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Oral Isotretinoin

Consensus of GLOBAL ALLIANCE: Oral isotretinoin is

the mainstay of therapy for severe acne

Targets all pathophysiologic factors in acne

May achieve dramatic results even in severe disease

Now used more frequently in moderate, non-responsive acne

Side effects are common, but usually manageable

Education is vital (side effects, teratogenicity, adversepsychiatric events, monitoring)

Leads to prolonged remission. Variable rate of recurrence; retreatment may be necessary


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Isotretinoin

Dramatic reduction in sebaceous gland activity and sebumproduction that leads to a significant decrease in the P acnespopulation.

Patients suitable for isotretinoin treatment are those with severe nodular or cystic acne; (acne conglobata)

moderate acne that is resistant to conventional treatment(that is, the patient having received two courses of oralantibiotics at the correct dose for the correct length of time);

late onset in the mid-20s or 30s (acne at this age is oftenresistant to oral antibiotics).

Delays in starting isotretinoin treatment for patients withsevere acne can result in substantial scarring, so it isimportant that such patients are referred urgently todermatology departments.

BMJ 1994;308:831-833 (26 March)


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Acne relapse Low rates usually seen as compared to other therapies 40% usually relapse in 3 yrs.

Relapses can increase due to following reasons

severe seborrhoea and a high score of inflammatorylesions at the end of the treatment,

an early age, a family history of acne,

prepubertal acne and acne extended to the trunk are the factors increasing

significantly the risk of relapse.


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Therapeutic Class: Anti acneIntroduced in 1982.

Chemical Class: Synthetic analogue of vitamin A(13-cis retinoic acid )

Structure 13-cis retinoic acid is producedby rotating the terminal carboxylgroup of neutrally occurringall trans-retinoic acid across thedouble bond in the 13 position


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Mechanism of actionKeratolytic effect Retinoids affect the keratinization process

(effective in many hyperkeratotic conditions )

Decrease keratinocyte adhesion The number of keratin precursors (tonofilaments and

tonofibrils) are reduced, desmosomes become smallerand less well-developed, and microvilli appear on the cellsurface

The stratum corneum becomes less well organized,losing its superficial layers and becoming thinner .

Comedones are shed and formation of microcomedonesis prevented.

Improves the differentiation of keratinocytes andfollicular cells in the pilosabaeceous unit.


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Mechanism of action

Anti- seborrheic effect Decreases the production of sebum in a dose-

related manner (Efficacy noted with doses as low as0.05 mg/kg/day)

decreases the size and secretion of thesebaceous glands ( shrinkage)

30% to 80% reduction in sebaceous gland

activity was still present 80 weeks afterdiscontinuing isotretinoin therapy

indirectly inhibits P acnesgrowth via changes ofthe follicular milieu & by substantial decrease in

sebum.


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Mechanism of action

Profound inhibition of both neutrophil andmonocyte chemotaxis across intactbiologic barriers - anti inflammatory effect.

Prolonged remissions (38 months) have alsobeen observed following 3 to 4 month treatment

Thus, oral isotretinoin is unique among

current acnetreatmentsin that itaffects all of the pathogenic factorsinvolved in this disease.


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Immunoadjuvant action

stimulation of the immune system:

Increase in levels of immunoglobulins and helperT cells at 8 weeks and increased levels of B cellsat 16 weeks

contributory factor to their marked clinical

improvement

British Journal of Dermatology (1984) 110, 343-345.


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Indications

Severe Nodular and/or Inflammatory Acne

Nodulocystic acne & Acne Conglobata

Recalcitrant Acne (failure of conventionaltreatment. eg, a combination of topicalretinoids, benzoyl peroxide and topical orsystemic antibiotics and, when

appropriate, hormonal therapies) Maintainence treatment to prevent relapse


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Cunliffe WJ, van DeKerkhof PC, Caputo R, Cavicchini S,

Cooper A, Fyrand OL et al. Dermatology 1997; 194:3517.

International experts in 1997 recommended expansion of indications


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Dosing recommendations

Importance of cumulative dosing Cumulative dosing more imp than daily dose in preventing

relapse.

Effective immediate and long term efficacy seen with mid -

to high dose regimens. Dose range, 0.51.0 mg/kg/day. In most patients, complete or near complete suppression of

acne is achieved with a treatment course of 56 months

Total cumulative dose: Should be 120 mg/kg

treatment extended to 2 months after complete clearing of theacne to avoid recurrence of inflammatory lesionsUnder certain circumstances, higher cumulative doses (possibly upto 200 mg/kg) may be required (e.g. patients showing clear signs

of ongoing resolution at the 150 mg/kg threshold)


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Low-dose regimens

Older patients: 0.250.5 mg/kg/day),which can then be doubled if there is nosatisfactory response after 2 months.

