Accutane users only

[bbdude]

Was wondering what are the dosage levels for this chemical are. Non users, PLEASE do not clutter the thread with chit chat about I heard or read. I am very aware of the sides. (I do blood work 4 times a year)Comments from those experienced with this only.
Thanks
Age ..........47
Ht..............5'6"
Wt.............185 Lbs
Bf..............8.5%

[JOEYZ]

Originally Posted by bbdude

Was wondering what are the dosage levels for this chemical are. Non users, PLEASE do not clutter the thread with chit chat about I heard or read. I am very aware of the sides. (I do blood work 4 times a year)Comments from those experienced with this only.
Thanks
Age ..........47
Ht..............5'6"
Wt.............185 Lbs
Bf..............8.5%

Just FYI..........members arent going to be as willing to answer your questions and attempt to help you if you dont somewhat appreciate their replies and "clutter". At any rate here is all of the info you will probably ever need:

ACCUTANE:


ACNE - SEVERE RECALCITRANT NODULAR
a. Therapy should be initiated with 0.5 to 2 milligrams/kilogram/day given orally with food in 2 divided doses for 15 to 20 weeks. If the total cyst count has been reduced by more than 70% during this time period, the drug may be discontinued. The dose should be adjusted according to the appearance of clinical side effects and the response of the disease. A second course of therapy may be initiated 2 months after discontinuation, if the patient experiences persistent or recurring severe nodular acne. In patients who have not completed skeletal growth, the optimal interval before retreatment has not been established; caution should be taken as reports of hyperostosis and premature epiphyseal closure are documented (Prod Info Accutane(R), 2000).
b. In clinical trials the average dose was 2 milligrams/kilogram/day (range 1 to 3.3 milligrams/kilogram/day) (Peck, 1980).
c. A dose-response study involving 150 patients with treatment-resistant nodulocystic acne indicated that isotretinoin in doses of 0.1, 0.5, or 1.0 milligrams/kilogram/day orally were similarly effective in producing clinical response; however, a greater number of patients receiving the lower dose 0.1 milligram/kilogram/day required retreatment with isotretinoin. Side effects were similar with all doses; however, there was a tendency for side effects to occur more frequently with high doses. The authors conclude that doses of 0.1 milligram/kilogram/day could not be recommended for nodulocystic acne. Doses of 0.5 and 1 milligram/kilogram/day appear to be optimal for most patients (Strauss et al, 1984).
4. HYPERTROPHIC LUPUS ERYTHEMATOSUS
a. The successful use of isotretinoin is described in the treatment of hypertrophic lupus erythematosus in a 44-year-old woman. Isotretinoin 1 milligram/kilogram/day for 3 weeks resulted in dramatic improvement of lesions, with disappearance of erythema, hyperkeratosis and thickness by 9 weeks; the drug was withdrawn after 11 weeks of treatment and the patient had remained free of occurrence for 9 months. This appears to be the first case report of resolution of hypertrophic lupus erythematosus with isotretinoin (Green & Piette, 1987).
5. KERATINIZATION DISORDERS
a. Average doses of 2.0 milligrams/kilogram/day (range 0.5 to 8.0 milligrams/kilogram/day) have been used in clinical trials (Peck, 1980).
6. SQUAMOUS CELL CARCINOMA
a. Isotretinoin 1 milligram/kilogram/daily in 2 divided doses for at least 4 weeks was reported effective in the treatment of advanced squamous cell carcinoma of the skin in 4 patients. Duration of response ranged from 2 to 23 plus months (Lippman & Meyskens, 1987).
B. TOPICAL
1. ACNE VULGARIS
a. Topical isotretinoin 0.05% gel, applied twice a day for 14 weeks, was reported effective in the treatment of mild-to-moderate acne vulgaris in a double-blind study (n=268). The preparation was effective in reducing both inflammatory and noninflammatory lesions. These data suggest benefits of topical isotretinoin in the treatment of mild-to-moderately severe acne vulgaris, and this form of therapy can limit side effects observed with oral isotretinoin. In this study, isotretinoin was well tolerated, with only 2 patients withdrawing due to the occurrence of irritation, which was also observed in one patient receiving vehicle alone (placebo group) (Chalker et al, 1987).
2. DARIER'S DISEASE
a. Topically applied isotretinoin 0.1% cream and tretinoin 0.05% cream were both effective in the treatment of Darier's disease in a 62-year-old male; however, tretinoin had to be discontinued due to irritation. Four representative test areas (20 X 20 cm) were treated: isotretinoin in 2 sections, tretinoin, and cream base only, respectively. Following 12 weeks of treatment with isotretinoin (first 6 weeks, twice daily application, second 6 weeks, once daily application), total remission in the treated area occurred (Steijlen et al, 1991).
1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY
A. Empirical dose reductions are indicated in hepatic disease due to extensive metabolism of the drug by the liver.
1.3.5 DOSAGE ADJUSTMENT DURING DIALYSIS
A. Since isotretinoin is highly protein bound, the drug would not be expected to be removed significantly during dialysis (Rofsky & Colburn, 1985).
1.4 PEDIATRIC DOSAGE
1.4.1 NORMAL DOSE
A. ORAL
1. ACNE - SEVERE RECALITRANT NODULAR
a. Isotretinoin at an oral dose of 1 milligram/kilogram/day has been used in pediatric patients (13 to 17 years) with severe recalcitrant nodular acne. Except for increased incidence of back pain, arthralgia, and myalgia, efficacy and toxicity was similar to those in adults (Anon, 2003).
2.0 PHARMACOKINETICS
2.2 DRUG CONCENTRATION LEVELS
2.2.1 THERAPEUTIC
A. TIME TO PEAK CONCENTRATION:
1. Following the oral administration of two 40 mg capsules, peak plasma levels ranged from 167 to 459 ng/mL (mean 256 ng/mL) and mean time to peak was 3.2 hours in NORMAL subjects. ACNE patients receiving the same dose experienced peak serum levels of 98 to 535 ng/mL (mean 262 ng/mL) with a mean time to peak of 2.9 hours (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982).
2. Oral, Following ingestion there is an apparent lag time of about 0.5 to 2 hours before the drug appears in the systemic circulation. Absorption after the lag time appears to be rapid and peak blood levels usually occur at 2 to 3 hours (Brazzell & Colburn, 1982).
2.2.2 TOXIC
A. The manufacturer does not recommend doses greater than 2 milligrams/kilogram/day. Symptoms of overdose include vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. Symptoms of overdose quickly resolve without apparent residual effects (Prod Info Accutane(R), 2000).
B. Toxic blood levels not established; however dosages above 1 mg/kg/day have been associated with a higher incidence of adverse effects (Prod Info Accutane(R), 2000).
2.3 ADME
2.3.1 ABSORPTION
A. EFFECTS OF FOOD: The oral absorption of isotretinoin is increased when administered with food or milk (Prod Info Accutane(R), 2000).
2.3.2 DISTRIBUTION
2.3.2.1 DISTRIBUTION SITES
A. TOTAL PROTEIN BINDING: 99.9% (Prod Info Accutane(R), 2000).
2.3.3 METABOLISM
2.3.3.2 METABOLITES
A. 4-oxo-isotretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
B. Tretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
C. 4-oxo-tretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
D. After 2 40-mg capsules of isotretinoin, maximum concentrations of 4-oxo-isotretinoin of 87 to 399 ng/mL occurred at 6 to 20 hours (Brazzell & Colburn, 1982). The blood concentration of the major metabolite generally exceeded that of isotretinoin after 6 hours. After single and multiple doses, the mean ratio of areas under the blood concentration time curves of 4-oxo-isotretinoin to isotretinoin was 3 to 3.5 (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982).
2.3.4 EXCRETION
2.3.4.1 BREAST MILK
A. BREASTFEEDING: Unknown
2.3.4.2 KIDNEY
A. Isotretinoin and its metabolites are excreted almost equally in the urine and feces. Following an 80 mg dose of liquid suspension ((14)C-isotretinoin), 65% to 83% of the dose was recovered in urine and feces (Prod Info Accutane(R), 2000).
2.3.4.3 OTHER
A. FECES
1. Isotretinoin and its metabolites are excreted almost equally in the urine and feces. Following an 80 mg dose of liquid suspension ((14)C-isotretinoin), 65% to 83% of the dose was recovered in urine and feces (Prod Info Accutane(R), 2000).
2.3.5 HALF-LIFE
2.3.5.1 PARENT COMPOUND
A. ELIMINATION HALF-LIFE, 10-20 hours (Prod Info Accutane(R), 2000; Colburn & Gibson, 1985; Brazzell et al, 1983; Khoo et al, 1982).
2.3.5.2 METABOLITES
A. 4-oxo-isotretinoin, 17 to 50 hours (Brazzell & Colburn, 1982; Prod Info Accutane(R), 2000).
3.0 CAUTIONS
3.1 CONTRAINDICATIONS
A. Pregnancy and lactation
B. Women of childbearing potential should NOT be given isotretinoin until ALL of the following criteria are met:
1. The patient is reliable in understanding and carrying out instructions
2. The patient must be capable of complying with the mandatory contraceptive measures required for therapy and understand behaviors associated with an increased risk of pregnancy.
1. Two forms of effective contraception should be used
simultaneously, one of which must be a primary form
(ie. tubal ligation, birth control pills) unless
abstinence is the chosen method or patient has had
a hysterectomy

