Isotretinoin

Structural formula
General
Non-proprietary name	Isotretinoin
other names	(2 Z , 4 E , 6 E , 8 E ) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohex-1-en-1-yl) nona-2,4,6,8-tetraenoic acid ( IUPAC ) CIS-RETINOIC ACID ( INCI )
Molecular formula	C 20 H 28 O 2
External identifiers / databases
CAS number 4759-48-2 EC number 225-296-0 ECHA InfoCard 100.022.996 PubChem 5282379 ChemSpider 4445539 DrugBank DB00982 Wikidata Q287029
Drug information
ATC code	D10 AD04 , D10 AD54
Drug class	Anti-acne drugs (non-aromatic retinoid )
properties
Molar mass	300.44 g · mol -1
Physical state	firmly
Melting point	172-175 ° C
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 315-319-335-360 P: 201-261-305 + 351 + 338-308 + 313
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Isotretinoin , also known as 13- cis retinoic acid , is a cis isomer of tretinoin and belongs to the first generation of retinoids (non-aromatic retinoids). Isotretinoin was launched on the market by Roche in 1982 as an active pharmaceutical ingredient for severe acne . The corresponding drug was named Accutane .

Natural occurrence

The 13- cis retinoic acid is a configuration isomer of retinoic acid part of the vitamin A - metabolism . Concentrations of 1-2 ng / ml have been described for human blood plasma . After vitamin A supplementation , a significant increase in plasma concentrations of this metabolite was observed.

Use as a medicinal substance

Isotretinoin has been approved as a medicinal substance in Germany, Austria and Switzerland for the treatment of acne . In addition it comes u. U. also used for gram-negative folliculitis , rosacea , psoriasis (psoriasis), seborrheic eczema or dermatitis and actinic keratosis . It hardly works against acne inversa .

Isotretinoin is used topically and systemically in the form of monopreparations . Because of the considerable risks and side effects, usually only severe and therapy-resistant disease courses are treated systemically.

The active ingredient is approved in many countries, including China, Germany, Colombia, India, Turkey and the United Arab Emirates, although the corresponding preparations usually have different names.

A topically applicable gel formulation in combination with the antibiotic erythromycin was developed to improve the effect on moderate, inflammatory forms of acne vulgaris .

Isotretinoin is currently being administered in a Phase II study for the treatment of children with refractory or recurrent neuroblastoma .

Experimentally, isotretinoin has also been used successfully against genital warts, which are caused by the human papillomavirus . However, there are currently few studies of isotretinoin's use on genital warts, and this therapy is currently off-label .

Mechanisms of Action

Systemic isotretinoin therapy reduces the size of the sebum glands . The amount and composition of the sebum lipids normalize. The acne is supposed to be healed in this way. However, recurrences (relapses) are possible. A study from 1998 put the recurrence rate three years after the first therapy at 61% of the treated cases.

An immunomodulating effect occurs through inhibition of granulocyte migration and stimulation of Langerhans cells . Isotretinoin also has a direct impact on lymphocytes .

Isotretinoin improves the maturation of the keratinocytes . This also applies to cells that show signs of malignant degeneration (“tumor protective effect”). These anti-tumor effects are also observed after UV radiation.

Isotretinoin is 99.9% bound to proteins. The plasma half-life is 17–50 hours. The metabolization takes place when applied topically in the keratinocytes , in systemic uptake in the liver . It is excreted via the liver and kidneys.

Side effects

With systemic intake , various parts of the body can be affected by undesirable effects. The side effects of topical application remain limited to the treated skin area.

skin and hair

Inflammation of the skin ( dermatitis ), flaking, itching, rash with reddening and increased skin vulnerability with the risk of scarring from abrasions are very common . Dry skin (xerosis cutis), especially lips (cheilitis), peeling of the skin, inflammation of the mucous membranes and nosebleeds are common. The skin's sensitivity to light is increased. Isotretinoin is not stable when exposed to sunlight and can therefore cause phototoxic reactions when applied topically . With systemic intake, hair loss occurs in some cases . At the beginning of isotretinoin therapy, there may be a temporary deterioration in the appearance of the skin due to additional inflammation. The immunomodulatory properties of the active ingredient are suspected to be the cause.

liver

With systemic intake, there is a risk of liver dysfunction and lipid metabolism disorders, which requires close monitoring of liver values . An increase in transaminases is very common . Inflammation of the liver ( hepatitis ) occurs very rarely .

