What is Isotretinoin?

Isotretinoin soft capsules, suitable for severe refractory nodular acne (nodular acne, that is, inflammatory lesions with a diameter of> 5rmn, nodules may be purulent or bleeding). Because there are obvious adverse reactions after the use of isotretinoin, it should be tested when other conventional treatments (including systemic antibiotics) are ineffective. In addition, because isotretinoin can cause severe birth defects, female patients are only suitable for those who are unprepared or unable to conceive.

Isotretinoin soft capsules, suitable for severe refractory nodular acne (nodular acne, that is, inflammatory lesions with a diameter of> 5rmn, nodules may be purulent or bleeding). Because there are obvious adverse reactions after the use of isotretinoin, it should be tested when other conventional treatments (including systemic antibiotics) are ineffective. In addition, because isotretinoin can cause severe birth defects, female patients are only suitable for those who are unprepared or unable to conceive.

Drug Name

Isotretinoin Soft Capsules

Drug type

Prescription drugs, medicines for medical workers' injuries

Use classification

Antikeratosis

Warnings of isotretinoin soft capsules

This product can cause birth defects, so don't get pregnant.
Isotretinoin is contraindicated in women who are pregnant or about to become pregnant. Pregnancy during any dose of isotretinoin, even if taken for short periods of time, has an extremely high risk of severe birth defects. Taking this drug during pregnancy may affect fetal development, and there is no precise way to determine whether fetuses exposed to isotretinoin are affected.
Birth defects confirmed after taking isotretinoin include: facial, eye, ear, and skull deformities, abnormalities in the central nervous system, cardiovascular system, thymus, and parathyroid glands. Cases with or without other abnormal IQ scores below 85 have been reported. Increased risk of spontaneous abortion and premature birth has been reported.
Proven external defects include: skull deformities; ear deformities (eg, no or small ears, small or missing external auditory canals); eye deformities (eg, small eye deformities); facial deformities; palate. Proven internal defects include: abnormal development of the central nervous system (such as brain malformations, cerebellar malformations, cerebral edema, microcephaly, and cranial nerve loss); abnormal cardiovascular development; abnormal development of the thymus; abnormal development of the parathyroid glands. Some deaths were confirmed in advance.
Therefore, women of childbearing age and their spouses should be strictly contraceptive within three months before and after taking the drug and during taking the drug.
If a female patient develops a pregnancy while taking the drug, she should discontinue the drug immediately and be further evaluated and consulted by an obstetrician and gynecologist experienced in reproductive toxicity.
Special prescription requirements Due to the teratogenicity of isotretinoin, in order to minimize the risk of fetal exposure, isotretinoin can only be prescribed by a specialist who has the qualifications of a licensed physician and has extensive experience in medication.

Isotretinoin Soft Capsule Ingredients

The main ingredient of this product is isotretinoin, also known as 13-cis retinoid. Chemical name: 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) 2cis-4trans-6trans-8trans-non-tetraenoic acid.
Structural formula:

Molecular formula: C ₂₀ H ₂₈ O ₂
Molecular weight: 300.44

Isotretinoin Soft Capsule Properties

This product is a dark brown soft capsule with an orange-yellow oily suspension.

Isotretinoin soft capsule indications

It is suitable for severe refractory nodular acne (nodular acne, ie, inflammatory lesions with a diameter of 5rmn, nodules may be purulent or bleeding).
Because there are obvious adverse reactions after the use of isotretinoin, it should be tested when other conventional treatments (including systemic antibiotics) are ineffective. In addition, because isotretinoin can cause severe birth defects, female patients are only suitable for those who are unprepared or unable to conceive.

Isotretinoin Soft Capsule Specifications

10mg

Isotretinoin soft capsule usage dosage

This product should be used under the guidance of a doctor. Take with food.
The dosage of oral treatment should vary from person to person, ranging from 0.1 to 1 mg / kg / d. Generally, the recommended starting dose is 0.5 mg / kg / d, divided into two doses with food immediately. After 2-4 weeks of treatment, the dose can be adjusted as appropriate based on clinical effects and adverse reactions. 6-8 weeks is a course of treatment or as directed by your doctor (see [Precautions]). Because the drug absorption can be significantly reduced if not taken with food, the patient's compliance with the food should be consulted in detail before increasing the dose.
The safety of isotretinoin once-daily administration has not been established, and once-daily administration is not recommended.
More than 2 months after discontinuation, and the skin lesion persists or severe nodular acne recurrence occurs, a second course of treatment may be considered. Experience has shown that symptoms can continue to improve in the short term after discontinuation, so if a second course of treatment is needed, the interval between the two courses should be more than 8 weeks. The optimal interval between patients with underdeveloped bones is unknown.
Effective contraception should be taken during any course of treatment.