2. Use effective contraceptives at least 1 month prior
to initiation of therapy, during, and for 1 month
after discontinuing therapy

3. The patient has received both oral and written warnings of the risk of taking isotretinoin during pregnancy and the risk of possible contraception failure and she acknowledges this understanding in writing. A consent form is included in the package insert
4. Negative serum pregnancy test with a sensitivity of at least 25 mIU/mL when qualified for therapy and a second negative serum or urine pregnancy test on the first 5 days of the menstrual period immediately preceding the beginning of therapy or in patients with amenorrhea, 11 days after last act of unprotected sexual intercourse.
5. Monthly pregnancy tests during therapy are required by the FDA
6. The patient is informed of importance and has the opportunity to participate in the Accutane Survey
C. Hypersensitivity to isotretinoin or parabens
3.2 PRECAUTIONS
A. Acute pancreatitis and fatal hemorrhagic pancreatitis (rare) have been reported
B. Avoid wax epilation and skin resurfacing procedures during isotretinoin therapy and for at least 6 months thereafter due to the risk of scarring
C. Blood donation during and for at least 1 month after discontinuing isotretinoin
D. Exposure to UV rays or sunlight
E. Hearing impairment
F. Hepatotoxicity- hepatitis and elevated live enzymes have been reported
G. Hyperlipidemia
H. Inflammatory bowel disease
I. Pseudotumor cerebri- some cases occurred with concomitant use of tetracyclines
J. Psychiatric disorders- depression, psychosis, suicide ideations/attempts (rare) have occurred; discontinuation of therapy is not always sufficient
K. Skeletal- hyperostosis, epiphyseal closure, age-related osteoporosis, osteomalacia, childhood osteoporosis, other bone metabolism disorders
L. Visual problems- corneal opacities, decreased night vision
M. Vitamin supplements containing vitamin A
3.3 ADVERSE REACTIONS
3.3.1 BLOOD
A. HEMATOLOGIC EFFECTS
1. Elevated erythrocyte sedimentation rates (ESR) have been reported in up to 40% of patients. Bleeding, bruising, anemia, and myelosuppression have been reported with isotretinoin therapy. Elevated platelets, a single case of agranulocytosis, and polycythemia have also been noted.
B. ANEMIA
1. SUMMARY:
a. It has been reported that isotretinoin can decrease erythrocyte count, hemoglobin concentration, and hematocrit in 10% to 20% of patients (Prod Info Accutane(R), 2000; Perry & McEvoy, 1983; Peck et al, 1979). A significant decrease in hemoglobin concentration was noted in a study involving 90 patients receiving 0.5 to 0.75 milligrams/kilogram/day of isotretinoin. The decrease in hemoglobin concentration was found to be reversible upon discontinuation of treatment (Michaelsson et al, 1986).
C. BLEEDING
1. SUMMARY:
a. Bleeding and bruising have been reported with isotretinoin therapy (Prod Info Accutane(R), 2000). During treatment for cystic acne, a patient with hemophilia A experienced an increase in the number of bleeding episodes and the amount of factor VIII administered. It was felt that the cause of bleeding may have been stimulation of plasminogen activator activity by isotretinoin (Dootson et al, 1992).
D. ERYTHROCYTE SEDIMENTATION RATE
1. SUMMARY:
a. Elevated ERYTHROCYTE SEDIMENTATION RATES (ESR) have been reported in up to 40% of patients (Prod Info Accutane(R), 2000).
E. LEUKOPENIA
1. SUMMARY:
a. Leukopenia and NEUTROPENIA have been reported in patients taking 0.5 milligrams to 0.95 milligrams/kilogram/day of isotretinoin. A single case of AGRANULOCYTOSIS with questionable association with isotretinoin therapy has been reported (Prod Info Accutane(R), 2000; Waisman, 1988). Accutane(R) therapy should be discontinued if clinically significant decreases in white cell counts occur (Prod Info Accutane(R), 2000).
2. LITERATURE REPORTS:
a. Agranulocytosis was described in a 16-year-old boy following administration of isotretinoin 40 to 80 milligrams daily for approximately 9 weeks. Following withdrawal of the drug, granulocyte count began to improve within 3 days and normalized within 4 weeks (Waisman, 1988). However, in the absence of re-challenge, is unclear if isotretinoin was the actual cause of this patient's granulocytopenia. In addition, the patient never developed symptoms in the presence of severe granulocytopenia, except for slight fatigue, making one question the possibility of laboratory error. Accutane(R) therapy should be discontinued if clinically significant decreases in white cell counts occur (Prod Info Accutane(R), 2000).
b. In one case, when therapy was withdrawn after 18 weeks, the neutrophil and leukocyte count increased sharply only to be followed by another decrease in both (Friedman, 1987).
c. Another study involved 90 patients taking isotretinoin for 3 to 6 months. Significant decreases in neutrophils and leukocytes occurred, but were reversible and dose-related (Michaelsson et al, 1986).
F. POLYCYTHEMIA
1. SUMMARY:
a. Polycythemia was reported in a 58-year old man during the tenth month of treatment with isotretinoin at a dosage of 20 milligrams/day (initial doses were 180 mg/day for 3 months and 80 mg/day for 6 months). Three months after discontinuation of isotretinoin the hemoglobin and hematocrit returned to normal values (Cakmakci et al, 2001).
G. THROMBOCYTOPENIA
1. SUMMARY:
a. Elevated platelet counts and thrombocytopenia have been reported. Thrombocytopenia has been reported in less than 10% of patients (Prod Info Accutane(R), 2000).
2. LITERATURE REPORTS:
a. A 20-year-old man with no personal or family history of bleeding disorder and no recent viral or bacterial infection presented with severe epistaxis and a petechial rash involving the face and thighs. Physical, biochemical, and immunologic investigations revealed no underlying abnormalities. A bone marrow aspirate demonstrated the presence of increased megakaryocytes, which were also larger than normal, but no erythroid or myeloid abnormalities. Two weeks before hospital admission, the patient had been placed on oral isotretinoin (dose unstated) for severe acne vulgaris; this medication was discontinued at the time of admission. Platelet counts subsequently increased spontaneously and steadily from 15 x 10(9)/liter on admission to 400 x 10(9)/liter seven days later (Hesdorffer et al, 1986).
b. Thrombocytopenia was described in a 15-year-old Hispanic adolescent with cystic acne following isotretinoin 60 milligram (mg) daily (1 milligram/kilogram (mg/kg)/day) for approximately 2 weeks. Withdrawal of isotretinoin resulted in increases in platelet count to normal values over the next 10 days. Re-challenge with 60 mg isotretinoin resulted in recurrence of thrombocytopenia within 1 day, with subsequent return to normal values in approximately 10 days. This appears to be the first case report of thrombocytopenia secondary to isotretinoin (Johnson & Rapini, 1987).
3.3.2 CARDIOVASCULAR
A. CARDIOVASCULAR EFFECTS
1. Chest pain and vasculitis have been reported with isotretinoin therapy.
2. In a case report, a patient receiving isotretinoin 1 milligram per kilogram daily for severe acne developed RIGHT BRANCH BUNDLE BLOCK (RBBB) associated with SINUS TACHYCARDIA. Discontinuation of isotretinoin resolved all signs and symptoms. Reintroduction of isotretinoin 10 days later induced RBBB again, which resolved upon drug discontinuation (Charalabopoulos et al, 2003).
B. CHEST PAIN
1. SUMMARY:
a. Transient chest pain has been associated with isotretinoin therapy; symptoms are usually reversible after discontinuation of therapy (Prod Info Accutane(R), 2000).
C. VASCULITIS
1. SUMMARY:
a. A few reports of vasculitis have been reported in patients receiving isotretinoin (Prod Info Accutane(R), 2000). It has occurred in patients taking isotretinoin in doses of 0.5 to 1.1 milligrams/kilogram/day. Reports indicate that vasculitis has occurred 14 to 16 weeks into therapy (Epstein et al, 1987). However, in one case, the patient received isotretinoin for 6 months, and vasculitis did not appear until 6 months after treatment was stopped (Reynolds et al, 1989).
2. LITERATURE REPORTS:
a. CUTANEOUS NECROTIZING VASCULITIS was reported in two patients taking isotretinoin. Symptoms gradually resolved with appropriate therapy and discontinuance of the drug; prednisone was a successful adjunct in one case (Dwyer et al, 1989).
3.3.3 CENTRAL NERVOUS SYSTEM
A. NEUROLOGIC EFFECTS
1. Isotretinoin therapy has been associated with seizures, dizziness, nervousness, insomnia, paresthesias, lethargy, fatigue, and headache. Pseudotumor cerebri and papilledema have also been reported in adults.
B. PSYCHIATRIC EFFECTS
1. Isotretinoin therapy may cause depression, psychosis and rarely, suicidal ideation, suicide attempts and suicide. Dream pattern changes has been reported.
C. HEADACHE
1. SUMMARY:
a. Headache may occur with therapeutic isotretinoin doses (Bigby & Stern, 1988; McLane, 2001; Lindemayr, 1986; Windhorst & Nigra, 1982).
2. LITERATURE REPORTS:
a. Headache was reported in 13.3% of patients treated with isotretinoin in one large trial (n=369). The mean duration of the headache was from 6 to 8 days (McLane, 2001).
b. The Adverse Drug Reaction Reporting System of the American Academy of Dermatology reported 104 suspected adverse reactions secondary to isotretinoin in 93 patients over a 4-year period (1982 to 1985) (Bigby & Stern, 1988). Central nervous system adverse effects were described in 23 patients, with 12 being considered as definitely or probably related to isotretinoin. This included 10 reports of headache). In the majority of cases, the headaches occurred within the first week of treatment.
D. NEUROLOGIC FINDINGS
1. SUMMARY:
a. Isotretinoin therapy has been associated with SEIZURES, DIZZINESS, NERVOUSNESS, INSOMNIA, and PARESTHESIAS (Prod Info Accutane(R), 2000; Perry & McEvoy, 1983; Windhorst & Nigra, 1982). CONFUSION has rarely been reported (Marroni et al, 1993).
E. PSEUDOTUMOR CEREBRI
1. SUMMARY:
a. Several cases of pseudotumor cerebri BENIGN INTRACRANIAL HYPERTENSION (or ELEVATED INTRACRANIAL PRESSURE) have been reported in patients receiving isotretinoin, usually associated with concomitant tetracycline therapy. PAPILLEDEMA, headache, nausea and vomiting and VISUAL DISTURBANCES have occurred as early signs and symptoms. Patients with these symptoms should be screened for papilledema and if a diagnosis is made, therapy should be immediately discontinued and the patient should be evaluated by a neurologist (Prod Info Accutane(R), 2000; Roytman et al, 1988; Bigby & Stern, 1988; Spector, 1984; FDA, 1983).
2. LITERATURE REPORTS:
