ACCUTANE ROCHE®
Roche
Isotretinoin
Acne Therapy
Action And Clinical Pharmacology: The mechanism of action of isotretinoin is unknown. Vitamin A is important for functional integrity of the skin and is known to affect the keratinization process. In acne patients, improvement occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to either the dose or duration of isotretinoin administration and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.
Following oral administration of 80 mg, peak plasma concentrations ranged from 167 to 459 ng/mL with a mean time to peak of 3.2 hours in volunteers, while in acne patients peak plasma concentrations ranged from 98 to 535 ng/mL (mean 262 ng/mL) with a mean time to peak of 2.9 hours. Isotretinoin is 99.9% protein bound in human plasma, almost exclusively to albumin. The mean terminal elimination half-life of isotretinoin in volunteers and patients ranged from 9 to 22 hours. Following oral administration of 4-isotretinoin, 4 activity in blood declined with a mean half-life of 90 hours. Approximately equal amounts of radioactivity were recovered in the urine and feces, with 65 to 83% of the dose recovered.
The major metabolite identified in blood and urine was 4-oxo-isotretinoin. Tretinoin and 4-oxo-tretinoin were also observed. The apparent half-life for elimination of the 4-oxo-isotretinoin ranged from 11 to 50 hours with a mean of 28 hours. Following 80 mg of isotretinoin administered orally, maximum plasma concentrations of the 4-oxo-isotretinoin was 87 to 399 ng/mL and maxima were observed between 6 and 20 hours. The blood concentration of the major metabolite generally exceeded that of isotretinoin after 6 hours. The data suggest that both isotretinoin and the major metabolite are excreted in the bile and reabsorbed.
The mean minimum steady state blood concentrations of isotretinoin were 160 ng/mL in 10 patients receiving 40 mg twice daily. After single and multiple doses, the mean ratio of areas under the curves of 4-oxo-isotretinoin to isotretinoin was between 3 and 3.5.
Indications And Clinical Uses: The treatment of severe nodular and/or inflammatory acne, acne conglobata and recalcitrant acne.
Because of significant side effects associated with its use, isotretinoin should be reserved for patients where the conditions listed above are unresponsive to conventional therapy, including systemic antibiotics. Isotretinoin should only be prescribed by physicians knowledgeable in the use of retinoids systemically. It is recommended that each isotretinoin prescription be limited to preferably a 1 month supply in order to encourage patients to return for their regular appointments.
Contra-Indications: Pregnancy: Isotretinoin is contraindicated in pregnancy. Females must not become pregnant while taking isotretinoin or for at least 1 month after its discontinuation. Isotretinoin causes severe birth defects in a very high percentage of infants born to women who take this drug even for a short period of time during pregnancy (see Warnings: Pregnancy, Pregnancy Testing and Contraception).
Isotretinoin is contraindicated in females of childbearing potential unless all of the following conditions apply:
1. The patient has severe disfiguring nodular and/or inflammatory acne, acne conglobata or recalcitrant acne that has not responded to standard therapy, including systemic antibiotics.
2. The patient is reliable in understanding and carrying out instructions.
3. The patient is able to comply with the mandatory contraceptive measures.
4. The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to isotretinoin, and the risk of possible contraception failure. This explanation may include showing a line drawing to the patient of an infant with the characteristic external deformities resulting from isotretinoin exposure during pregnancy.
5. The patient has had a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL with a negative result, performed in a licensed laboratory, within 2 weeks prior to initiating therapy. The patient has had 2 or 3 days of the next normal menstrual period before isotretinoin therapy is initiated.
Note: Re: items 2 to 5 see Warnings: Pregnancy, Pregnancy Testing and Contraception.
Isotretinoin is also contraindicated in patients who are sensitive to parabens or to those with known hypersensitivity to retinoids.
Manufacturers’ Warnings In Clinical States: Pregnancy : Pregnancy, Pregnancy Testing and Contraception: There is an extremely high risk (25% or greater) that major human fetal abnormalities will occur if pregnancy occurs during treatment with isotretinoin or up to 1 month following its discontinuation. Potentially any exposed fetus can be affected. These abnormalities, associated with isotretinoin administration during pregnancy, have been reported and include: CNS (hydrocephalus, hydranencephaly, microcephaly, posterior fossa abnormalities, cranial nerve dysfunction, cerebellar malformation); craniofacial (anotia, microtia, low set ears, small or absent canals, microphthalmia, facial dysmorphia, cleft palate); cardiac (septal defects, aortic arch abnormalities, tetralogy of Fallot); thymus gland abnormalities; and parathyroid hormone deficiency.