Isotretinoin soft capsule adverse reactions

Listed below are adverse reactions that have been detected in isotretinoin clinical trials and after marketing, and the relationship between some adverse events and isotretinoin treatment is unclear. Most of the adverse reactions of isotretinoin are similar to the symptoms of excessive vitamin A (mainly dry skin and mucous membranes, such as lips, nasal cavity and eyes, etc.).
Dose-related adverse reactions: Cheilitis and hypertriglyceridemia are often dose-related. Most of the adverse reactions reported in clinical trials are reversible and gradually recover after stopping the drug, but some will continue after stopping the drug.
Systemic damage; allergic reactions (including vasculitis, systemic allergic reactions), edema, fatigue, lymphadenopathy, and weight loss.
Cardiovascular system: palpitations, tachycardia, thrombosis, stroke.
Endocrine / metabolic system: hypertriglyceridemia, blood sugar fluctuations.
Digestive system: inflammatory bowel disease, hepatitis, pancreatitis, bleeding gums, gingivitis, colitis, esophagitis / esophageal ulcers, ileitis, nausea and other non-specific gastrointestinal symptoms.
Blood system: Anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis.
Musculoskeletal system: osteogenesis, calcification of tendons and ligaments, premature epiphyseal closure, decreased bone density, musculoskeletal symptoms (partially severe) including back pain, myalgia, arthralgia, transient chest pain, arthritis, tendon Inflammation and other bone abnormalities, reports of elevated creatine phosphokinase / rare rhabdomyolysis, etc.
Nervous system: benign intracranial pressure (also known as pseudo brain tumor), dizziness, drowsiness, headache, insomnia, salivation, discomfort, nervousness, abnormalities in the world, seizures, stroke, syncope, weakness.
Mental system: suicidal ideation, suicidal tendency, suicide, depression, insanity, aggressive behavior, violent behavior. In the related reports of depression, some patients have reduced their symptoms of depression after stopping the drug, but depression will reappear after re-administration.
Reproductive system: Menstrual disorders.
Respiratory system: bronchospasm (with or without history of asthma), respiratory infections, sound changes.
Skin and skin appendages: acne outbreak, hair loss (some patients persist after discontinuation), ecchymosis, cheilitis, dry mouth, dry nose, dry skin, epistaxis, polymorphic erythema, facial flushing, increased skin fragility, Hirsutism, hyperpigmentation and hypopigmentation, infections (including diffuse herpes simplex), nail dystrophy, paronychia, palmoplantar peeling, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, Itching, purulent granuloma, rashes (including facial erythema, seborrheic dermatitis, and eczema), urticaria, vasculitis (including Wegener's granulomatosis), and delayed wound healing.
Other feelings: hearing, hearing impairment, tinnitus. Vision: corneal opacities, possible night vision loss after drug withdrawal, cataract, color blindness, conjunctivitis. Dry eyes, blepharitis, keratitis, optic neuritis, photophobia, visual impairment.
Urinary cashmere: Glomerulonephritis, non-specific urinary system examination found.
Laboratory inspection:
During treatment, serum triglycerides increased, high-density lipoprotein (HDL) decreased, and serum cholesterol increased. Alkaline phosphatase, ALT, AST, GGTP or LDH are elevated.
Fasting blood glucose increased, CPK increased, and blood uric acid increased.
Decreased red blood cell count, decreased white blood cell count (including severe neutropenia and rare agranulocytosis), accelerated erythrocyte sedimentation, increased platelet count, and thrombocytopenia. White blood cells, proteinuria appear in the urine, and hematuria under the microscope or the naked eye.

Isotretinoin soft capsule contraindications

Those who are allergic to any component of this product are prohibited. This product is prohibited for use in pregnant women or women who are about to become pregnant. Women of childbearing age or their spouses should use effective contraceptive measures 3 months before, 3 months after treatment and 3 months after treatment with isotretinoin.