Severe inflammatory acne:(0.5 mg/kg/day).Acute flare

High-dose regimens: defined as >1.0mg/kg/day young patients with acne of shortduration

male patients with truncal acne


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Clinical experience

The effect in severe nodulocystic acne can be dramatic, most

cases respond to a single 4- to 6 month therapeutic course .

In general, pustules clear more rapidly than papules

or nodules. Also, lesions on the face, upper arms andlegs tend to respond more quickly than truncal lesions

Results are not evident for 1 to 2 months after start of therapy;

similarly, therapeutic benefits continue for several months afterdiscontinuation of therapy.

In a few cases, complete clearing may occur 1 to 2 months after

oral isotretinoin is stopped, usually without additional treatment


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Contraindications hypersensitivity to isotretinoin hepatic and renal failure, hypervitaminosis A, and in

patients with excessively elevated blood lipid values.

Pregnant females contraindicated in females of childbearing potential

unless all of the following conditions apply:

1. The patient has severe disfiguring nodular and/orinflammatory acne, acne conglobata or recalcitrant acne thathas not responded to standard therapy, including systemicantibiotics.

2. The patient is reliable in understanding and carrying outinstructions.


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3. The patient is able and willing to comply with the mandatoryeffective contraceptive measures.

4. The patient has received, and acknowledges understanding of

oral and printed explanation of the hazards of fetal exposureto isotretinoin and the risk of possible contraception failure.

5. The patient uses effective contraception without anyinterruption for one month before beginning therapy, during

therapy and for one month following discontinuation ofisotretinoin therapy. It is recommended that two reliableforms of contraception be used simultaneously .

6. The patient has had two negative pregnancy tests before

starting therapy with the second pregnancy test 11 daysprior to initiating therapy. & two or three days of the normalmenstrual period before therapy is initiated.

7. In the event of relapse treatment, the same uninterrupted andeffective contraceptive measures must be usedone monthprior to, during and for one month after isotretinoin therapy.


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Pharmacokinetics Due to its high lipophilicity, Absorption increases with

food or milk .

Bioavailability is doubled relative to fasting conditions

Highly protein bound = 99.9%

Following oral administration of 80 mg, peak plasmaconcentrations ranged 98 to 535 ng/mL from with atime to peak of 2.9 3.2 hrs in acne patients.


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Pharmacokinetics Isotretinoin and its metabolites are excreted almost

equally in the urine and feces. Following an 80 mgdose 65% to 83% of the dose was recovered inurine and feces.

Elimination half life of isotretinoin: 10-20 hours

Metabolite: 4-oxo-isotretinoin: 17 to 50 hours

mean minimum steady-state blood concentrationsof isotretinoin were 160 ng/mL in 10 patients

receiving 40 mg b.i.d. doses No statistically significant differences in the

pharmacokinetics of isotretinoin between

pediatric(12- 15 yrs) and adult patients


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Adverse effects Cheilitis and hypertriglyceridemia are usually dose

related.

The common side effects are dermatologic.

cheilitis (96%), Dry or chapped lips are seen in almost

all patients treated with isotretinoin. facial erythema/dermatitis (55%), dry nose

(51%), desquamation (50%),pruritus (30%), dryskin (22%), conjunctivitis (19%), alopecia (13%),

irritation of the eyes (11%), rash (


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Adverse effects Secondary skin infection with S aureusis not uncommon

and should be treated with topical antiseptics or oralantibiotics.

Melasma can occur

ERYTHEMA NODOSUM, ERYTHEMA MULTIFORME Some patients have muscle aches and backaches, and

some have mild headaches at the start of therapy, butthese often resolve during the course of treatment.

Nosebleeds and skin fragility may also occur

13% of patients experience joint pain during treatment.

Retinoid induced osteoporosis and osteophyte formation.

Loss of bone density occurs.


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Adverse effectsOphthalmic S/E: Decreased Night Vision, Cataracts and corneal opacities ,visual disturbances have also been reported.

optic neuritis, photophobia, eye lid inflammation, keratitis, and colour visiondisturbances . Dry eyes and/or decreased tolerance to contact lenses.

Gastrointestinal: nausea, mild gastrointestinal bleeding, rectal bleeding.Severe pancreatitis has been reported (especially those with high

triglyceride levels)

Cardiovascular: edema, transient pain in the chest, palpitations,tachycardia. RIGHT BRANCH BUNDLE BLOCK (RBBB) associated with SINUSTACHYCARDIA

Respiratory: respiratory infections, Bronchospasm in pts with history ofasthma.Psychiatric Disorders: Depression, psychotic symptoms and, rarely,suicide attempts, suicide and aggressive and/or violent behaviours.Emotional instabilityCNS: seizures, dizziness, nervousness, drowsiness, malaise, weakness,

insomnia, lethargy, paresthesia.