a. A case of pseudotumor cerebri was reported that developed in a patient receiving 0.7 milligrams/kilogram/day of isotretinoin without concomitant use of tetracycline. Two months into therapy the patient developed severe headaches and dizzy spells. Isotretinoin therapy was stopped and administration of dexamethasone begun. Six weeks later the patient was symptom-free (Roytman et al, 1988).
F. PSYCHIATRIC DISORDERS
1. SUMMARY:
a. Isotretinoin therapy may cause DEPRESSION, PSYCHOSIS and rarely, SUICIDAL IDEATION, suicide attempts and suicide. Symptoms have subsided after discontinuation of therapy and recurred with isotretinoin re-challenge. Dream pattern changes was reported (McLane, 2001; Prod Info Accutane(R),2000; Ling & Highet, 2000; Gatti et al, 1991; Scheinman et al, 1990; Villalobos et al, 1989).
2. LITERATURE REPORTS:
a. Two cases of sustained dreaming were reported in college students receiving isotretinoin for the treatment of cystic acne. The sustained dreams onset was within 2 to 3 weeks of initiation of isotretinoin and lasted 4 to 5 weeks with continued treatment (Gupta & Gupta, 2001).
b. One case report identifies a 36-year-old man who experienced an enhanced craving for cigarettes while receiving treatment with isotretinoin, which suggests the psychological adverse effects associated with isotretinoin may not be restricted to depression and its related features. The patient had been a smoker for 18 years and previously received a 4-month course of isotretinoin without incident at the age of 19. At the age of 36, the patient presented with recurrent acne and isotretinoin therapy was initiated at a dose of 1 milligram per kilogram daily. Three months later, the dose was reduced to 0.5 milligrams per kilogram due to a patient complaint of increased sweating of palms. A total course of 6 months was completed with an excellent response. Upon review, the patient reported an intense craving for cigarettes within 2 weeks of beginning therapy. Prior to therapy the patient smoked 10 cigarettes daily and during therapy his consumption increased to 40 per day. In addition, there was no reduction in the craving when the isotretinoin dose was reduced at 3 months. Since the patient did not report any increased levels of stress, fatigue, mood swings or other psychological changes, this case suggests that the increased craving for cigarettes may be a psychological change associated with isotretinoin (Ling & Highet, 2000).
c. One month following a successful 4-month course of treatment with isotretinoin (0.5 milligrams/kilogram/day) a patient developed severe depression that led to suicide (Gatti et al, 1991).
d. Of 700 patients receiving isotretinoin 0.3 to 0.7 milligrams/kilogram/day, 7 developed depression. The onset of depression was not related to dose or the length of therapy. When patients developed signs of depression, isotretinoin therapy was stopped and all symptoms disappeared within 2 to 7 days (Scheinman et al, 1990).
e. A 16-year-old male was started on isotretinoin 40 milligrams/day. On day 11 he began to experience hallucinations, paranoia, and incoherent speech. This behavior subsided when isotretinoin was stopped, but recurred when therapy was resumed (Villalobos et al, 1989).
f. The Adverse Drug Reaction Reporting System of the American Academy of Dermatology reported 23 suspected central nervous systems adverse reactions secondary to isotretinoin over a 4-year period (1982 to 1985). 12 of these cases being considered as definitely or probably related to isotretinoin. This included 1 case of depression and a single case of a DISULFIRAM-LIKE REACTION (Bigby & Stern, 1988).
G. SOMNOLENCE
1. SUMMARY:
a. LETHARGY and FATIGUE have been noted with therapeutic isotretinoin doses (Prod Info Accutane(R), 2000; Reuter,1984; Windhorst & Nigra, 1982).
3.3.4 ENDOCRINE/METABOLIC
A. ENDOCRINE EFFECTS
1. Hyperglycemia, thyroglossal duct cyst and thyrotoxicosis have been reported in patients treated with therapeutic doses of isotretinoin.
B. FLUID-ELECTROLYTE EFFECTS
1. A single case of hypercalcemia has been noted with high dose therapeutic isotretinoin.
C. METABOLIC EFFECTS
1. Lipid abnormalities may be seen with isotretinoin therapy.
D. HYPERCALCEMIA
1. SUMMARY:
a. One case of hypercalcemia has been reported in a patient receiving isotretinoin therapy; a causal relationship was not established (Valentic et al, 1983). A literature search from 1983 to 1993 did not reveal any further information on isotretinoin induced hypercalcemia.
2. LITERATURE REPORTS:
a. Hypercalcemia was reported in a 19-year-old male with cystic acne receiving isotretinoin. The patient was given 30 milligrams (mg) isotretinoin twice daily (0.9 milligrams/kilogram/day (mg/kg/day)) increased gradually to 60 mg every morning and 50 mg at bedtime in the second month. After approximately 4 months of therapy, serum calcium levels had increased to 11.5 milligrams/deciliter (mg/dL), over a baseline of 9.4 mg/dL prior to therapy. Calcium levels continued to increase with continued therapy to 12.3 mg/dL in 1 week. Isotretinoin was discontinued followed by a decrease in serum calcium to 10.5 mg/dL within 3 days. The patient also developed anemia during isotretinoin treatment, however a cause-effect relationship was unclear. The patient was re-challenged with isotretinoin at a lower dose without reoccurrence of hypercalcemia. Although isotretinoin could not be definitely implicated in this case, monitoring of serum calcium levels is advisable during isotretinoin therapy since hypervitaminosis A has caused hypercalcemia (Valentic et al, 1983).