Female patients of childbearing potential must not be given isotretinoin until pregnancy is excluded. A pregnancy test must be performed within 2 weeks prior to starting treatment. Isotretinoin treatment should start on the second or third day of the next normal menstrual period following this negative pregnancy test. Effective contraception must be used for at least 1 month before starting isotretinoin treatment, during treatment and for at least 1 month following the discontinuation of treatment. It is recommended that 2 reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Pregnancy occurring during treatment with isotretinoin and for 1 month after its discontinuation, carries the risk of fetal malformation (see Warnings above). Females should be fully counselled on the serious risk to the fetus should they become pregnant while undergoing treatment. If pregnancy does occur during this time the physician and patient should discuss the desirability of continuing the pregnancy.
It is strongly recommended that all female patients of childbearing potential treated with isotretinoin have regular monthly pregnancy tests during treatment and 1 month after the discontinuation of treatment. These pregnancy tests will: serve primarily to reinforce to the patient the necessity of avoiding pregnancy and in the event of accidental pregnancy, provide the physician and patient an immediate opportunity to discuss the serious risk to the fetus from this exposure to isotretinoin and the desirability of continuing the pregnancy in view of the potential teratogenic effect of isotretinoin (see Warnings above).
Lactation: It is not known whether isotretinoin is excreted in human milk. Because of the potential for adverse effects, women should not breast-feed if they are receiving isotretinoin.
Hyperostosis: In clinical trials of disorders of keratinization, with a mean dose of 2.24 mg/kg/day, a high prevalence of skeletal hyperostosis was noted. Two children showed x-ray findings suggestive of premature closure of the epiphysis. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective study of disorders of keratinization. Minimal skeletal hyperostosis has also been observed by x-rays in prospective studies of cystic acne patients treated with a single course of therapy at recommended doses.
Hepatotoxicity: Liver function tests should be monitored before treatment and at regular intervals during treatment. Several cases of clinical hepatitis have been noted which are considered to be possibly or probably related to isotretinoin therapy. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur, or if hepatitis is suspected during treatment with isotretinoin, the drug should be discontinued and the etiology further investigated.
Precautions: Benign Intracranial Hypertension (pseudotumor cerebri): Isotretinoin has been associated with a number of cases of benign intracranial hypertension. Early signs and symptoms of this disorder usually include headache, visual disturbances, nausea and vomiting. Patients with these symptoms should be examined for papilledema. If present, isotretinoin should be discontinued immediately and the patient referred to a neurologist for diagnosis and care.
Decreased Night Vision: A number of cases of decreased night vision have occurred during isotretinoin therapy. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored.
Corneal Opacities: Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. All isotretinoin patients experiencing visual difficulties should discontinue the drug and have an ophthalmological examination. The corneal opacities that have been observed in patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see Adverse Effects).
Inflammatory Bowel Disease: Isotretinoin has been temporally associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue isotretinoin immediately.
Lipids: Blood lipid determinations should be performed before isotretinoin is given and then at intervals until the lipid response to isotretinoin is established, which usually occurs within 4 weeks.
Approximately 25% of patients receiving isotretinoin experienced an elevation in plasma triglycerides. Approximately 15% developed a decrease in high density lipoproteins and about 7% showed an increase in cholesterol levels. These effects on triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy.
Patients with increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, obesity, increased alcohol intake and familial history.
The cardiovascular consequences of hypertriglyceridemia are not well understood, but may increase the patient’s risk status. In addition, elevation of serum triglycerides in excess of 800 mg/dL has been associated with acute pancreatitis. Therefore, every attempt should be made to control significant triglyceride elevation. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing isotretinoin. An obese male patient with Darier’s disease developed elevated triglycerides and subsequent eruptive xanthomas.
Diabetes: Patients with diabetes or a family history of diabetes may experience problems with the control of their blood sugar during isotretinoin therapy. Therefore, known or suspected diabetics should have periodic blood sugar determinations.
Vitamin A: Because of the relationship of isotretinoin to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A, to avoid additive toxic effects.
Children: The long-term safety of isotretinoin in prepubertal children has not been established.
Blood Donation: It is recommended that blood donation for transfusion purposes be deferred during therapy with isotretinoin and for 1 month after discontinuation of treatment. Theoretically, blood from such donors could present a small risk to the fetus if transfused to a pregnant mother during the first trimester of pregnancy.