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Adverse effects

Reproductive system: abnormal menses.

Urinary system: glomerulonephritis

Hematological: hematuria/proteinuria

Body as a whole: weight loss, anemia,lymphadenopathy, vasculitis including allergic vasculitis,allergic responses, and systemic hypersensitivity.

Musculoskeletal: arthritis, muscle pain (myalgia;

elevations of serum CPK values), arthralgia, calcification of ligaments and tendon and tendinitis.

Hearing: impaired hearing at certain frequencies.

Ad ff t


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Adverse effectsPotent teratogen:

women of child-bearing age must not start therapy until a

negative pregnancy test result has been obtained. Adequate contraception is essential before and during oral

isotretinoin therapy, as well as for 6 weeks post-therapy.

Therapy should start on the first, second, or third day of the

menstrual period once the results of the pregnancy test havebeen obtained.

CNS (hydrocephalus, hydranecephaly, microcephaly, posteriorfossa abnormalities, cranial nerve dysfunction, cerebellarmalformation);

Craniofacial (microtia, low set ears, small or absent externalauditory canals, microphthalmia, facial dysmorphia, cleft palate);

Cardiac (septal defects, aortic arch abnormalities, tetralogy ofFallot);

Thymus gland abnormalities; and parathyroid hormone


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Adverse effects

If pregnancy does occur during treatment ofa female patient who is taking isotretinoin,

isotretinoin must be discontinuedimmediately.

she should be referred to an Obstetrician-

Gynecologist


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Carcinogenesis, Mutagenesis andImpairment of Fertility

In rats :dose-related increased incidence of pheochromocytoma adrenal medullary hyperplasia was also increased at the higher dosage

No human reportsof increase in carcinogenecity.

Ames test was positive in one and negative in other centre. Other tests designed to assess genotoxicity (Chinese

hamster cell assay, mouse micronucleus test, S. cerevisiaeD7 assay, in vitro clastogenesis assay with human-derived

lymphocytes, and unscheduled DNA synthesis assay) wereall negative.

In rats, no adverse effects on gonadal function, fertility,

conception rate, gestation or parturition were observed


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Impairment of Fertility In dogs, testicular atrophy : at 20 to 30

times doses for 30 weeks. microscopicevidence for depression of spermatogenesis

In human studies of 66 men: no significant changesin spermatozoa count or motility

In study of 50 men (17 to 32 years)no significant effectson ejaculate volume, sperm count, total sperm motility,morphology or seminal plasma fructose.


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Lab abnormalities

Elevation of serum triglycerides (25% of patients),mild to moderate decrease in serum high densitylipoprotein (HDL) (16% of patients), and minimalelevations of serum cholesterol (7% of patients).

Elevated blood glucose have been reported, andnew cases of diabetes

A rise in serum levels of liver enzymes may occur,

especially with higher dosages elevated CPK, and hyperuricemia.

White blood cells and red blood cells in the

urine and proteinuria.


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Precautions Acute pancreatitis and fatal hemorrhagic pancreatitis (rare)

Caution in h/0 depression , psychiatric disorder

Avoid Blood donation : till 1 mnth discontinuation

Exposure to UV rays or sunlight

Cautious when driving or operating any vehicle at night-decreased night vision

Hearing impairment

Hepatotoxicity- hepatitis and elevated liver enzymes havebeen; monitor LFT at before Rx and 1, 3, 6 mnths.

Benign intracellular hypertension


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Hyperlipidemia Inflammatory bowel disease

Psychiatric disorders- depression, psychosis

Skeletal- age-related osteoporosis, osteomalacia,childhood osteoporosis, other bone metabolismdisorders

Visual problems- corneal opacities, decreasednight vision

Vitamin supplements containing vitamin A:additional toxicity

Precautions


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Precautions

Avoid resurfacing procedure (e.g., laserdermabrasion ) and wax epilation duringtherapy and till 6 months after therapy.

Photosensitivity can occur - avoid uv light

and sunlight for long time.

Patients experiencing abdominal pain,rectal bleeding or severe diarrhea should

discontinue

high risk patients (with diabetes, obesity,alcoholism or lipid metabolism disorder)

more frequent lipid and glucose levels .


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Drug interactions

Microdosed progesterone preparations(minipills) are not a suitable method ofcontraception

Vitamin A: Tetracyclines: Rare cases of benign

intracranial hypertension pseudotumorcerebri

Caution : phenytoin and steroids.

Methotrexate: hepatotoxicity

Alcohol : a disulfiram-like reaction

D


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Dosage Therapeutic response to isotretinoin is dose-related

and varies between patients, necessitates individualadjustment of dosage weight and severity ofthe disease.

