin use.

 

5.) Generic isotretinoin: a new risk for unborn children

Source: http://cmaj.ca/

CMAJ • May 11, 2004; 170 (10). doi:10.1503/cmaj.1040317.

Gideon Koren, Marina Avner and Neil Shear

From the Motherisk program, Division of Clinical Pharmacology, The Hospital for Sick Children and Sunnybrook and Women's College Health Sciences Centre and the University of Toronto, Toronto, Ont.

The introduction of isotretinoin (Accutane) in 1982 was a milestone in the treatment of recalcitrant nodular acne. Although the severe teratogenic effects of the drug quickly became evident,1 its use rapidly increased and was inappropriately extended to patients with less severe forms of acne.2,3 Of 1000 patients who participated in an international survey in 1997, 45% did not have the labelled indication for the drug.4 Also, new off-label uses have emerged, including treatment of dermatologic conditions such as gram-negative folliculitis, recalcitrant rosacea, pyoderma faciale, generalized lichen planus, psoriasis, cutaneous lupus erythematosus and acne fulminans 5 —as well as, more recently, the treatment of squamous cell carcinomas 6 and leukemias.7

Pre-market studies in animals showed high rates of central nervous system and facial malformation after gestational exposure; indeed, within months of the introduction of isotretinoin into the market, severe malformations reported in infants of women taking the drug revealed that it is a potent human teratogen.8 Box 1 presents the features of isotretinoin embryopathy. About 40% of infants exposed to isotretinoin in the first trimester will have major malformations. In addition, children exposed in utero who are spared from major malformation may still be affected by cognitive deficits.

In 1988 the US Food and Drug Administration (FDA) and the manufacturer of Accutane (Roche) developed a Pregnancy Prevention Program aimed at increasing women's awareness of the teratogenicity of the drug and of the importance of preventing conception.9 This program called for women to give written informed consent and commit to using 2 contraceptive methods simultaneously while taking isotretinoin therapy (see Box 2). This program was adopted by Health Canada soon after.


In spite of these efforts, reports of fetal exposure continued to accumulate through the 1990s.10 As a result, in 2002 the Pregnancy Prevention Program was modified to include additional measures (see Box 3) and was renamed SMART (System to Manage Accutane Related Teratogenicity).11The SMART program has not been adopted in Canada.

At the outset, the FDA indicated that, if SMART did not succeed in reducing gestational exposures to isotretinoin, additional restrictions would be imposed on the drug. In February 2004, an FDA advisory committee recommended that, in view of continuing safety issues, a mandatory registration for isotretinoin users and prescribers should be implemented.12

The expiry of the patent exclusivity of Accutane has opened up a lucrative market, prompting the rapid introduction of 3 generic forms of the drug in the United States: Amnesteem (November 2002), Sotret (December 2002) and Claravis (April 2003). Over 30 generic forms of isotretinoin are now available internationally. Currently, several manufacturers are considering the introduction of generic isotretinoin in Canada.

As part of the Motherisk program, we have been monitoring isotretinoin use since 1991. Between January 2002 and December 2003, we received 11 calls from women who had become pregnant while taking Accutane. Of these, only 4 had recalcitrant nodular acne, the only indication approved by Health Canada. A similar trend continues in the United States, where only 2 of 11 cases collected in 2003 by the Organization of Teratology Information Services had the labelled indication.

Moreover, although the drug was originally intended to be prescribed by dermatologists, many family physicians now prescribe it. Of the 11 Canadian women who consulted Motherisk, only 5 had a prescription written by a dermatologist, only 5 had seen printed information on the Pregnancy Prevention Program, and only 2 had signed a consent form. Only 1 of the 11 reported using 2 forms of contraception, yet 10 of the women had been warned verbally about fetal risk. Of the 5 prescriptions written by dermatologists, only 3 were for recalcitrant nodular acne.

The introduction of generic forms of isotretinoin, together with decreasing prices, will further increase the use of this drug by sexually active young women. It is also evident that the means used to avert the tremendous teratogenic risk of isotretinoin have not been effective. If, 20 years after the drug's introduction in clinical use, cases of fetal exposure continue to be reported, we see little reason to believe that the SMART program will be sufficient to reverse this trend. The flooding of the market with new and cheaper forms of generic isotretinoin is likely to endanger the lives of many more unborn Canadian babies. We need to take steps to protect the unborn from irresponsible prescribing; simply warning women (and their partners) about fetal risk is not enough.

