Instructions for Roaccutane capsules 10 mg blister No. 30
Composition
active ingredient: isotretinoin;
1 capsule contains 10 mg or 20 mg of isotretinoin;
excipients: yellow beeswax, hydrogenated soybean oil, partially hydrogenated soybean oil, refined soybean oil;
capsule shell: gelatin, glycerol (85%), dry substance Karion 83 (sorbitol (E 420), mannitol (E 421), hydrolyzed hydrogenated starch), titanium dioxide (E 171), red iron oxide (E 172), printing ink.
Dosage form
Capsules.
Main physicochemical properties:
10 mg capsules: oval opaque capsules of brownish-red color, clearly imprinted with “ROA 10” on the surface of the capsule, capsule length 8.3–10.7 mm, capsule diameter 5.3–7.7 mm; capsule contents — a homogeneous suspension of dark yellow color;
20 mg capsules: oval opaque capsules, one half is brownish-red, the other half is white, the surface of the capsule has a clear imprint of “ROA 20”, the length of the capsules is 12.4–14.2 mm, the diameter of the capsules is 7.3–9.1 mm; the contents of the capsule are a homogeneous suspension of dark yellow color.
Pharmacotherapeutic group
Means for systemic treatment of acne.
ATX code D10B A01.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been fully elucidated, but it has been established that the improvement of the clinical picture of severe acne is associated with a decrease in the activity of the sebaceous glands and a histologically confirmed decrease in their size. In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.
Efficiency
Hyperkeratosis of the epithelial cells of the hair follicle and sebaceous gland leads to desquamation of corneocytes in the duct of the gland and to the blockage of the latter with keratin and excess sebum. After which a comedone is formed and in some cases an inflammatory process joins. Roaccutane® inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Sebum is the main substrate for the growth of Propinibacterium acnes. Reducing sebum production inhibits bacterial colonization of the duct.
Pharmacokinetics
Absorption
The absorption of isotretinoin from the gastrointestinal tract is variable and linearly dependent on the dose of the drug in the therapeutic dosage range. The absolute bioavailability of isotretinoin has not been determined, since there is no dosage form for intravenous administration, but extrapolation of the results of a study in dogs suggests a very low and variable systemic bioavailability. Taking isotretinoin with food increases its bioavailability by twofold compared with taking it on an empty stomach.
Distribution
Isotretinoin is almost completely bound to plasma proteins (99.9%), mainly albumin. The volume of distribution of isotretinoin in humans is unknown, as there is no intravenous formulation. Epidermal concentrations of isotretinoin are only half those in serum. Plasma concentrations of isotretinoin are approximately 1.7 times higher than whole blood concentrations due to poor penetration of isotretinoin into erythrocytes.
Metabolism
After oral administration, three major metabolites are observed in plasma: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid), and 4-oxo-retinoin. These metabolites have demonstrated biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in several clinical studies to provide a significant portion of the therapeutic activity of isotretinoin (sebum suppression, independent of plasma levels of isotretinoin and tretinoin). The major metabolite is 4-oxo-isotretinoin, with steady-state plasma concentrations 2.5-fold higher than those of the parent drug. Other metabolites, including glucuronide conjugates, are minor.
Since isotretinoin and tretinoin (all-trans-retinoic acid) are reversibly converted to each other, the metabolism of tretinoin is linked to that of isotretinoin. It has been found that 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 CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. No one isoform appears to play a dominant role. Roaccutane® and its metabolites have no significant effect on the activity of CYP enzymes.
Breeding
After oral administration of radiolabeled isotretinoin, approximately equal amounts are recovered in urine and feces. The terminal elimination half-life of unchanged drug after oral administration in acne patients averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.
Isotretinoin belongs to the natural (physiological) retinoids. Endogenous retinoid concentrations are restored approximately 2 weeks after stopping Roaccutane®.
Since isotretinoin is contraindicated in patients with impaired liver function, data on the pharmacokinetics of the drug in this group of patients are limited.
Renal failure does not significantly reduce the plasma clearance of isotretinoin and 4-oxo-isotretinoin.
Indication
Severe forms of acne (including nodular and conglobatic acne, acne with a tendency to permanent scarring) that are not amenable to standard treatment methods (systemic antibacterial therapy, topical treatment).
Before initiating treatment with isotretinoin in patients under 18 years of age, two independent prescribing physicians must agree that there is no other suitable effective treatment (see section “Children”).