OVERVIEW
A. Isotretinoin is a synthetic analogue of vitamin A.
B. DOSING INFORMATION: The initial oral dose should be 0.5 to 2 mg/kg/day in 2 divided doses. Oral doses up to 8.2 mg/kg/day have been used in basal cell carcinoma. Topical isotretinoin 0.05% should be applied twice daily for 14 weeks.
C. PHARMACOKINETICS: Peak plasma concentrations are achieved 1 to 6 hours (mean 3.2) following oral administration. Isotretinoin is 99.9% plasma protein bound, metabolized in the liver, and is excreted almost equally in the urine and feces.
D. CAUTIONS: Due to its teratogenic effects, oral isotretinoin should not be administered to women who are pregnant or may become pregnant during treatment. Women of childbearing potential should use 2 forms of effective contraception simultaneously 1 month before, during, and 1 month after therapy; monthly pregnancy tests are required by the United States Food and Drug Administration (FDA). The most commonly occurring adverse effects of the drug are cutaneous reactions including dry skin, pruritus, and dry mouth. Other significant effects include psychiatric disorders, pseudotumor cerebri, decreased night vision, corneal opacities, inflammatory bowel disease, hyperostosis, hepatotoxicity, and hypertriglyceridemia.
E. CLINICAL APPLICATIONS: Isotretinoin is used primarily in the treatment of cystic acne. The drug has also been used in several other conditions including basal cell carcinoma.
1.0 DOSING INFORMATION
1.1 DOSAGE FORMS
A. Information on specific products and dosage forms can be obtained by referring to the Product Index.
B. SYNONYMS
1. RO-43,780
2. 13-cis retinoic acid