Precautions for isotretinoin soft capsules

1. Use with caution in patients with diabetes, obesity, increased alcohol intake, and abnormal lipid metabolism or familial lipid metabolism.
2. The clinical research of foreign isotope A fusion original research products shows that most patients with severe refractory nodular acne can completely clear or alleviate symptoms during treatment with this drug for 15-20 weeks, so its recommended course of treatment is 15-20 weeks, and it states that Before the end of the 15-20 week course of treatment, the drug can be discontinued if the total count of acne nodules has decreased by more than 70%. Because there are individual differences between patients, the following related information can be used as a reference for clinical individualized treatment.
3 Long-term use of isotretinoin (even in small doses) has not been studied and long-term use is not recommended. The effect of long-term isotretinoin on bone loss is unknown (see [Adverse Reactions] for details).
4 Women of childbearing age should take a pregnancy test before, during, and after discontinuation.
-Women of childbearing age. Before this product is prescribed, it must be confirmed twice that the urine or serum pregnancy test is negative (minimum sensitive concentration: 25mIU / mL). The first test (screening test) is performed by the prescriber when determining whether to use this product for eligible patients. The second test (confirmation check) must be performed in a quality control laboratory, and the interval between the two tests should be no less than 19 days.
-Patients with regular menstruation should use two effective contraceptives for one month before starting this product. They must perform a second pregnancy test within the first 5 days of the menstrual period.
-Patients with amenorrhea, irregular menstruation, or the use of contraceptive methods to stop menstrual cramps must use 2 effective contraceptives for 1 month and perform a second pregnancy test before starting this product.
-Urine or serology pregnancy tests must be performed every month during treatment to exclude pregnancy. Female patients should be tested for pregnancy tests in a quality control laboratory before each prescription.
5. Blood glucose, blood lipid, liver function, and creatine phosphokinase should be checked regularly (weekly or every 2 weeks) during the medication.
6. In the event of depression, agitation, mental disorders or aggressive behavior, the patient should stop taking the drug immediately, and the patient or his family should contact the prescriber in a timely manner.
7. This medicine should be taken at the same time as tetracycline drugs. If patients have symptoms of pseudo brain tumor (benign intracranial pressure increase), such as optic nerve papillary edema, headache, nausea, vomiting and blurred vision, the drug should be stopped immediately and the optic nerve should be taken. Examination, if necessary, refer to a neurologist for further diagnosis and treatment.
8. Patients who may suffer from osteoporosis (such as the elderly or patients with previous osteoporosis, osteomalacia and other bone metabolism abnormalities) should be used with caution. Patients with anorexia nervosa and in combination with other drugs that can cause drug-induced osteoporosis, osteomalacia, and / or affect vitamin D metabolism should also be noted.
9. Mild adverse reactions may not need to be discontinued or used in reduced doses; if the following serious adverse reactions occur, they should be discontinued immediately and taken to the hospital for appropriate treatment, including: triglycerideemia cannot be controlled to an acceptable level, Pancreatitis, severe skin adverse reactions (eg Stevens-Johnson syndrome, toxic epidermal necrolysis), tinnitus, hearing impairment, continuous increase in liver enzymes, no decline or suspected hepatitis, abdominal pain, rectal bleeding or Severe diarrhea, vision difficulties, severe allergic reactions, etc.
10 This product should be avoided in conjunction with vitamin A-containing vitamin supplements.
11. Avoid prolonged exposure to sunlight and ultraviolet rays.
12. No blood donation is allowed during medication and within three months after discontinuation.
13. The symptoms of acne may be temporarily exacerbated in the early stage of treatment. If there are no other abnormalities, you can continue to take the drug under close observation. It is not appropriate to take other keratolytic agents or epidermal peeling anti-acne drugs at the same time.
14. If necessary, mild external medicine can be used as adjuvant treatment.
15. This product should be prescribed for use by a doctor who is qualified to practise and has extensive clinical experience.

Isotretinoin soft capsules for pregnant and lactating women

Women of childbearing age or their spouses should be strictly contracepted within three months before and after the medication, and must not be pregnant. It is unknown whether isotretinoin is secreted through breast milk. Given the potential adverse effects of this drug, breastfeeding women are strictly prohibited from using isotretinoin.

Isotretinoin soft capsules for children

Isotretinoin use in children under 12 years has not been studied. Overdose can cause changes in bone structure, including precocious fusion of the epiphyseal disc in children. In children with severe refractory nodular acne 12 to 17 years of age, especially when it is known to be associated with metabolic or skeletal disorders, treatment with isotretinoin should be performed with caution.
In the clinical studies of isotretinoin, the incidence of back pain, Guan's pain, and myalgia in children was higher than that in adults. Other adverse reactions were similar to those in adults.

Isotretinoin Soft Capsules for the Elderly

A sufficient number of subjects over 65 years have not been included in clinical studies to determine whether their drug response is consistent with younger subjects. Although clinical use has not found any differences between medications for elderly patients and other populations, taking into account the effects of age, it is expected that elderly patients will increase their risk when they are treated with isotretinoin.