Contraindication
Pregnancy and lactation. Do not use in women of reproductive age unless all conditions of the "Pregnancy Prevention Program" are met. Hypersensitivity to isotretinoin or to any of the components of the drug; hepatic insufficiency; severe hyperlipidemia; hypervitaminosis A; concomitant therapy with tetracyclines. Due to the fact that Roaccutane® contains refined soybean oil, partially hydrogenated soybean oil and hydrogenated soybean oil, the drug is contraindicated for use in patients with peanut or soy allergy.
Interaction with other medicinal products and other types of interactions
Due to the possible exacerbation of symptoms of hypervitaminosis A, the simultaneous administration of Roaccutane® and vitamin A should be avoided.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin with tetracyclines. Therefore, concomitant use with tetracyclines is contraindicated (see sections "Contraindications", "Special warnings and precautions for use").
Combined use with topical keratolytic or exfoliative drugs for the treatment of acne should be avoided due to possible increased local irritation (see section "Special instructions").
Application features
Teratogenic effects
The drug Roaccutane® is a potent human teratogen and induces a high incidence of severe and life-threatening birth defects.
Roaccutane® is clearly contraindicated:
pregnant women;
to women of reproductive age, if all the conditions of the "Pregnancy Prevention Program" are not met.
Pregnancy prevention program
This drug is TERATOGENIC.
Roaccutane® is contraindicated in women of reproductive age unless all of the following conditions are met:
a woman has been diagnosed with a severe form of acne (nodular and conglobatic acne, acne with a tendency to permanent scarring), which is not amenable to standard treatment methods (systemic antibacterial therapy, topical treatment) (see the "Indications" section);
the woman's potential for pregnancy has been assessed;
the woman understands the teratogenic risk of the drug;
the woman understands the need for a mandatory visit to the doctor every month;
the woman understands and agrees to the need to use effective contraception continuously for 1 month before starting treatment, during the entire treatment period and for one month after the end of treatment. At least one highly effective method of contraception (the effectiveness of which does not depend on the user) or two complementary methods of contraception, the effectiveness of which depends on the user, should be used simultaneously;
when choosing a contraceptive method in each specific case, individual circumstances are assessed, and the patient is involved in discussing the choice of contraceptive method in order to obtain her approval and agreement to adhere to the rules for using the selected methods;
even with amenorrhea, a woman uses reliable methods of contraception;
the woman is informed about the risk of pregnancy during treatment with Roaccutane® and understands the need for immediate consultation in case of suspicion of pregnancy or in case of pregnancy;
the woman understands the need and agrees to regularly perform a pregnancy test before treatment, ideally monthly during treatment and 1 month after completion of treatment;
The woman confirms that she is aware of the dangers of using isotretinoin and the need to take precautions.
These conditions also apply to sexually inactive women, unless the doctor is confident that there is no risk of pregnancy.
The doctor must be sure that:
the patient is able to fulfill all of the above conditions to prevent pregnancy, and also has an appropriate level of understanding;
the patient is familiar with the above conditions;
the patient is aware of the need to consistently and correctly use one highly effective method of contraception (i.e. a method whose effectiveness does not depend on the user) or simultaneously use two complementary methods of contraception whose effectiveness depends on the user, for at least 1 month before starting treatment, as well as to continue using effective contraception during the entire treatment period and for at least 1 month after stopping treatment;
If pregnancy occurs in a woman receiving isotretinoin, treatment with the drug should be discontinued and the patient should be referred to a physician who specializes in or has experience in teratology for examination and advice.
If pregnancy occurs after treatment has ended, there is a risk of severe and serious birth defects in the fetus. This risk persists until the drug is completely eliminated from the body, which takes about one month after treatment has ended.
Pregnancy prevention.
Patients should be informed about contraceptive methods. If they are not using contraceptive methods, the physician should provide the necessary recommendations. If the supervising physician is unable to provide such information, the patient should be referred to a physician of the appropriate specialization.
As a minimum, women of childbearing potential should use at least one highly effective method of contraception (the effectiveness of which is not dependent on the user) or two complementary methods of contraception at the same time, the effectiveness of which is dependent on the user. Contraceptive methods should be used for at least 1 month before starting treatment, as well as during the entire treatment period and for at least 1 month after stopping treatment with Roaccutane®, even in patients with amenorrhea.
When choosing a contraceptive method in each specific case, individual conditions should be assessed, and the patient should be involved in discussing the choice of contraceptive method in order to obtain her approval and agreement to follow the rules for using the selected methods.
Pregnancy test.
In accordance with current practice, it is recommended to perform a pregnancy test with a minimum sensitivity of 25 mIU/ml, under medical supervision, as indicated below.
