Roaccutane^® (Capsules) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Catalent Germany Eberbach, GmbH (Germany)

ATC Code

D10BA01 (Isotretinoin)

Active Substance

Isotretinoin (Rec.INN registered by WHO)

Dosage Forms

	Roaccutane®	Capsules 10 mg: 30 or 100 pcs.
		Capsules 20 mg: 30 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules brownish-red, opaque, oval, with an inscription on the surface in black ink “ROA 10”; the capsule contents are a homogeneous suspension from yellow to dark yellow.

Excipients: soybean oil – 107.92 mg, yellow beeswax – 7.68 mg, hydrogenated soybean oil – 7.68 mg, partially hydrogenated soybean oil – 30.72 mg.

Capsule shell composition glycerol 85% – 31.275 mg, gelatin – 75.64 mg, Carion 83 (hydrolyzed potato starch, mannitol, sorbitol) – 8.065 mg, iron oxide red dye (E172) – 0.185 mg, titanium dioxide (E171) – 1.185 mg.
Ink composition shellac, iron oxide black dye (E172); the use of ready-made Opacode Black S-1-27794 ink is permitted.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Capsules one half brownish-red, the other half white, opaque, oval, with an inscription on the surface in black ink “ROA 20”; the capsule contents are a homogeneous suspension from yellow to dark yellow.

Excipients: soybean oil – 215.84 mg, yellow beeswax – 15.36 mg, hydrogenated soybean oil – 15.36 mg, partially hydrogenated soybean oil – 61.44 mg.

Capsule shell composition glycerol 85% – 49.835 mg, gelatin – 120.66 mg, Carion 83 (hydrolyzed potato starch, mannitol, sorbitol) – 12.86 mg, iron oxide red dye (E172) – 0.145 mg, titanium dioxide (E171) – 1.97 mg.
Ink composition shellac, iron oxide black dye (E172); the use of ready-made Opacode Black S-1-27794 ink is permitted.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Acne treatment drug. Retinoid

Pharmacotherapeutic Group

Acne treatment agent

Pharmacological Action

Isotretinoin is a stereoisomer of all-trans-retinoic acid (tretinoin).

The exact mechanism of action of isotretinoin has not yet been elucidated. Improvement in the clinical picture of severe forms of acne is associated with the suppression of sebaceous gland activity and histologically confirmed reduction in their size. The anti-inflammatory effect of isotretinoin on the skin has been proven.

Hyperkeratosis of the epithelial cells of the hair follicle and sebaceous gland leads to the desquamation of corneocytes into the gland duct and its blockage by keratin and excess sebum. This is followed by the formation of a comedo and, in some cases, the addition of an inflammatory process. Isotretinoin suppresses the proliferation of sebocytes and acts on acne by restoring the normal process of cell differentiation. Sebum is the main substrate for the growth of Propionibacterium acnes, so reducing sebum production suppresses bacterial colonization of the duct.

Pharmacokinetics

Absorption

The absorption of isotretinoin from the gastrointestinal tract varies and is linearly dependent on the administered dose within the therapeutic range. The absolute bioavailability of isotretinoin has not been determined. Taking isotretinoin with food doubles bioavailability compared to taking it on an empty stomach.

Distribution

Isotretinoin is highly (99.9%) bound to plasma proteins, mainly albumin. The V_d of isotretinoin in humans has not been determined because there is no intravenous dosage form. Isotretinoin concentrations in the epidermis are 2 times lower than in serum. Isotretinoin concentrations in plasma are approximately 1.7 times higher than in blood, due to poor penetration of isotretinoin into erythrocytes.

Metabolism

After oral administration, 3 main metabolites are detected in plasma: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-isotretinoin, whose plasma concentrations at steady state are 2.5 times higher than those of the parent drug. Since in vivo Isotretinoin and tretinoin (all-trans-retinoic acid) are reversibly converted into each other, the metabolism of tretinoin is related to the metabolism of isotretinoin. 20-30% of the isotretinoin dose is metabolized by isomerization.

Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.

In vitro metabolism studies have shown that several cytochrome P450 (CYP) system enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Isotretinoin and its metabolites do not significantly affect the activity of CYP system enzymes.

Elimination

After oral administration of radioactively labeled isotretinoin, approximately equal amounts are found in urine and feces. The terminal T_1/2 for the unchanged drug in acne patients is, on average, 19 hours. The terminal T_1/2 for 4-oxo-isotretinoin is longer and averages 29 hours.