Nervous system and psyche

Headache is common with systemic therapy. Very rarely there is an increase in the pressure in the skull (intracranial pressure in the brain) , cramps and drowsiness. An influence on the brain metabolism could be proven in 2005. In vitro , isotretinoin increased the production of proteins and cellular metabolites that are known to decrease the production of serotonin . Depression and increased suicidality are under discussion. A prospective cohort study from Canada in 2007 found no correlation between isotretinoin use and the development of depression. The systematic review by Marqueling and Zane published in the same year found no correlation between isotretinoin use and suicidal behavior. The literature evaluated by the authors also did not support any causal relationship between the use of isotretinoin and the occurrence of depression. A 2016 study found no association between isotretinoin and depression or anxiety. A systematic review article from 2015 found in some studies increased symptoms in bipolar disorder and in a few studies a possible connection between isotretinoin and psychosis and schizophrenia .

Blood and lymphatic system

Increased sedimentation rate and anemia are very frequently observed with systemic therapy. Likewise thrombocytopenia and thrombocytosis . Frequently it comes to neutropenia (lack of white blood cells ). Lymph nodes ( lymphadenopathy ) very rarely become diseased .

eyes

Very often the eyes can feel dry and slightly irritated due to the therapy and inflammation of the eyelid margins and conjunctiva can occur. A comparative study in 2009 found that dry eyes are related to the dose of active ingredient used, at least during the treatment period. The disorder of the meibomian gland function is a primary cause of dry eyes. In 2013, Ding et al. in vitro indications that isotretinoin could have a comparable effect on the meibomian gland as on the sebum gland . They found that isotretinoin suppresses cell proliferation , induces cell death and significantly changes the expression of 6726 genes. These effects could be at least partially responsible for the disruption of the meibomian gland function associated with isotretinoin use. Dry eyes can be treated with tear substitute fluid . In very rare cases, contact lens wearers must wear glasses for the duration of systemic treatment with isotretinoin due to dry eyes. Blurred vision, cataracts , color blindness , corneal opacity , night blindness , corneal inflammation, changes in the fundus with swelling ( papillary edema ) as a sign of a pseudotumor cerebri and photophobia occur very rarely . As a rule, the side effects affecting the eye subside within one month of stopping the active ingredient. Visual disturbances that persist after systemic use of isotretinoin is stopped are rare. Cases of permanent change in dark adaptation with significant loss of vision at night have been described.

Musculoskeletal system

Reversible muscle and joint pain are very common. There are individual reports of rhabdomyolysis with involvement of the heart muscles during the therapy, especially with simultaneous strong physical stress, so that sport should be viewed critically during the therapy period. As part of routine laboratory diagnostics during the course, creatine kinase (CK) should also be determined. Joint inflammation, premature closure of the bone growth plates, excessive formation of bone substance ( hyperostosis and exostosis ) and the calcification of ligaments and tendons ( calcinosis ) occur very rarely . The product information for the medicinal product states that bone changes such as the premature closure of the bone growth plates, hyperostoses and the calcification of tendons and ligaments only occurred after several years of use in very high doses in the treatment of keratinization disorders. The level of dosage, the duration of therapy and the total cumulative dose in the affected patients would generally have been far higher than those recommended for acne therapy. A comparative study carried out in the context of a low-dose therapy over 36 months showed in 1992 that significantly more patients in the isotretinoin group developed new hyperostoses in the spinal area than in the placebo group . Also, significantly more patients in the isotretinoin group were affected by the progression of existing hyperostotic abnormalities than in the placebo group. The authors concluded that the low-dose long-term treatment with isotretinoin can induce comparable hyperostotic skeletal changes, as previously reported with higher doses. The exposure of the body with unphysiologically high Isotretinoindosen regarded as a suspected, pathogenetic factor for the Diffuse idiopathic skeletal hyperostosis (DISH) .

Kidney and urinary tract

A more common side effect is blood and / or protein excretion in the urine, but this is usually reversible. Glomerulonephritis occurs very rarely .