Initial Therapy: 0.5 mg/kg body weight daily

Either single dose or two divided doses for 2 to4weeks. Capsules taken with food.

Maintenance Therapy: between 0.1 and 1

mg/kg body weight daily up to 2 mg/kg bodyweight daily (120 mg per day maximally)

Duration : 15 to 20 weeks.


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Dosage

Complete or near-complete suppression of acne isachieved with a single 12 to 16 week course oftherapy.

total nodule count has been reduced by more than70% - isotretinoin can be discontinued

If a second course of therapy is needed, it can beinitiated eight or more weeks after completion of the

first course Long-term use (> 1yr) even in low doses, has not

been studied, and is not recommended.

Contraceptive measures must be followed .


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Kaymak and Ilter. JEADV 2006,20, 12561260


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Clinical studies


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Pigatto et al, 1986

Efficacy of isotretinoin was compared withminocycline in 24 men with severe cystic acne

At the end of treatment isotretinoin wassignificantly more effective than minocyclineand induced remission in all subjects.


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Isotretioin Vs. tetracycline

For severe nodulocystic acne

Double blind randomised clinical trial

2 groups : isotretinoin 1-2 mg/kg/day tetracycline 500- 1000 mg/kg/day

3 weeks wash up, 16 week therapy and 8

week follow up.


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Isotretinoin vs. tetracyline

During the 8-week post treatment period, patients who hadbeen treated with isotretinoin continued to improve, while theacne condition of tetracycline-treated patients remained

unchanged

isotretinoin VS. tetracycline

82% 88% 85%

58% 64%

48%

0%

10%

20%

30%

40%50%

60%

70%

80%

90%

100%

no of cysts cyst size No. comedones and

pustules

percentage

iso

tetra


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Long term efficacy

N=88, acne for many years (mean 7.4 years). an initial dose of 0- 5 or 1 0 mg/kg/day

Most patients only required 4 months' therapy to produce atleast 85% clinical improvement.

The patients were seen up to 10 years post-therapy (mean 9 yrs). Sixty-one per cent of the patients were non-

relapsers: 40% required no further therapy,

and 21% required topical therapy alone. Thirty-nine per cent relapsed, and required

systemic therapy in the form of oral antibiotics

(16%) or further isotretinoin (23%)


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Long term efficacy

Those patients who received 0. 5 mg/kg daily,or a cumulative dose of < 120 mg/kg, had asignificantly higher relapse rate than patients

receiving a larger dose. long-term remission in the majority of acne

patients can be achieved , particularly if given

in a dose regimen of 1 mg/kg/day. or a cumulative dose of > 120 mg/kg.

Layton AM et al. BJD 1993;129:292-296.

Factors may predict the need for


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Factors may predict the need formore than one course

299 patients treated 5 years ago withisotretinoin followed for 5 years post treatment

22.7 % required repeat courses.

Factors contributing to the need for furthercourses of treatment included lower doseregimens (0-1 and 0-5 mg/kg). the presence

of severe acne, being a female over the ageof 25 at the onset of therapy, and having aprolonged history of acne.

BJD (1993)129,297-301.

Two studies that show lack of


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Two studies that show lack ofcorrelation between isotretinoin

and depression Australasian Journal of Dermatology (2002), 43, 262268.

No correlation between isotretinoin dose and depressionscore was found. Although five isotretinoin patients were

withdrawn during the study because of worsening of mood,no definite causal relationship was established. It may be arare unpredictable idiosyncratic side-effect.

Can J Clin Pharmacol Vol 14 (2) 2007.Isotretinoin does not appear to be associated with thedevelopment of depression. Thus, denying patients withsignificant acne an effective medication for fear of developing

depression may not be indicated at this point in time.


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Current view in patients whocould be prone to depression

Patients taking isotretinoin should let theirphysicians know about any depressive

symptoms, self-destructive thoughts, orother mood changes, and maybe aboutheadaches as well.

Depressed persons need not avoidisotretinoin.

J Alcalay et al : Study to determine


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J Alcalay et al: Study to determineneed for routine lab tests.

Aside from its teratogenic effect, isotretinoin isa safe for acne

In authors opinion there is no need for a

routine laboratory follow-up in young, healthypatients aside from a pregnancy test in females.

considered as the DOC for moderate to severeacne.

Journal of Dermatological Treatment (2001) 12, 912


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Infantile acne

Oral isotretinoin has been used withsuccess to treat resistant occurrences ofinfantile acne causing severe scarring and

cosmetic sequelae

0.2 mg/kg/day to 1.5 mg/kg/day for

5 to 14 months.

Barnes et al: Pediatric Dermatology Vol.22No. 2 166-169,2005

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