Isotretinoin belongs to natural (physiological) retinoids. Endogenous retinoid concentrations are restored approximately 2 weeks after discontinuation of isotretinoin.

Indications

• Severe forms of acne (nodulocystic, conglobate acne or acne with risk of scarring);
• Acne that does not respond to other types of therapy.

ICD codes

Dosage Regimen

Isotretinoin therapy should be prescribed or supervised by physicians experienced in the use of systemic retinoids for the treatment of severe forms of acne.

Orally. Isotretinoin treatment should be started at a dose of 0.5 mg/kg/day. The therapeutic efficacy of isotretinoin and some of its adverse events are dose-dependent and vary among patients, requiring individual dose adjustment during treatment. For most patients, the dose ranges from 0.5 to 1.0 mg/kg/day.

Complete remission of acne is usually achieved within 16-24 weeks of treatment.

In most patients, acne completely disappears after a single course of treatment. In case of obvious relapse, a repeat course of treatment is indicated at the same daily and course dose as the first one. Since improvement may continue for up to 8 weeks after discontinuation of the drug, a repeat course should be prescribed no earlier than the end of this period.

In patients with severe renal impairment, treatment with Roaccutane^® should be started at a lower dose (e.g., 10 mg/day) and then increased to 1 mg/kg/day or the maximum tolerated dose.

Adverse Reactions

The most frequently reported symptoms as adverse events with isotretinoin use were: dryness of the skin, mucous membranes, for example, lips (cheilitis), nasal cavity (bleeding) and eyes (conjunctivitis).

Infections and infestations: very rarely – bacterial infections (of the skin and mucous membranes) caused by gram-positive pathogens.

Blood and lymphatic system disorders: very common – thrombocytopenia, anemia, thrombocytosis, increased ESR; very common – neutropenia; very rarely – lymphadenopathy.

Immune system disorders: rarely – anaphylactic reactions, hypersensitivity, skin allergic reactions.

Metabolism and nutrition disorders very rarely – diabetes mellitus, hyperuricemia.

Psychiatric disorders rarely – depression, aggravated depression, aggressive tendencies, anxiety, mood swings; very rarely – suicide, suicide attempts, suicidal behavior, psychotic disorder, abnormal behavior.

Nervous system disorders: common – headache; very rarely – benign intracranial hypertension, seizures, drowsiness, dizziness.

Eye disorders: very common – blepharitis, conjunctivitis, dry eyes, eye irritation; very rarely – optic disc edema (as a sign of benign intracranial hypertension), cataract, color vision deficiency (impaired color perception), contact lens intolerance, corneal opacity, impaired night vision, keratitis, photophobia, visual impairment, blurred vision.

Ear and labyrinth disorders very rarely – hearing impairment.

Vascular disorders: very rarely – vasculitis (e.g., Wegener’s granulomatosis, allergic vasculitis).

Respiratory, thoracic and mediastinal disorders: common – nasopharyngitis, epistaxis, dryness of the nasal mucosa; very rarely – bronchospasm (especially in patients with asthma), dysphonia.

Gastrointestinal disorders: very rarely – inflammatory bowel disease, colitis, ileitis, pancreatitis, gastrointestinal bleeding, hemorrhagic diarrhea, nausea, dry throat.

Hepatobiliary disorders very common – increased activity of liver transaminases; very rarely – hepatitis.

Skin and subcutaneous tissue disorders very common – pruritus, erythematous rash, dermatitis, cheilitis, dry skin, localized exfoliation, skin fragility (risk of friction injury); rarely – alopecia; very rarely – fulminant forms of acne, exacerbation of acne, erythema (on the face), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reactions, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency unknown – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: very common – arthralgia, myalgia, back pain (especially in children and adolescents); very rarely – arthritis, calcification (calcification of tendons and ligaments), premature epiphyseal closure, exostosis (hyperostosis), decreased bone density, tendinitis; frequency unknown – rhabdomyolysis, sacroiliitis.

Renal and urinary disorders very rarely – glomerulonephritis; frequency unknown – urethritis.

Reproductive system and breast disorders frequency unknown – sexual dysfunction (including erectile dysfunction and decreased libido), gynecomastia, vulvovaginal dryness.

General disorders and administration site conditions very rarely – granulation tissue overgrowth, malaise.

Investigations very common – increased blood triglycerides, decreased high-density lipoproteins; common – increased blood cholesterol, increased blood glucose, hematuria, proteinuria; very rarely – increased blood CPK activity.