Isotretinoin Soft Capsule Drug Interactions

1. Isotretinoin combined with tetracycline antibiotics can cause false "brain tumors" and cause benign brain pressure. Clinical manifestations are hypertension, dizziness, and visual impairment with headache.
2. Isotretinoin is used in conjunction with vitamin A and can produce symptoms similar to those seen when vitamin A is overdosed.
3 The simultaneous application of isotretinoin and carbamazepine can reduce the blood concentration of carbamazepine, and the simultaneous use with warfarin can enhance the therapeutic effect of warfarin, and methotrexate ( MTX) can increase liver damage due to the increase of MTX blood concentration. 1. Tetracycline: The combination of isotretinoin and tetracycline drugs can lead to the production of "pseudo brain tumors" and cause benign intracranial pressure. The clinical manifestations are hypertension with headache, dizziness, and visual impairment.
2. Vitamin A: The simultaneous use of isotretinoin and vitamin A may increase the toxicity of isotretinoin, and symptoms similar to those of overdose of vitamin A may occur.
3 Carbamazepine: The simultaneous application of isotretinoin and Carbamazepine can cause the blood concentration of Carbamazepine to decrease, and the simultaneous use with Warfarin can enhance the therapeutic effect of warfarin. Used with methotrexate (MTX). May increase liver damage due to increased blood concentration of MTX.
4 Low-dose progesterone preparations (small-dose oral contraceptives without estrogen): during the treatment of isotretinoin, low-dose progesterone preparations are not a suitable contraceptive method, although) other hormonal contraceptives work better, but There have been reports of pregnancy using topical, intramuscular, implantation, and hormonal contraceptive methods. And pregnancy rates were higher in patients who used only one method of contraception. It is unclear whether the combination of isotretinoin affects the contraceptive effect of hormones. Therefore, it is strongly recommended that women of childbearing age who use isotretinoin use more than two effective contraceptive methods, and at least one of them is the main recommended method of contraception.
5. Norethindrone / ethinyl estradiol: 31 women with severe menopausal nodular acne who were not menopausal in one study, taking OrthoNovum contraceptives while taking 1 mg / kg / d isotretinoin, contraceptive The pharmacokinetics of diol and norethisterone and the levels of progesterone, follicle stimulating hormone, and luteinizing hormone in plasma did not change clinically.
6. St. John's wort: Isotretinoin use is associated with depression in some cases. Patients should be warned not to use the herbal medicine St. John's Wort for treatment. Studies have shown that St. John's Bamboo and sex hormone contraceptives can interact with the service. There have been reports of pregnant women taking the contraceptive while using St. John's Wort.
7. Phenytoin: A study of seven healthy subjects showed that isotretinoin did not change the pharmacokinetics of cristotoin, which is consistent with the results of in vitro tests. In vitro tests found that neither isotretinoin nor its metabolites could induce or inhibit the activity of human liver P450 enzyme CYP2C9. Phenytoin is known to cause chondropathy, but no formal clinical trials have evaluated whether isotretinoin and phenytoin interact with each other in terms of bone loss, so caution should be exercised when the two are combined.
8. Systemic corticosteroids: Systemic corticosteroids are known to cause osteoporosis. However, there are no formal clinical trials to study whether isotretinoin and systemic corticosteroids interact in bone loss, so caution should be exercised when combining the two.

Isotretinoin Soft Capsule Overdose

Overdose can cause vomiting, facial redness, chapped lips, abdominal pain, headache, dizziness, and ataxia. These symptoms can quickly disappear without significant after effects.

Isotretinoin Soft Capsules Pharmacology and Toxicology

Pharmacological effects: The mechanism of action of this drug is not completely clear. When used to treat acne, it can reduce sebaceous gland tissue, inhibit sebaceous gland activity, reduce sebum secretion, reduce keratinization of epithelial cells and horny embolism of hair follicle sebaceous gland, and inhibit the growth and reproduction of Propionibacterium acnes. Recent studies have also shown that the drug can regulate the inflammatory immune mediators involved in the pathogenesis of acne and selectively bind to the retinoic acid nuclear receptor to play a therapeutic role.
Toxicology research:
Genotoxicity: Ames test was performed in two laboratories, one of which was negative, and the other was weakly positive (less than 1.6 times the substrate) when tested for metabolite activity using S. typhimurium TA100 strain marker. No dose correlation was seen, and the results using other strains were all negative. In addition, other series of studies on genotoxicity (Chinese hamster cell research, mouse micronucleus test, S.cerevisiaeD7 series strains, in vitro study of human lymphocytes, unscheduled DNA synthesis studies) were negative.
Reproductive toxicity: Rats were given isotretinoin 2, 8, or 32 mg / kg / d (after conversion to standard body surface area, 0.3, 1.3, or 5.3 times the clinically recommended dose of 1.0 mg / kg / d, respectively), no gonads were seen Changes in function, fertility, fertility rate, pregnancy and childbirth. However, tests have shown that this product has serious teratogenic effects (see "Contraindications and Warnings").
Double testicular atrophy is seen in dogs after about 30 weeks of isotretinoin 20 or 60 mg / kg / d (10 and 30 times the clinically recommended dose of 1.0 mg / kg / d in terms of body surface area). In addition, obvious spermatogenesis inhibition was found in the samples that were examined by microscopy, but some normal spermatozoa were still present, and no complete seminiferous tubule atrophy was found in all examinations.
Carcinogenicity: Male and female Fischer344 rats take isotretinoin 8 or 32mg / kg / d (in terms of body surface area, 1.3 or 5.3 times the clinically recommended dose of 1.0mg / kg / d) for more than 18 months, and Compared with the blank control group, the incidence of pheochromocytoma was related to the dose. The incidence of adrenal hyperplasia in the high-dose group also increased significantly in both sexes. Pheochromocytoma has a relatively high incidence in male Fischer344 mice, and the relevance of this tumor to humans is unclear.