Adverse Reactions: Many of the side effects and adverse reactions seen or expected in patients receiving isotretinoin are similar to those described in patients taking high doses of vitamin A.
Clinical Adverse Experiences: The most common side effects are mucocutaneous or dermatologic. The common side effects include: cheilitis (96%), facial dermatitis (55%), dry nose (51%), desquamation (50%), pruritus (30%), dry skin (22%), conjunctivitis (19%), alopecia (13%), irritation of the eyes (11%).
Approximately 13% of patients experience joint pain during treatment.
Peeling of palms and soles, skin infections, increased susceptibility to sunburn, nonspecific urogenital symptoms, nonspecific gastrointestinal symptoms, headache, fatigue occur in approximately 5% of patients.
Skeletal hyperostosis has been observed on x-rays of patients treated with isotretinoin (see Warnings, Hyperostosis).
Isotretinoin has been associated with a number of cases of pseudotumor cerebri, some of which involved concomitant use of tetracyclines (see Precautions, Benign Intracranial Hypertension).
Of 72 patients who had normal pretreatment ophthalmological examinations, 5 developed corneal opacities while on isotretinoin (all 5 patients had a disorder of keratinization). Corneal opacities have also been reported in nodular and/or inflammatory acne patients treated with isotretinoin (see Precautions, Corneal Opacities). Decrease in night vision has been reported and in rare instances has persisted (see Precautions, Decreased Night Vision). Cataracts and visual disturbances have also been reported.
Isotretinoin has been temporally associated with inflammatory bowel disease, including regional ileitis (see Precautions, Inflammatory Bowel Disease).
Other adverse reactions which have been reported infrequently and may bear no relationship to therapy include:
Mucocutaneous and Dermatologic: flushing, changes in skin pigment, urticaria, bruising, disseminated herpes simplex, hair problems (other than thinning), hirsutism, erythema nodosum, paronychia, nail dystrophy, pyogenic granuloma, bleeding and inflammation of the gums, acne fulminans.
CNS: seizures, emotional instability, dizziness, nervousness, drowsiness, malaise, weakness, insomnia, lethargy, paresthesia.
Ophthalmologic: optic neuritis, photophobia, eye lid inflammation.
Gastrointestinal: mild gastrointestinal bleeding, rectal bleeding, pancreatitis.
Cardiovascular: edema, transient pain in the chest, palpitations, tachycardia.
Respiratory: respiratory infections.
Urogenital: abnormal menses.
Other: weight loss, arthritis, anemia, lymphadenopathy, vasculitis including Wegener’s granulomatosis.
Depression has been reported during and after therapy. In some of these patients, depression has subsided with discontinuation of therapy and recurred when isotretinoin therapy was reintroduced.
Dry eyes and/or decreased tolerance to contact lenses have also been reported during therapy. In some instances these conditions have persisted after cessation of therapy.
Laboratory Abnormalities: Isotretinoin therapy induces changes in serum lipids in a significant number of treated subjects. These changes consisted of: elevation of serum triglycerides, (25% of patients) mild to moderate decreases in serum high density lipoprotein (HDL) (16% of patients), and minimal elevations of serum cholesterol (7% of patients). Abnormalities of serum triglycerides, HDL and cholesterol were reversible upon cessation of therapy.
A rise in serum levels of liver enzymes may occur, especially with higher dosages. Although the changes have usually been within the normal range and may return to baseline levels despite continued treatment, significant increases have occurred in a few cases, necessitating dosage reduction or discontinuation of isotretinoin (see Warnings, Hepatotoxicity). An elevated erythrocyte sedimentation rate may also occur (40% of patients).
Other less commonly reported laboratory abnormalities were: decreases in red blood cell parameters and white blood cell counts, elevated platelet counts, white cells in the urine, proteinuria, red blood cells in the urine, elevated fasting blood sugar, elevated creatinine phosphokinase (CPK) or hyperuricemia.
Dose-relationship and duration: Cheilitis and hypertriglyceridemia are usually dose related.
Adverse reactions were generally reversible when therapy was discontinued; however, some have persisted after cessation of therapy.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of acute overdose, evacuation of the stomach should be considered during the first few hours after this overdose. Signs and symptoms of acute overdose have been associated with headache, vomiting, facial flushing, cheilitis, abdominal pain, dizziness and ataxia. To date, all symptoms quickly resolved without apparent residual effects and usually without treatment. Elevated intracranial pressure has been reported with patients receiving therapeutic doses of isotretinoin. Patients with an isotretinoin overdose should be monitored closely for signs of increased intracranial pressure.