Contraindications

• Pregnancy;
• Breastfeeding period;
• Women of childbearing potential, unless the woman’s condition meets all the criteria of the Pregnancy Prevention Program;
• Hypersensitivity to isotretinoin or to the components of the drug;
• Hepatic insufficiency;
• Hypervitaminosis A;
• Severe hyperlipidemia;
• Concomitant therapy with tetracyclines;
• Children under 12 years of age.

Roaccutane^® should not be used to treat prepubertal acne.

Use in Pregnancy and Lactation

Pregnancy

Pregnancy is an absolute contraindication for isotretinoin therapy. A woman of childbearing potential must use effective methods of contraception during treatment and for one month after the end of therapy.

If pregnancy occurs, despite precautions, during treatment with Roaccutane^® or within one month after the end of therapy, there is a very high risk of having a child with very severe and serious birth defects.

Congenital malformations associated with the use of isotretinoin include malformations of the central nervous system (hydrocephalus, microcephaly, malformations/abnormalities of the cerebellum), facial dysmorphism, cleft palate, abnormalities of the external ear (absence of the external ear, narrowing or absence of the external auditory canal), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of the great vessels, septal defects), abnormalities of the thymus and parathyroid glands. An increased frequency of spontaneous abortions has also been noted.

If pregnancy occurs in a patient receiving Isotretinoin, therapy must be discontinued. The situation should be discussed with a physician specializing in or experienced in teratology for assessment and recommendations.

Breastfeeding

Since Isotretinoin is highly lipophilic, it is very likely that it passes into breast milk. Due to possible adverse events, Roaccutane^® is contraindicated during breastfeeding.

Fertility

Isotretinoin at therapeutic doses does not affect sperm count, motility and morphology, and does not impair embryo formation and development when used by men.

Use in Hepatic Impairment

Contraindication: hepatic insufficiency.

Use in Renal Impairment

In patients with severe renal impairment, treatment with Roaccutane^® should be started at a lower dose (e.g., 10 mg/day) and then increased to 1 mg/kg/day or the maximum tolerated dose.

Pediatric Use

Contraindication: children under 12 years of age.

Special Precautions

Roaccutane^® is a potent teratogen, often causing severe and life-threatening birth defects in humans.

Isotretinoin is contraindicated in women of childbearing potential unless the woman’s condition meets all of the following criteria of the Pregnancy Prevention Program

• Severe forms of acne (nodulocystic, conglobate acne or acne with risk of scarring), acne that does not respond to other types of therapy;
• The possibility of pregnancy should be assessed for all female patients;
• The patient must understand the teratogenic risk;
• The patient must understand the need for mandatory doctor visits every month;
• The patient must understand and continuously use effective methods of contraception for one month before isotretinoin treatment, during treatment and for one month after its end. It is necessary to use at least one highly effective method of contraception (i.e., a method of contraception that is user-independent) or 2 different methods of contraception simultaneously (which are user-dependent);
• When choosing a method of contraception in each individual case, individual circumstances should be assessed, involving the patient in the discussion to guarantee her commitment and use of the chosen method of contraception;
• Even in case of amenorrhea, all recommendations for effective contraception must be followed;
• The patient must be informed and understand the potential consequences of pregnancy and the need for urgent consultation in cases where there is a risk of pregnancy, or she may be pregnant;
• The patient understands the need and agrees to undergo regular pregnancy tests before starting therapy, preferably monthly during therapy and 1 month after completion of therapy;
• The patient confirms understanding of the risks and necessary precautions associated with the use of isotretinoin.

These conditions also apply to women who are not currently sexually active, unless the physician believes there are compelling reasons indicating no risk of pregnancy.

The physician must be sure that

• The patient meets all the above conditions for pregnancy prevention, including confirmation that she has an adequate level of understanding;
• The patient is familiar with the above conditions;
• The patient understands the need for continuous and correct use of one highly effective method of contraception (i.e., a method of contraception that is user-independent) or 2 different methods of contraception simultaneously (which are user-dependent), for at least one month before starting isotretinoin treatment, during treatment and for at least one month after its end;
• A negative pregnancy test result has been obtained before starting the drug, during therapy and one month after the end of therapy; the dates and results of the pregnancy test must be documented.

If pregnancy occurs in a patient receiving Isotretinoin, treatment should be discontinued and the patient should be referred to a physician specializing in or experienced in teratology for assessment and recommendations.