Gastrointestinal tract

Since isotretinoin was approved, the development of chronic inflammatory bowel disease has been described in individual patients treated with it . Recent studies have shown an association between the occurrence of ulcerative colitis and previous therapy with isotretinoin. The absolute risk of developing ulcerative colitis from isotretinoin therapy is nevertheless very low. An association with the occurrence of Crohn's disease could not be confirmed.

Interactions

The simultaneous intake of isotretinoin and tetracyclines can result in a pseudotumor cerebri , since isotretinoin as well as the tetracyclines increase the intracranial pressure. The combination of isotretinoin with other keratolytic agents can increase local irritation. To avoid overdosing with vitamin A, isotretinoin must not be taken together with high-dose vitamin A-containing medicines and food supplements. Liver and liver products can also contain high doses of vitamin A, which must be taken into account when determining the amount consumed.

Contraindications

Isotretinoin must not be administered systemically to persons suffering from a lipid metabolism disorder (hyperlipoproteinemia) or hypervitaminosis  A. With topical application, diseases such as acute eczema , rosacea or perioral dermatitis on the skin surface to be treated are an obstacle. Regardless of the form of administration, a known intolerance to the active ingredient or preparation components is also a contraindication.

pregnancy and breast feeding period

Isotretinoin must not be used systemically in women of childbearing potential or only after pregnancy has been excluded (including four weeks beyond treatment). Otherwise there is a risk of severe malformations in the fetus . Users of the active ingredient must perform a new pregnancy test every month and submit it to the doctor. Also needs a dual prevention, usually pill plus a condom , during the entire treatment period can be ensured.

Because of the teratogenic effects of isotretinoin, no blood may be donated during and up to four weeks after the end of systemic therapy - the unborn child of a recipient of the blood donation could be endangered.

The safety of topical application during pregnancy and breastfeeding has not been adequately investigated, so that it is also not recommended.

Trade names

Monopreparations

Systemic: Aknenormin (D), Ciscutan (A), Curakne (CH), Isoderm (D), IsoGalen (D), Isotret-HEXAL (D), Roaccutan (CH), Trétinac (CH)

Topical: Isotrex Cream / Gel (A, D), Roaccutane Gel (CH)

Combination preparations

Topical, combination with erythromycin : Isotrexin Gel (A, D)

