Isotretinoin dosing

Gastrointestinal A systematic search for case reports, case series, and clinical studies of the association between isotretinoin and inflammatory bowel disease yielded 12 case reports and one case series of such an association, to which the Bradford Hill guidelines to evaluate causality [36 ] were applied [37 ]. The cases occurred in seven countries over 23 years and differed with respect to isotretinoin dose, duration of treatment before development of the disease, whether the disease developed on or off medication, and the clinical presentation. There have been no prospective or retrospective studies. An estimated 59 coincident cases of inflammatory bowel disease would be expected in isotretinoin users each year, assuming no increased risk. The current evidence is insufficient to confirm or refute a causal association. 

Isotretinoin Capsules 10, 20, 40 mg 0.5-1 mg/kg/per day in two divided doses Maximum dose 2 mg/kg per day Cumulative dose 120-150 mg/day Dry skin and mucous membranes, muscle and joint pain, elevated liver enzymes and triglycerides, depression, teratogenicity... 

The answer is d. (Hardman, p 1575.) Isotretinoin is actually a form of high-dose vitamin A therapy Vitamin A itself or retinol (vitamin A could be used, but they have less advantageous pharmacokinetic properties. Antibiotics such as tetracyclines are used in acne, but they have little effect on the nodulocystic form... 

Recommended course of therapy The recommended dose is 0.5 to 1 mg/kg/day divided into 2 doses for 15 to 20 weeks. Administer isotretinoin with food. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may P.1212... 

Clinical improvement in nodular acne occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary, is related to the dose and duration of treatment with isotretinoin, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. Pharmacokinetics ... 

Absorption - Because of its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (two 40 mg capsules) of isotretinoin under fasted and fed conditions. Peak plasma concentration (Cmax)... 

After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared with the extent of formation under fasted conditions. 

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (18 years of age and older), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicated that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. 

Excretion - Following oral administration of an 80 mg dose of C-isotretinoin as a liquid suspension, C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects underfed conditions, the mean elimination half-lives of isotretinoin and 4-oxo-isotretinoin were approximately 21 and 24 hours, respectively. After single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. 

Reduction of weight, dietary fat intake, alcohol intake, and dose may reverse the effects on serum triglycerides, allowing patients to continue therapy. Musculoskeletal effects In a clinical trial (N = 217) of a single course of therapy for isotretinoin, 7.9% of patients had decreases in lumbar spine bone mineral density greater than 4%, and 10.6% of patients had decreases in total hip bone mineral density greater than 5%. 

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. 

Minimal skeletal hyperostosis and calcification of ligaments and tendons has been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown. 

Isotretinoin is rapidly absorbed orally, with peak blood concentrations 3 hours after ingestion. It is not stored in tissue, and the elimination half-life is 10 to 20 hours, either after a single dose or during chronic therapy. 

Unlike isotretinoin, acitretin (Soriatane) is not primarily sebosuppressive. Rather, it promotes normalization of dysregulated keratinocyte proliferative activity in the epidermis and is also antiinflammatory. Oral absorption is optimal when acitretin is taken with a fatty meal peak levels are reached approximately 3 hours after ingestion, while steady-state plasma levels are achieved after approximately 3 weeks of daily dosing. The mean terminal elimination half-life of the parent compound is 49 hours. However, when consumed with ethanol, acitretin may be transesterifled to form etretinate, a retinoid that is stored in adipose tissue, resulting in a much longer half-life (3-4 months or longer). 

Most patients with cystic acne respond to 1-2 mg/kg, given in two divided doses daily for 4-5 months. If severe cystic acne persists following this initial treatment, after a period of 2 months, a second course of therapy may be initiated. Common adverse effects resemble hypervitaminosis A and include dryness and itching of the skin and mucous membranes. Less common side effects are headache, corneal opacities, pseudotumor cerebri, inflammatory bowel disease, anorexia, alopecia, and muscle and joint pains. These effects are all reversible on discontinuance of therapy. Skeletal hyperostosis has been observed in patients receiving isotretinoin with premature closure of epiphyses noted in children... 

Impairment of dark adaptation with or without excessive glare sensitivity has been reported with isotretinoin therapy in doses of 1 mgAg of body weight daily.These complaints may be associated with an abnormal ERG or abnormal EOG. Once therapy is discontinued, both the abnormal dark adaptation and abnormal ERG usually resolve within several months. 

Excessive use of vitamin A can result in ocular dryness, loss of lashes, night blindness, and even intracranial hypertension, the latter of which is similar to that occurring with the other forms of vitamin A such as isotretinoin, approved for the treatment of cystic acne. With large doses, increased intracranial pressure is considered certain. ... 

The initial do.se is 0.5 to I mg/kg daily in two divided doses. AKsorption is rapid, but bioavailability is low ( 25%) because of degradation in the lumen and metabolism by the gastrointestinal mucosa and the liver on the first pass. The chief metabolite is 4-oxoisotretinoin. Both isotretinoin and its metabolite are conjugated to the glucuronide and excreted in the urine and feces. The usual course of therapy is 15 to 20 weeks. 

Accutane is a potent rat and rabbit developmental toxin (teratogen). Testicular atrophy and evidence of lower spermatogenesis was noted in dogs given isotretinoin for 30 weeks at 20 or 60 mg kg day Fischer 344 rats dosed at 8 or 32 mg kg day for over 18 months had a dose-related raised incidence of pheochromocytoma, an adrenal gland tumor. The relevance in man is unknown since this animal develops spontaneous pheochromocytoma at a significant rate. 

Oral isotretinoin (9-a s-retinoic acid) is often used in treating severe or stubborn acne rosacea. A 1994 study compared the treatment of rosacea with 10 mg/day low-dose oral isotretinoin, 0.025% low-dose topical tretinoin and a combination of the two. The results showed that before the 16th week of treatment, isotretinoin was more effective, but that afterwards there was no difference between tretinoin and isotretinoin. The combination of systemic and topical treatment does not give any further improvement in low doses. 

Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol 1994 130 319-24. 

Adverse effects from orally administered isotretinoin are numerous, frequent, and often dose related. About 90% of patients receiving isotretinoin therapy suffer from mucocutaneous effects. Drying of the mucosa of the mouth, nose, and eyes is the most common problem, with relatively rare involvement of the genito-anal mucosa. Cheilitis and skin desquamation occurs in more than 80% of patients. Less frequently, the conjunctiva and nasal mucosa are affected. Table 95-4 shows selected responses to some of the adverse effects of oral isotretinoin. 

A 6-month course of therapy is sufficient for most patients, but it has been observed that an initial dose of 1 mg/kg per day for 3 months, then reduced to 0.5 mg/kg per day, and if possible, to 0.2 mg/kg per day for 3 to 9 additional months will optimize the therapeutic outcome. Generally, after 2 to 4 weeks of treatment, a 50% reduction of the pustules can be expected. Pustules clear more rapidly than papules or nodules. Improvement continues during the posttreatment period. In female patients contraception is required because of teratogenicity, recommended to begin 1 month before therapy, continuing during the entire period of treatment, and for up to 3 months after discontinuation of isotretinoin. ... 

Isotretinoin is administered orally. The recommended dose is 0.5 to 2 mg/kg per day for 15 to 20 weeks. Lower doses are effective but are associated with shorter remissions. The cumulative dose also is important, so smaller doses for longer periods can be used to achieve a total dose in the range of 120 mg/kg. Approximately 40% of patients will relapse, usually within 3 years of therapy, and may require retreatment. Preteens and patients with acne con-globata or androgen excess are at increased risk of relapse. However, mild relapses may respond to conventional management with topical and systemic antiacne agents. 

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