If pregnancy occurs after discontinuation of treatment, the risk of severe and serious fetal malformations persists until the drug is completely eliminated from the body, which occurs 1 month after the end of therapy.

Contraception

Patients should be provided with complete information regarding pregnancy prevention and given recommendations for patients who do not use effective methods of contraception. If the treating physician cannot provide such information, the patient should be referred to another physician of appropriate specialization and qualification.

The minimum requirement for women of childbearing potential is the use of one highly effective method of contraception (i.e., a method of contraception that is user-independent) or 2 different methods of contraception simultaneously (which are user-dependent) for at least one month before starting isotretinoin treatment, during treatment and for at least one month after its end, even in patients with amenorrhea.

When choosing a method of contraception in each individual case, individual circumstances should be assessed, involving the patient in the discussion to guarantee her commitment and use of the chosen method of contraception.

Pregnancy Test

In accordance with existing practice, a pregnancy test with a minimum sensitivity of 25 mIU/ml should be performed under the guidance of a healthcare professional according to the following recommendations.

Before starting therapy

A pregnancy test should be performed at least 1 month after the initiation of contraception and as soon as possible (preferably a few days) before the initial prescription of the drug. The pregnancy test should be performed under the guidance of a healthcare professional. This test ensures that the patient is not pregnant before starting isotretinoin.

During therapy

The patient should visit the doctor regularly, preferably monthly. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity, previous menstrual cycle disorders (abnormal menstruation, missed period, amenorrhea) and the method of contraception. If indicated, the pregnancy test is performed on the day of the visit or within 3 days before the doctor’s visit.

End of therapy

A final test is performed one month after the end of therapy to rule out pregnancy.

Prescription and dispensing of the drug

The prescription for Roaccutane^® for a woman of childbearing potential should preferably be written for 30 days of treatment to ensure regular monitoring, including pregnancy tests and monitoring. It is advisable to perform the pregnancy test, write the prescription, and obtain the drug on the same day.

Dispensing of Roaccutane^® at the pharmacy should be done on the same day and within no more than 7 days from the date of prescription.

Monthly visits will allow for regular pregnancy testing and monitoring, ensuring that the patient is not pregnant before starting the next cycle of drug intake.

For male patients

Existing data indicate that exposure to the drug from the semen and seminal fluid of men taking Roaccutane^® is insufficient to cause teratogenic effects in women.

The drug must not be passed on to other persons, especially women.

Additional precautions

Patients should be informed about the prohibition of transferring Roaccutane^® to other persons and about disposing of unused capsules according to local recommendations.

To avoid accidental exposure of the fetus to the drug (in case of recipient pregnancy during transfusion), donor blood should not be taken from patients who are receiving or have received Isotretinoin within one month prior.

Mental disorders

Depression, worsening of depression, anxiety, aggressive tendencies, mood swings, and psychotic symptoms have been reported in patients treated with Isotretinoin; very rarely, suicidal behavior, suicide attempts, and suicide have occurred. Special caution is required in patients with a history of depression, and all patients should be monitored for signs of depression during treatment with the drug, referring them to an appropriate specialist if necessary. However, discontinuing isotretinoin may not lead to the disappearance of symptoms, and further monitoring and treatment by an appropriate specialist may be required.

Disorders of the skin and subcutaneous tissues

In rare cases, an exacerbation of acne may occur at the beginning of therapy, which usually resolves within 7-10 days without adjusting the drug dose.

Exposure to sunlight and ultraviolet rays should be limited. If necessary, a sunscreen with a high protection factor of at least 15 SPF should be used.

Deep chemical dermabrasion and laser treatment should be avoided in patients receiving Isotretinoin, and for 5-6 months after the end of treatment, due to the possibility of increased scarring in atypical locations and (less commonly) the occurrence of post-inflammatory hyper- and hypopigmentation. During treatment with isotretinoin and for at least 6 months thereafter, wax epilation should not be performed due to the risk of epidermal detachment.

Concomitant use of isotretinoin with topical keratolytic or exfoliative agents for the treatment of acne should be avoided due to possible increased local irritation.

Patients receiving Isotretinoin are recommended to use moisturizing ointments or body creams, and lip balm to reduce dryness of the skin and mucous membranes from the start of therapy, as dryness of the skin and lips is likely to occur with the use of isotretinoin.