Individual evidence

1. ↑ Entry on CIS-RETINOIC ACID in the CosIng database of the EU Commission, accessed on February 24, 2020.
2. ↑ ^{a b c} Data sheet 13-cis-Retinoic acid from Sigma-Aldrich , accessed on April 6, 2011 ( PDF ).
3. ↑ Thomas Arnhold: 1.4.5.1 Biosynthesis of retinoic acids In: Studies on the metabolism of vitamin A / retinoids with regard to a risk assessment of their teratogenic effects in humans ; P. 16; Dissertation; Braunschweig, March 7, 2000 ( full text ).
4. ↑ Gram-negative folliculitis simulates acne, but therapy is different. In: Doctors newspaper from January 25, 2006. Doctors newspaper Verlagsgesellschaft mbH.
5. ^ Otto Braun-Falco, Helmut Heinrich Wolff: Seborrheic eczema therapy. In: Dermatologie und Venerologie , 5th edition, p. 401; Springer 2005. ISBN 978-3-540-40525-2 ( limited preview in Google book search).
6. ↑ jne: If there is intertriginous inflammation, think of acne inversa. In: Dtsch Arztebl 1999 ; 96 (16): A-1061 / B-883 / C-827.
7. ↑ Isotretinoin. In: drugs.com. Retrieved June 26, 2015 . 
8. ↑ S Georgala, AC Katoulis, C Georgala, e Bozi, A Mortakis: Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: a randomized placebo-controlled trial . In: Sexually Transmitted Infections . 80, No. 3, 2004, pp. 216-218. doi : 10.1136 / sti.2003.006841 .
9. ↑ Virendra N. Sehgal MD, Govind Srivastava MD, Kabir Sardana MD: Isotretinoin - unapproved indications / uses and dosage: a physician's reference . In: International Journal of Dermatology . 45, No. 6, 2006, pp. 772-777. doi : 10.1111 / j.1365-4632.2006.02830.x .
10. ^ GM White et al .: Recurrence rates after the first course of isotretinoin . In: Archives of Dermatology 1998; 134: 376-378. PMID 9521042 ( full text ).
11. ↑ Bremner et al .: Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin . In: Am J Psychiatry 162: 983-991; 2005. doi : 10.1176 / appi.ajp.162.5.983 , PMID 15863802 .
12. ↑ KC O'Reilly et al .: 13-cis-Retinoic Acid Age Intracellular Serotonin, Increases 5-HT1A Receptor, and Serotonin Reuptake Transporter Levels In Vitro. In: Experimental Biology and Medicine , 232: 1195-1203 (2007). PMID 17895527 , full text .
13. ^ J. Cohen, S. Adams, S. Patten: No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort. In: Can J Clin Pharmacol. 2007; 14 (2): e227 – e233. PMID 17556790 .
14. ^ AL Marqueling, LT Zane: Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. In: Seminars in Cutaneous Medicine and Surgery . 2007; 26 (4): 210-220. doi : 10.1016 / j.sder.2008.03.005 , PMID 18395669 .
15. ^ B. Suarez, A. Serrano, Y. Cova, T. Baptista: Isotretinoin was not associated with depression or anxiety: A twelve-week study. In: World journal of psychiatry. Volume 6, number 1, March 2016, pp. 136-142, doi : 10.5498 / wjp.v6.i1.136 , PMID 27014604 , PMC 4804262 (free full text).
16. ↑ M. Ludot, S. Mouchabac, F. Ferreri: Inter-relationships between isotretinoin treatment and psychiatric disorders: Depression, bipolar disorder, anxiety, psychosis and suicide risks. In: World journal of psychiatry. Volume 5, Number 2, June 2015, pp. 222-227, doi : 10.5498 / wjp.v5.i2.222 , PMID 26110123 , PMC 4473493 (free full text).
17. ↑ ^{a b} Technical information Roaccutan® capsules In: compendium.ch , June 2013.
18. ↑ T. Cumurcu, E. Sezer, R. Kilic, Y. Bulut: Comparison of dose-related ocular side effects during systemic isotretinoin administration. In: Eur J Ophthalmol. 2009; 19 (2): 196-200. PMID 19253234 .
19. ↑ J. Ding, WR Kam, J. Dieckow, DA Sullivan: The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. In: Invest Ophthalmol Vis Sci. 2013 26; 54 (6): 4341-4350. PMID 23722388 . PMC 3694789 (free full text).
20. ↑ ^{a b c} Federal Institute for Drugs and Medical Devices : Isotretinoin: What you need to know - information brochure for patients (PDF; 213 kB).
21. ↑ ^{a b} S. P. Mollan, M. Woodcock, R. Siddiqi, J. Hunt Bach, P. Good, RAH Scott: Does use of isotretinoin rule out a career in flying? In: Br J Ophthalmol. 2006; 90 (8): 957-959. doi : 10.1136 / bjo.2006.092833 . PMID 16723361 . PMC 1857209 (free full text).
22. ↑ rhabdomyolysis according to isotretinoin (from the UAW database) ; Deutsches Ärzteblatt, vol. 110, issue 6, February 8, 2013.
23. ↑ JA Tangrea, RF Kilcoyne, PR Taylor, WE Helsel, ME Adrianza, AM Hartman, BK Edwards, GL Peck: Skeletal hyperostosis in patients receiving chronic, very-low-dose isotretinoin. In: Arch Dermatol. 1992; 128 (7): 921-925. doi : 10.1001 / archderm.1992.01680170053004 , PMID 1626958 .
24. ↑ Fábio A. Nascimento et al .: Diffuse idiopathic skeletal hyperostosis: A review. In: Surg Neurol Int. 2014, 16; 5 (Suppl 3): S122 – S125. doi : 10.4103 / 2152-7806.130675 (currently unavailable) , PMID 24843807 , PMC 4023007 (free full text).
25. ↑ SD Crocket, CQ Porter, CF Martin, RS Sandler, RD Kappelman: Isotretinoin Use and the Risk of Inflammatory Bowel Disease: A Case-Control Study . In: Am J Gastroenterol . 2010. doi : 10.1038 / ajg.2010.124 . PMID 20354506 .
26. ↑ Package insert for Roaccutan ^® 10 mg capsules, status: August 2003. Available in the drug information system of the federal and state governments (online) ( Memento of the original from July 5, 2013 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . 
27. ↑ Package insert Isotrex Creme 0.05%, as of June 2005. Available in the drug information system of the federal and state governments.

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