We propose that certification and registration be required for physicians who wish to prescribe isotretinoin. Certification would entail a brief training program that covers the dos and don'ts of prescribing, followed by successful completion of a test. Training can be offered as CME in accredited institutions or through the Internet. Successful Web-based programs of this kind do exist. For example, US researchers who wish to be involved in publicly funded research involving humans must pass the NIH-initiated test on bioethics.13

A registration program works very well with respect to methadone prescribing in many countries, including Canada, the United Kingdom, Israel, France and Australia.14 The administration of such a program for isotretinoin could be handled provincially by pharmacists' organization, colleges of physicians or other suitable organizations. As part of this new strategy, Internet sales of the drug should be prohibited. In parallel, it would make sense to involve more meaningfully the pharmacists who dispense isotretinoin, who should present to female patients verbal and printed instructions that reinforce the information given by physicians.

One may argue that certification for isotretinoin prescription is not justified, as many other medications can have severe adverse effects. However, irresponsible prescribing of isotretinoin damages innocent fetuses who did not consent to exposure. The proposed program is easy to implement and can help to prevent irreparable, life-long damage to unborn children. We urge Health Canada, the manufacturers, physicians, pharmacists and their associations to adopt this initiative.


Footnotes

This article has been peer reviewed.

Contributors: Gideon Koren initiated, coordinated and wrote the commentary. Marina Avner conducted the study in the Motherisk program and reviewed the literature. Neil Shear was responsible for the dermatology aspects of this commentary.

Acknowledgement: Dr. Koren is a Senior Scientist with the Canadian Institute for Health Research. His work is supported in part by Jonathan's Allert, The Hospital for Sick Children, Toronto, Ont.

Competing interests: Neil Shear has received educational grants from Hoffman- La Roche.

Correspondence to: Dr. Gideon Koren, Division of Clinical Pharmacology, The Hospital for Sick Children, 555 University Ave., Toronto ON M5G 1X8; fax 416 813-7562, gkoren@sickkids.ca


References


Adverse effects with isotretinoin. FDA Drug Bull 1983;13:21-2.[Medline]
Shear NH. Oral isotretinoin: prescribers beware. CMAJ 1999;160(12):1723-4.[Free Full Text]
Wysowski DK, Swann J, Vega A. Use of isotretinoin (Accutane) in the United States: rapid increase from 1992 through 2000. J Am Acad Dermatol 2002;46: 505-9.[CrossRef][Medline]
Cunliffe WJ, van de Kerkhof PC, Caputo R, Cavicchini S, Cooper A, Fyrand OL, et al. Roaccutane treatment guidelines: results of an international survey. Dermatology 1997;194(4):351-7.[Medline]
Ortonne JP. Oral isotretinoin treatment policy. Do we all agree? Dermatology 1997;195(Suppl 1):34-7.[Medline]
Wieder R, Pavlick AC, Bryan M, Hameed M, Baredes S, Pliner L, et al. Phase I/II trial of accutane as a potentiator of carboplatin and paclitaxel in squamous cell carcinoma. Am J Clin Oncol 2002;25(2):447-50.[CrossRef][Medline]
Reynolds CP, Lemons RS. Retinoid therapy of childhood cancer. Hematol Oncol Clin North Am 2002;15:867-910.
Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med 1985;313(14):837-41.[Abstract]
Roche Canada. Information for the consumer. Available: www.rochecanada.com/pdf/Accutane%20PI%20E.pdf (accessed 2004 Apr 21).
Pastuszak AP, Koren G. The retinoid pregnancy prevention program. Koren G, editor. In: Retinoids in clinical practice: the risk-benefit ratio. New York: Marcel Dekker; 1993. p. 147-76.
Lowenstein EJ. Isotretinoin made S.M.A.R.T. and simple. Cutis 2002;70:115-20.[Medline]
Elliott VS. FDA panel back patient registry for acne drug. AMNews 2004 Mar 22/29. Available: www.ama-assn.org/amednews/2004/03/22/hlsc0322.htm#w1 (accessed 2004 Apr 17).
National Institutes of Health. Human participant protections education for research teams. Bethesda (MD): The Institutes; 2002. Available: http://69.5.4.33/c01/ (accessed 2004 Apr 17).
Bell J, Dru A, Fischer B, Levit S, Sarfraz MA. Substitution therapy for heroin addiction. Subst Use Misuse 2002;37:1149-78.[CrossRef][Medline]

 

6.) Ocular side effects associated with isotretinoin.