During post-marketing surveillance, cases of severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been described with the use of isotretinoin. These phenomena may be difficult to distinguish from other skin reactions that occur with isotretinoin use. If a severe skin reaction is suspected, isotretinoin should be discontinued.

Allergic reactions

Anaphylactic reactions have been rarely reported, in some cases occurring only after previous topical use of retinoids. Allergic skin reactions have been reported in rare cases. Serious cases of allergic vasculitis have been observed, often accompanied by purpura (bruises and red spots) on the extremities and extracutaneously. Severe allergic reactions necessitate discontinuation of the drug and careful monitoring of the patient.

Disorders of the organ of vision

Dryness of the conjunctiva, corneal opacities, impaired night vision, and keratitis usually resolve after discontinuation of the drug. Reports have been received of dry eyes that did not resolve after cessation of therapy. For dryness of the eye mucosa, applications of a moisturizing eye ointment or artificial tear preparations can be used. If contact lens intolerance occurs, glasses should be used during therapy.

Impaired night vision has been observed with the use of the drug; the onset of this phenomenon in some patients was sudden. Patients complaining of vision should be referred to an ophthalmologist and the advisability of discontinuing isotretinoin should be considered.

Disorders of the muscular, skeletal, and connective tissues

Arthralgia and myalgia, increased serum CPK activity have been reported during isotretinoin intake, especially in patients undergoing intense physical exertion. In some cases, these phenomena may progress to potentially life-threatening rhabdomyolysis.

Several years after the use of isotretinoin for the treatment of dyskeratosis in very high doses, bone changes developed, including premature closure of epiphyseal growth plates, hyperostosis, and calcification of ligaments and tendons. The dose level, duration of therapy, and total cumulative dose in such patients usually significantly exceeded those recommended for acne therapy.

Reports of sacroiliitis development have been received with the use of isotretinoin. In patients with clinical signs of sacroiliitis, differential diagnosis with other causes of back pain should be performed.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been described, in some cases with concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances, and papilledema. In such patients, Isotretinoin should be discontinued immediately.

Disorders of the liver and biliary tract

It is recommended to monitor liver enzymes before treatment, 1 month after its initiation, and then every 3 months or as indicated. Transient and reversible increases in liver transaminases have been noted. In most cases, the increase was within normal limits, and the values returned to baseline during therapy. However, in case of a persistent clinically significant increase in liver transaminase levels, it is necessary to reduce the drug dose or discontinue it.

Renal failure

Renal failure and impaired renal function do not affect the pharmacokinetics of isotretinoin. Thus, Isotretinoin can be used in patients with renal failure. However, it is recommended to start isotretinoin treatment with a lower dose and then increase it to the maximum tolerated dose.

Lipid metabolism

Fasting serum lipid concentrations should be determined before treatment, 1 month after initiation, and then every 3 months or as indicated. Lipid concentrations usually normalize after dose reduction or drug discontinuation, as well as with diet adherence.

The use of isotretinoin has been associated with an increase in plasma triglyceride concentrations. If hypertriglyceridemia cannot be controlled at an acceptable level or symptoms of pancreatitis occur, Isotretinoin should be discontinued. An increase in triglyceride concentration above 800 mg/dL or 9 mmol/L may be accompanied by the development of acute pancreatitis, possibly fatal.

Gastrointestinal disorders

The occurrence of inflammatory bowel disease (including regional ileitis) has been reported during isotretinoin therapy in patients without a history of bowel disorders. In patients with severe (hemorrhagic) diarrhea, Isotretinoin must be discontinued immediately.

High-risk patients

High-risk patients (with diabetes mellitus, obesity, alcoholism, or lipid metabolism disorders) may require more frequent laboratory monitoring of serum glucose and/or lipid concentrations during isotretinoin treatment. An increase in fasting blood sugar levels has been noted with the use of isotretinoin, and cases of diabetes mellitus have been diagnosed for the first time.

Effect on the ability to drive vehicles and operate machinery

Roaccutane^® may affect the ability to drive vehicles and operate machinery.

Drug Interactions

Vitamin A and Isotretinoin should not be used concomitantly due to the risk of hypervitaminosis A.

Cases of benign intracranial hypertension (“pseudotumor cerebri”) have been observed with the concomitant use of tetracyclines and isotretinoin; the use of tetracyclines concomitantly with isotretinoin should be avoided.

Concomitant use with topical keratolytic or exfoliative agents for the treatment of acne should be avoided due to possible increased local irritation.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.