Pharmacokinetics of isotretinoin soft capsule

Absorption: Due to its high lipophilicity, the absorption of isotretinoin increases when taken with a high-fat meal. In a crossover study, 74 healthy adult subjects took a single oral 80mg isotretinoin (2 mg 40 capsules) under fasting and meal conditions. The Cmax and AUC all increased by more than two times than when fasted (see Table 1), but the elimination half-life was changed, which suggests that food can increase the bioavailability of isotretinoin without changing its distribution. Prolonged peak time (Tmax) during eating may be associated with longer absorption phases. Therefore, isotretinoin capsules should be taken with food. Clinical studies have shown no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution: The binding rate of isotretinoin to serum albumin is above 99.9%, of which it is mainly bound to albumin.
Metabolism: After oral isotretinoin, at least three metabolites were detected in human plasma: 4-oxo-isoretinoic acid, retinoid and 4-oxo-retinoic acid. Retinoic acid and 13-cis-retinoic acid (isoretinoic acid) are geometric isomers and can be reversibly converted. Taking one of these isomers can cause an increase in the other. Isotretinoin can also be irreversibly oxidized to 4-oxo-retinoic acid, and its geometric isomer is 4-oxo-retinoic acid.
After a single oral administration of 80 mg isotretinoin in 74 healthy adult subjects, the amount of all metabolite isomers in the plasma was increased under the conditions of taking the drug compared to when fasting.
All of these metabolites show stronger vitamin A-like activity than the parent isotretinoin in some in vitro models, but the clinical significance of these models is unclear. In adult cystic acne patients, after taking oral isotretinoin multiple times, the concentration of 4-oxo-isoretinoic acid reached about 3.4 times that of isotretinoin when they reached steady state under feeding and fasting conditions.
In vitro studies have shown that the main P450 isomers included in isotretinoin metabolites are 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates and excreted with feces and urine.
Excretion: After oral administration of 80mg of 14C-labeled isotretinoin suspension, the activity of 14C was halved in the blood for 90 hours. Isotretinoin metabolites and metabolic end products (conjugates) are excreted from urine and feces in relatively equal amounts (65% to 83% of the total). After a single oral administration of 80 mg isotretinoin in 74 healthy adult subjects, the elimination half-lives (t1 / 2) of isotretinoin and 4-oxy-isoretinoin were 21.0 ± 8.2h and 24.0 ± 5.3h. After single and multiple administrations of cystic acne patients, the accumulation ratio of isotretinoin ranges from 0.90 to 5.43.
Children: 38 pediatric patients (12-15 years old) and 19 adult patients (18 years old) took single and multiple isotretinoin for severe refractory nodular acne, drug action on isotretinoin Scientific studies show that in both age groups, the main metabolites are 4-oxo-retinoic acid, and there are also retinoids and 4-oxo-retinoic acid. The pharmacokinetic parameters of pediatric patients after single and multiple doses of isotretinoin are shown in Table 2. There was no statistical difference in the pharmacokinetic parameters of isotretinoin between children and adults.

Isotretinoin soft capsule storage

Sealed and stored in a cool (not more than 20 ° C) dry place.

Isotretinoin Softgel Packaging

Aluminum-plastic packaging (medical aluminum foil: polyvinyl chloride solid medicinal hard tablets): 10 tablets per plate, 1 plate or 2 plates per box.

Isotretinoin Softgels Validity Period

24 months

Isotretinoin Soft Capsules

"Chinese Pharmacopoeia" 2010 edition two ^[1]