Drugs Today (Barc). 2004 Jan;40(1):23-7.

Fraunfelder FW.

National Registry of Drug-Induced Ocular Side Effects, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97201-4197, USA. eyedrug@ohsu.edu

Isotretinoin is used for severe recalcitrant nodular acne and has a variety of associated ocular side effects. This review classifies these ocular side effects according to World Health Organization (WHO) criteria and reviews the existing literature as well as 2449 spontaneous case reports collected from around the world. Ocular sicca, decreased dark adaptation and intracranial hypertension are identified as "certain" side effects from isotretinoin and clinicians are provided guidelines for care and follow-up.

 

 7.) Solid facial edema of acne: failure of treatment with isotretinoin.

Eur J Dermatol. 2003 Sep-Oct;13(5):503-4.

Kilinc I, Gencoglan G, Inanir I, Dereli T.

Ege University Medical Faculty, Department of Dermatology, 35100 Bornova, Izmir, Turkey.

Solid facial edema of acne is a rare persistent skin condition which occurs as a late complication of acne vulgaris. It is difficult to treat and isotretinoin seems to be the most effective agent. Here we present a 25-year-old man with a facial edema which arose after the complete remission of acne. Treatment with isotretinoin for 4 months was unsuccessful in this case.

 

8.) [Psychiatric symptoms during isotretinoin therapy].

Ned Tijdschr Geneeskd. 2003 Nov 22;147(47):2341-3.

[Article in Dutch]

van Broekhoven F, Verkes RJ, Janzing JG.

Universitair Medisch Centrum St Radboud, afd. Psychiatrie, Postbus 9101, 6500 HB Nijmegen. f.vanbroekhoven@psy.umcn.nl

A 22-year-old man with a known bipolar disorder was admitted to a psychiatric department for depression and suicidal ideation. He was being given isotretinoin to treat acne conglobata. During admission, he committed suicide. In the literature, isotretinoin is associated with the emergence of psychiatric symptoms. Although any casual relationship has not been identified, such a relationship cannot be ruled out. Methodologically well-performed research is lacking. However, positive dechallenge and rechallenge cases have been reported. Consequently, physicians must look out for the onset or worsening of psychiatric symptoms in patients treated with isotretinoin.

 

9.) Acne, isotretinoin and depression.

Acne, isotretinoin and depression.

Drug Ther Bull. 2003 Oct;41(10):76-8.

[No authors listed]

At any one time, most 16-18-years-old and up to half of adults have acne. In 60% of all teenagers, the condition will be sufficiently severe for them to self-treat or seek medical advice. Up to half of 12-20-year-olds with acne develop psychological or social problems. Oral isotretinoin, which is used for the treatment of severe acne, might be expected to improve psychological functioning. However, there have been suggestions that the drug itself might cause depression and suicide. Here we consider these concerns, and the implications for the use of isotretinoin when managing patients of all ages.

 

10.) [Enduring oral dryness after acne treatment].

Ned Tijdschr Tandheelkd. 2003 Jul;110(7):295-7.

[Article in Dutch]

Bots CP, van Nieuw Amerongen A, Brand HS.

Afdeling Tandheelkundige Basiswetenschappen, sectie Orale Biochemie van het Academisch Centrum Tandheelkunde Amsterdam (ACTA). c.bots.obc.acta@med.vu.nl

Medication influences the salivary flow rate frequently. In this paper a 26-year old patient is described, who used a systemic retinoid (a vitamin A derivate) when he was 18 years old. Since then, irreversible xerostomia was present. The oral complaints have been monitored during three years. Saliva was collected to assess the salivary flow rate and pH. The visco-elasticity of unstimulated whole saliva was high. This indicates a relatively low contribution of the gl. parotidea and a high mucin concentration in the collected saliva. Furthermore, parafilm only slightly stimulated the salivary flow rate. On the other hand, application of a 4% citric acid solution raised the flow rate to normal levels, without any delay. The medical history revealed no factors which could explain the the severe oral dryness and low salivary flow rate in rest. It was concluded that the low salivary flow rates and xerostomia might be related to the previous use of isotretinoin (Roaccutane). It is suggested to register and monitor the use of medication in patients with sudden oral health changes.



 

 

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