1.2 STORAGE AND STABILITY
A. ORAL
1. Store at 59 to 86 degrees F (15 to 30 degrees C); protect from light (Prod Info Accutane(R), 2000).
2. ISOTRETINOIN is a compound which is inherently heat stable. It is, however, subject to degradation if exposed to light. If the capsules were contained in an amber light resistant prescription container, they should still be usable through their labeled expiration date, even if their shape is somewhat distorted, as long as they are not ruptured or leaking and have not been exposed to light. Any capsules not intact should be discarded (Pers Comm, 1987).
1.3 ADULT DOSAGE
1.3.1 NORMAL DOSE
A. ORAL
1. IMPORTANT NOTE
a. Due to its teratogenic effects, oral isotretinoin should not be administered to women who are pregnant or who may become pregnant during treatment. Women of childbearing potential should use 2 forms of effective contraception simultaneously 1 month before, during, and 1 month after therapy; monthly pregnancy tests are required by the United States Food and Drug Administration (FDA)(Anon, 2001; Prod Info Accutane(R), 2000).
2. BASAL CELL CARCINOMA
a. Clinical trials have utilized doses of isotretinoin ranging from 1.5 to 8.2 milligrams/kilogram/day with the average dose of 4.6 milligrams/kilogram/day (Peck, 1980).
3. ACNE - SEVERE RECALCITRANT NODULAR
a. Therapy should be initiated with 0.5 to 2 milligrams/kilogram/day given orally with food in 2 divided doses for 15 to 20 weeks. If the total cyst count has been reduced by more than 70% during this time period, the drug may be discontinued. The dose should be adjusted according to the appearance of clinical side effects and the response of the disease. A second course of therapy may be initiated 2 months after discontinuation, if the patient experiences persistent or recurring severe nodular acne. In patients who have not completed skeletal growth, the optimal interval before retreatment has not been established; caution should be taken as reports of hyperostosis and premature epiphyseal closure are documented (Prod Info Accutane(R), 2000).
b. In clinical trials the average dose was 2 milligrams/kilogram/day (range 1 to 3.3 milligrams/kilogram/day) (Peck, 1980).
c. A dose-response study involving 150 patients with treatment-resistant nodulocystic acne indicated that isotretinoin in doses of 0.1, 0.5, or 1.0 milligrams/kilogram/day orally were similarly effective in producing clinical response; however, a greater number of patients receiving the lower dose 0.1 milligram/kilogram/day required retreatment with isotretinoin. Side effects were similar with all doses; however, there was a tendency for side effects to occur more frequently with high doses. The authors conclude that doses of 0.1 milligram/kilogram/day could not be recommended for nodulocystic acne. Doses of 0.5 and 1 milligram/kilogram/day appear to be optimal for most patients (Strauss et al, 1984).
4. HYPERTROPHIC LUPUS ERYTHEMATOSUS
a. The successful use of isotretinoin is described in the treatment of hypertrophic lupus erythematosus in a 44-year-old woman. Isotretinoin 1 milligram/kilogram/day for 3 weeks resulted in dramatic improvement of lesions, with disappearance of erythema, hyperkeratosis and thickness by 9 weeks; the drug was withdrawn after 11 weeks of treatment and the patient had remained free of occurrence for 9 months. This appears to be the first case report of resolution of hypertrophic lupus erythematosus with isotretinoin (Green & Piette, 1987).
5. KERATINIZATION DISORDERS
a. Average doses of 2.0 milligrams/kilogram/day (range 0.5 to 8.0 milligrams/kilogram/day) have been used in clinical trials (Peck, 1980).
6. SQUAMOUS CELL CARCINOMA
a. Isotretinoin 1 milligram/kilogram/daily in 2 divided doses for at least 4 weeks was reported effective in the treatment of advanced squamous cell carcinoma of the skin in 4 patients. Duration of response ranged from 2 to 23 plus months (Lippman & Meyskens, 1987).
B. TOPICAL
1. ACNE VULGARIS
a. Topical isotretinoin 0.05% gel, applied twice a day for 14 weeks, was reported effective in the treatment of mild-to-moderate acne vulgaris in a double-blind study (n=268). The preparation was effective in reducing both inflammatory and noninflammatory lesions. These data suggest benefits of topical isotretinoin in the treatment of mild-to-moderately severe acne vulgaris, and this form of therapy can limit side effects observed with oral isotretinoin. In this study, isotretinoin was well tolerated, with only 2 patients withdrawing due to the occurrence of irritation, which was also observed in one patient receiving vehicle alone (placebo group) (Chalker et al, 1987).
2. DARIER'S DISEASE
a. Topically applied isotretinoin 0.1% cream and tretinoin 0.05% cream were both effective in the treatment of Darier's disease in a 62-year-old male; however, tretinoin had to be discontinued due to irritation. Four representative test areas (20 X 20 cm) were treated: isotretinoin in 2 sections, tretinoin, and cream base only, respectively. Following 12 weeks of treatment with isotretinoin (first 6 weeks, twice daily application, second 6 weeks, once daily application), total remission in the treated area occurred (Steijlen et al, 1991).
1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY
A. Empirical dose reductions are indicated in hepatic disease due to extensive metabolism of the drug by the liver.
1.3.5 DOSAGE ADJUSTMENT DURING DIALYSIS
A. Since isotretinoin is highly protein bound, the drug would not be expected to be removed significantly during dialysis (Rofsky & Colburn, 1985).
1.4 PEDIATRIC DOSAGE
1.4.1 NORMAL DOSE
A. ORAL
1. ACNE - SEVERE RECALITRANT NODULAR
a. Isotretinoin at an oral dose of 1 milligram/kilogram/day has been used in pediatric patients (13 to 17 years) with severe recalcitrant nodular acne. Except for increased incidence of back pain, arthralgia, and myalgia, efficacy and toxicity was similar to those in adults (Anon, 2003).
2.0 PHARMACOKINETICS
2.2 DRUG CONCENTRATION LEVELS
2.2.1 THERAPEUTIC
A. TIME TO PEAK CONCENTRATION:
1. Following the oral administration of two 40 mg capsules, peak plasma levels ranged from 167 to 459 ng/mL (mean 256 ng/mL) and mean time to peak was 3.2 hours in NORMAL subjects. ACNE patients receiving the same dose experienced peak serum levels of 98 to 535 ng/mL (mean 262 ng/mL) with a mean time to peak of 2.9 hours (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982).
2. Oral, Following ingestion there is an apparent lag time of about 0.5 to 2 hours before the drug appears in the systemic circulation. Absorption after the lag time appears to be rapid and peak blood levels usually occur at 2 to 3 hours (Brazzell & Colburn, 1982).
2.2.2 TOXIC
A. The manufacturer does not recommend doses greater than 2 milligrams/kilogram/day. Symptoms of overdose include vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. Symptoms of overdose quickly resolve without apparent residual effects (Prod Info Accutane(R), 2000).
B. Toxic blood levels not established; however dosages above 1 mg/kg/day have been associated with a higher incidence of adverse effects (Prod Info Accutane(R), 2000).
2.3 ADME
2.3.1 ABSORPTION
A. EFFECTS OF FOOD: The oral absorption of isotretinoin is increased when administered with food or milk (Prod Info Accutane(R), 2000).
2.3.2 DISTRIBUTION
2.3.2.1 DISTRIBUTION SITES
A. TOTAL PROTEIN BINDING: 99.9% (Prod Info Accutane(R), 2000).
2.3.3 METABOLISM
2.3.3.2 METABOLITES
A. 4-oxo-isotretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
B. Tretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
C. 4-oxo-tretinoin (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982)
D. After 2 40-mg capsules of isotretinoin, maximum concentrations of 4-oxo-isotretinoin of 87 to 399 ng/mL occurred at 6 to 20 hours (Brazzell & Colburn, 1982). The blood concentration of the major metabolite generally exceeded that of isotretinoin after 6 hours. After single and multiple doses, the mean ratio of areas under the blood concentration time curves of 4-oxo-isotretinoin to isotretinoin was 3 to 3.5 (Prod Info Accutane(R), 2000; Brazzell & Colburn, 1982).
2.3.4 EXCRETION
2.3.4.1 BREAST MILK
A. BREASTFEEDING: Unknown
2.3.4.2 KIDNEY
A. Isotretinoin and its metabolites are excreted almost equally in the urine and feces. Following an 80 mg dose of liquid suspension ((14)C-isotretinoin), 65% to 83% of the dose was recovered in urine and feces (Prod Info Accutane(R), 2000).
2.3.4.3 OTHER
A. FECES
1. Isotretinoin and its metabolites are excreted almost equally in the urine and feces. Following an 80 mg dose of liquid suspension ((14)C-isotretinoin), 65% to 83% of the dose was recovered in urine and feces (Prod Info Accutane(R), 2000).
2.3.5 HALF-LIFE
2.3.5.1 PARENT COMPOUND
A. ELIMINATION HALF-LIFE, 10-20 hours (Prod Info Accutane(R), 2000; Colburn & Gibson, 1985; Brazzell et al, 1983; Khoo et al, 1982).
2.3.5.2 METABOLITES
A. 4-oxo-isotretinoin, 17 to 50 hours (Brazzell & Colburn, 1982; Prod Info Accutane(R), 2000).
3.0 CAUTIONS
3.1 CONTRAINDICATIONS
A. Pregnancy and lactation
B. Women of childbearing potential should NOT be given isotretinoin until ALL of the following criteria are met:
1. The patient is reliable in understanding and carrying out instructions
2. The patient must be capable of complying with the mandatory contraceptive measures required for therapy and understand behaviors associated with an increased risk of pregnancy.
1. Two forms of effective contraception should be used
simultaneously, one of which must be a primary form
(ie. tubal ligation, birth control pills) unless
abstinence is the chosen method or patient has had
a hysterectomy