Limited data exist on the pharmacokinetic characteristics of isotretinoin in an overdose situation. Following the oral administration of single 80, 160, 240 and 340 mg doses to 12 healthy male subjects Cmax was 366, 820, 1 056 and 981 ng/mL, and t1/2 was 13.6, 14.1, 14.4 and 16.5 hours for isotretinoin, respectively. Twenty-three compromised cancer patients received weekly oral doses of 200 (3 patients); 400 (7 patients); 660 (2 patients); 1 000 (3 patients); 1 400 (6 patients) and 1 800 (1 patient) mg/m Normal body surface area for healthy subjects is 1.73 m After the first dose, Cmax was 1.5, 3.8, 3.5, 2.5, 2.7 and 4.6 µg/mL, and t1/2 was 45, 9.1, 14.5, 57, 13.1 and 6.1 hours for isotretinoin, respectively. The absorption of isotretinoin appears to be a saturable process.
Since it is difficult to extrapolate from the results of these studies to the overdose situation, the following precautions should be taken with all female patients of childbearing potential who have taken an overdose of isotretinoin.
1. At the time of the overdose, a pregnancy test must be performed and a blood sample collected for the determination of isotretinoin and metabolite concentrations.
2. One complete menstrual cycle after the overdose, a second pregnancy test must be performed and a second blood sample collected for the determination of isotretinoin and metabolite concentrations.
3. Effective contraception must be used for at least one complete menstrual cycle after the overdose and continued longer if necessary until isotretinoin and its metabolites are no longer measurable in the blood.
Patients who present with a positive pregnancy test at the time of the overdose, one complete menstrual cycle after the overdose, or while isotretinoin or metabolite blood concentrations are measurable, should be fully counselled on the serious risk to the fetus from this exposure to isotretinoin and the physician and patient should discuss the desirability of continuing the pregnancy (see Contraindications and Warnings).
Canadian Regional Poison Information Centres have been advised on the proper collection and handling of isotretinoin blood samples and also on the laboratory(s) equipped to assay these samples.
Dosage And Administration: The therapeutic response to isotretinoin is dose-related and varies between patients. This necessitates individual adjustments of dosage according to the response of the condition and the patient’s tolerance of the drug. In most cases complete or near-complete suppression of acne is achieved with a single 12- to 16-week course of therapy. If a second course of therapy is needed, it can be initiated 8 or more weeks after completion of the first course, since experience has shown that patients may continue to improve while off the drug.
Initial Therapy: The initial dose should be individualized according to the patient’s weight and severity of the disease.
In general patients initially should receive isotretinoin 0.5 mg/kg body weight daily for a period of 2 to 4 weeks, when their responsiveness to the drug will usually be apparent. It should be noted that transient exacerbation of acne is occasionally seen during this initial period.
The daily dosage should be taken with food in the nearest number of whole capsules, either as a single dose or in 2 divided doses during the day, whichever is more convenient.
Maintenance Therapy: Maintenance dose should be adjusted between 0.1 and 1 mg/kg body weight daily and, in exceptional instances, up to 2 mg/kg body weight daily, depending upon individual patient response and tolerance to the drug.
A complete course of therapy consists of 12 to 16 weeks of isotretinoin administration.
Patients may show additional improvement for up to several months after a course of isotretinoin has been completed. With effective treatment, appearance of new lesions will not normally be evident for a period of at least 3 to 6 months.
Availability And Storage: 10 mg: Each opaque, oval-shaped, soft gelatin capsule contains: isotretinoin 10 mg (purple, imprinted ROA10). Nonmedicinal ingredients: beeswax, canthaxanthin 10%, gelatin, glycerin, hydrogenated palm oil, Karion 83, soybean and hydrogenated soybean oil and titanium dioxide. Energy: 6.4 kJ (1.5 kcal).
40 mg: Each opaque, oval-shaped, soft gelatin capsule contains: isotretinoin 40 mg (yellow, imprinted ROA40). Nonmedicinal ingredients: beeswax, gelatin, glycerin, methylparaben, hydrogenated palm oil, propylparaben, quinoline yellow WS, soybean and hydrogenated soybean oil, sunset yellow FCF and titanium dioxide. Energy: 11.7 kJ (2.8 kcal).
Alcohol-, gluten-, lactose-, sodium-, sulfite- and tartrazine-free. Blister packs of 30. Protect from light at all times. Store at 15 to 30°C. Dispense with information for the consumer. (Shown in Product Recognition Section)
ACCUTANE ROCHE® Roche Isotretinoin Acne Therapy
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