2. Use effective contraceptives at least 1 month prior
to initiation of therapy, during, and for 1 month
after discontinuing therapy

3. The patient has received both oral and written warnings of the risk of taking isotretinoin during pregnancy and the risk of possible contraception failure and she acknowledges this understanding in writing. A consent form is included in the package insert
4. Negative serum pregnancy test with a sensitivity of at least 25 mIU/mL when qualified for therapy and a second negative serum or urine pregnancy test on the first 5 days of the menstrual period immediately preceding the beginning of therapy or in patients with amenorrhea, 11 days after last act of unprotected sexual intercourse.
5. Monthly pregnancy tests during therapy are required by the FDA
6. The patient is informed of importance and has the opportunity to participate in the Accutane Survey
C. Hypersensitivity to isotretinoin or parabens
3.2 PRECAUTIONS
A. Acute pancreatitis and fatal hemorrhagic pancreatitis (rare) have been reported
B. Avoid wax epilation and skin resurfacing procedures during isotretinoin therapy and for at least 6 months thereafter due to the risk of scarring
C. Blood donation during and for at least 1 month after discontinuing isotretinoin
D. Exposure to UV rays or sunlight
E. Hearing impairment
F. Hepatotoxicity- hepatitis and elevated live enzymes have been reported
G. Hyperlipidemia
H. Inflammatory bowel disease
I. Pseudotumor cerebri- some cases occurred with concomitant use of tetracyclines
J. Psychiatric disorders- depression, psychosis, suicide ideations/attempts (rare) have occurred; discontinuation of therapy is not always sufficient
K. Skeletal- hyperostosis, epiphyseal closure, age-related osteoporosis, osteomalacia, childhood osteoporosis, other bone metabolism disorders
L. Visual problems- corneal opacities, decreased night vision
M. Vitamin supplements containing vitamin A
3.3 ADVERSE REACTIONS
3.3.1 BLOOD
A. HEMATOLOGIC EFFECTS
1. Elevated erythrocyte sedimentation rates (ESR) have been reported in up to 40% of patients. Bleeding, bruising, anemia, and myelosuppression have been reported with isotretinoin therapy. Elevated platelets, a single case of agranulocytosis, and polycythemia have also been noted.
B. ANEMIA
1. SUMMARY:
a. It has been reported that isotretinoin can decrease erythrocyte count, hemoglobin concentration, and hematocrit in 10% to 20% of patients (Prod Info Accutane(R), 2000; Perry & McEvoy, 1983; Peck et al, 1979). A significant decrease in hemoglobin concentration was noted in a study involving 90 patients receiving 0.5 to 0.75 milligrams/kilogram/day of isotretinoin. The decrease in hemoglobin concentration was found to be reversible upon discontinuation of treatment (Michaelsson et al, 1986).
C. BLEEDING
1. SUMMARY:
a. Bleeding and bruising have been reported with isotretinoin therapy (Prod Info Accutane(R), 2000). During treatment for cystic acne, a patient with hemophilia A experienced an increase in the number of bleeding episodes and the amount of factor VIII administered. It was felt that the cause of bleeding may have been stimulation of plasminogen activator activity by isotretinoin (Dootson et al, 1992).
D. ERYTHROCYTE SEDIMENTATION RATE
1. SUMMARY:
a. Elevated ERYTHROCYTE SEDIMENTATION RATES (ESR) have been reported in up to 40% of patients (Prod Info Accutane(R), 2000).
E. LEUKOPENIA
1. SUMMARY:
a. Leukopenia and NEUTROPENIA have been reported in patients taking 0.5 milligrams to 0.95 milligrams/kilogram/day of isotretinoin. A single case of AGRANULOCYTOSIS with questionable association with isotretinoin therapy has been reported (Prod Info Accutane(R), 2000; Waisman, 1988). Accutane(R) therapy should be discontinued if clinically significant decreases in white cell counts occur (Prod Info Accutane(R), 2000).
2. LITERATURE REPORTS:
a. Agranulocytosis was described in a 16-year-old boy following administration of isotretinoin 40 to 80 milligrams daily for approximately 9 weeks. Following withdrawal of the drug, granulocyte count began to improve within 3 days and normalized within 4 weeks (Waisman, 1988). However, in the absence of re-challenge, is unclear if isotretinoin was the actual cause of this patient's granulocytopenia. In addition, the patient never developed symptoms in the presence of severe granulocytopenia, except for slight fatigue, making one question the possibility of laboratory error. Accutane(R) therapy should be discontinued if clinically significant decreases in white cell counts occur (Prod Info Accutane(R), 2000).
b. In one case, when therapy was withdrawn after 18 weeks, the neutrophil and leukocyte count increased sharply only to be followed by another decrease in both (Friedman, 1987).
c. Another study involved 90 patients taking isotretinoin for 3 to 6 months. Significant decreases in neutrophils and leukocytes occurred, but were reversible and dose-related (Michaelsson et al, 1986).
F. POLYCYTHEMIA
1. SUMMARY:
a. Polycythemia was reported in a 58-year old man during the tenth month of treatment with isotretinoin at a dosage of 20 milligrams/day (initial doses were 180 mg/day for 3 months and 80 mg/day for 6 months). Three months after discontinuation of isotretinoin the hemoglobin and hematocrit returned to normal values (Cakmakci et al, 2001).
G. THROMBOCYTOPENIA
1. SUMMARY:
a. Elevated platelet counts and thrombocytopenia have been reported. Thrombocytopenia has been reported in less than 10% of patients (Prod Info Accutane(R), 2000).
2. LITERATURE REPORTS:
a. A 20-year-old man with no personal or family history of bleeding disorder and no recent viral or bacterial infection presented with severe epistaxis and a petechial rash involving the face and thighs. Physical, biochemical, and immunologic investigations revealed no underlying abnormalities. A bone marrow aspirate demonstrated the presence of increased megakaryocytes, which were also larger than normal, but no erythroid or myeloid abnormalities. Two weeks before hospital admission, the patient had been placed on oral isotretinoin (dose unstated) for severe acne vulgaris; this medication was discontinued at the time of admission. Platelet counts subsequently increased spontaneously and steadily from 15 x 10(9)/liter on admission to 400 x 10(9)/liter seven days later (Hesdorffer et al, 1986).
b. Thrombocytopenia was described in a 15-year-old Hispanic adolescent with cystic acne following isotretinoin 60 milligram (mg) daily (1 milligram/kilogram (mg/kg)/day) for approximately 2 weeks. Withdrawal of isotretinoin resulted in increases in platelet count to normal values over the next 10 days. Re-challenge with 60 mg isotretinoin resulted in recurrence of thrombocytopenia within 1 day, with subsequent return to normal values in approximately 10 days. This appears to be the first case report of thrombocytopenia secondary to isotretinoin (Johnson & Rapini, 1987).
3.3.2 CARDIOVASCULAR
A. CARDIOVASCULAR EFFECTS
1. Chest pain and vasculitis have been reported with isotretinoin therapy.
2. In a case report, a patient receiving isotretinoin 1 milligram per kilogram daily for severe acne developed RIGHT BRANCH BUNDLE BLOCK (RBBB) associated with SINUS TACHYCARDIA. Discontinuation of isotretinoin resolved all signs and symptoms. Reintroduction of isotretinoin 10 days later induced RBBB again, which resolved upon drug discontinuation (Charalabopoulos et al, 2003).
B. CHEST PAIN
1. SUMMARY:
a. Transient chest pain has been associated with isotretinoin therapy; symptoms are usually reversible after discontinuation of therapy (Prod Info Accutane(R), 2000).
C. VASCULITIS
1. SUMMARY:
a. A few reports of vasculitis have been reported in patients receiving isotretinoin (Prod Info Accutane(R), 2000). It has occurred in patients taking isotretinoin in doses of 0.5 to 1.1 milligrams/kilogram/day. Reports indicate that vasculitis has occurred 14 to 16 weeks into therapy (Epstein et al, 1987). However, in one case, the patient received isotretinoin for 6 months, and vasculitis did not appear until 6 months after treatment was stopped (Reynolds et al, 1989).
2. LITERATURE REPORTS:
a. CUTANEOUS NECROTIZING VASCULITIS was reported in two patients taking isotretinoin. Symptoms gradually resolved with appropriate therapy and discontinuance of the drug; prednisone was a successful adjunct in one case (Dwyer et al, 1989).
3.3.3 CENTRAL NERVOUS SYSTEM
A. NEUROLOGIC EFFECTS
1. Isotretinoin therapy has been associated with seizures, dizziness, nervousness, insomnia, paresthesias, lethargy, fatigue, and headache. Pseudotumor cerebri and papilledema have also been reported in adults.
B. PSYCHIATRIC EFFECTS
1. Isotretinoin therapy may cause depression, psychosis and rarely, suicidal ideation, suicide attempts and suicide. Dream pattern changes has been reported.
C. HEADACHE
1. SUMMARY:
a. Headache may occur with therapeutic isotretinoin doses (Bigby & Stern, 1988; McLane, 2001; Lindemayr, 1986; Windhorst & Nigra, 1982).
2. LITERATURE REPORTS:
a. Headache was reported in 13.3% of patients treated with isotretinoin in one large trial (n=369). The mean duration of the headache was from 6 to 8 days (McLane, 2001).
b. The Adverse Drug Reaction Reporting System of the American Academy of Dermatology reported 104 suspected adverse reactions secondary to isotretinoin in 93 patients over a 4-year period (1982 to 1985) (Bigby & Stern, 1988). Central nervous system adverse effects were described in 23 patients, with 12 being considered as definitely or probably related to isotretinoin. This included 10 reports of headache). In the majority of cases, the headaches occurred within the first week of treatment.
D. NEUROLOGIC FINDINGS
1. SUMMARY:
a. Isotretinoin therapy has been associated with SEIZURES, DIZZINESS, NERVOUSNESS, INSOMNIA, and PARESTHESIAS (Prod Info Accutane(R), 2000; Perry & McEvoy, 1983; Windhorst & Nigra, 1982). CONFUSION has rarely been reported (Marroni et al, 1993).
E. PSEUDOTUMOR CEREBRI
1. SUMMARY:
a. Several cases of pseudotumor cerebri BENIGN INTRACRANIAL HYPERTENSION (or ELEVATED INTRACRANIAL PRESSURE) have been reported in patients receiving isotretinoin, usually associated with concomitant tetracycline therapy. PAPILLEDEMA, headache, nausea and vomiting and VISUAL DISTURBANCES have occurred as early signs and symptoms. Patients with these symptoms should be screened for papilledema and if a diagnosis is made, therapy should be immediately discontinued and the patient should be evaluated by a neurologist (Prod Info Accutane(R), 2000; Roytman et al, 1988; Bigby & Stern, 1988; Spector, 1984; FDA, 1983).
2. LITERATURE REPORTS:
a. A case of pseudotumor cerebri was reported that developed in a patient receiving 0.7 milligrams/kilogram/day of isotretinoin without concomitant use of tetracycline. Two months into therapy the patient developed severe headaches and dizzy spells. Isotretinoin therapy was stopped and administration of dexamethasone begun. Six weeks later the patient was symptom-free (Roytman et al, 1988).

	Supps

	protein

[Naughty Nurse]

Wow, Joeyz, good stuff.

[JOEYZ]

Originally Posted by Naughty Nurse

Wow, Joeyz, good stuff.

Micromedex is great. I have it on my Palm for work. It is updated every few days so there is always cutting edge drug information on it.

[Naughty Nurse]

Originally Posted by JOEYZ

Micromedex is great. I have it on my Palm for work. It is updated every few days so there is always cutting edge drug information on it.

If I can ever in to teaching the up-and-coming nurses, maybe I could actually use the one I've got...otherwise I barely have time to pee let alone use my Palm :(