Before starting treatment
At least one month after starting contraception and shortly (preferably a few days) before the first dose of the drug, the patient should undergo a pregnancy test under medical supervision to ensure that she is not pregnant at the time of starting isotretinoin treatment.
During treatment
The patient should visit the doctor regularly, ideally monthly. The need for monthly supervised pregnancy testing is determined according to local practice, taking into account the patient's sexual activity and recent menstrual history (abnormal menstruation, amenorrhea, or amenorrhea) and contraceptive method. If indicated, a pregnancy test should be performed on the day of the scheduled visit or 3 days prior to the visit.
Completion of treatment
One month after the end of treatment, a final pregnancy test is performed.
For women of reproductive age, the prescription of Roaccutane® should ideally be limited to 30 days to ensure regular follow-up, including pregnancy testing and monitoring. It is recommended that the pregnancy test, prescription and receipt of Roaccutane® be carried out within the same day. Roaccutane® should be dispensed from the pharmacy no later than 7 days after the prescription is issued.
Such monthly follow-up will allow for regular pregnancy testing and monitoring, as well as to ensure that the patient is not pregnant before prescribing the next course of medication.
For those patients who, in the opinion of the prescribing physician, have good reason to indicate that there is no risk of pregnancy, after stable intake of isotretinoin without pregnancy (after the first 1–3 months), subsequent prescriptions may be written for a treatment period of more than 30 days (up to 12 weeks).
Male patients.
Available data suggest that in women, exposure to the drug from the semen and seminal fluid of men taking Roaccutane® is insufficient to cause teratogenic effects.
Male patients should be reminded that they should not give the drug to other individuals, especially women.
Additional warnings
Microdose progesterone preparations may be an inadequate method of contraception during treatment with Roaccutane®.
Patients should never give this medicine to other people and should return any unused capsules to their doctor after treatment is finished.
Patients should not donate blood during treatment and for 1 month after its cessation, as there is a risk of transfusion transmission to the fetus of a pregnant woman.
Mental disorders
Depression, aggravated depression, anxiety, aggressive tendencies, mood swings, psychotic symptoms, suicidal thoughts, suicide attempts and suicide have been reported in patients treated with Roaccutane (see section 4.8).
All patients should undergo a mental health assessment before starting treatment with isotretinoin and should be monitored regularly during treatment for the development or worsening of psychiatric disorders. In particular, caution should be exercised in patients with a history of depression. If necessary, patients should be prescribed appropriate psychiatric treatment. Discontinuation of Roaccutane® may not resolve psychiatric symptoms - in this case, the patient should be monitored by specialists.
Awareness from family or friends can be helpful in identifying mental disorders.
Sexual disorders
Isotretinoin may be associated with sexual dysfunction (see section 4.8). There have been reports of persistent sexual dysfunction where symptoms persist despite discontinuation of isotretinoin.
Patients and, where appropriate, their parents or guardians, should be counselled about the risk of sexual dysfunction with isotretinoin before prescribing the drug, and ideally before any referral to an appropriate physician who may consider treatment with isotretinoin. The age and sexual maturity of the patient should be taken into account in deciding the most appropriate approach to such counselling, including the possibility of discussing the matter without the presence of parents or guardians, if appropriate.
Before starting treatment with isotretinoin, all patients should be asked about the presence of symptoms of sexual dysfunction and patients should be monitored for the appearance of new sexual disorders during treatment.
Educational materials
To help physicians, pharmacists and patients avoid the risk of isotretinoin exposure to the fetus, the marketing authorisation holder provides educational materials with warnings regarding the teratogenic effects of isotretinoin, as well as recommendations on the use of contraception before starting therapy and the need for pregnancy testing.
Physicians should provide full information about the teratogenic risk and strict measures to prevent pregnancy according to the “Pregnancy Prevention Program” to all patients, both men and women of reproductive age (every woman who can become pregnant).
In addition, educational materials contain warnings about other risks associated with the use of isotretinoin, including for mental health and sexual function.
Skin and subcutaneous tissue disorders
In rare cases, at the beginning of therapy, an exacerbation of acne is observed, which usually resolves after 7–10 days without adjusting the dose of the drug.
Excessive exposure to sunlight or UV rays should be avoided. If sun protection is necessary, use sunscreen with an SPF of at least 15.
Deep chemical dermabrasion and laser treatment should not be performed during treatment with Roaccutane® and for 5–6 months after treatment, as there is a high risk of hypertrophic scars in atypical areas and, less commonly, hyper- and hypopigmentation in the treatment areas. Waxing should not be performed during treatment with Roaccutane® and for 6 months after treatment due to the risk of epidermal detachment.
The concomitant use of Roaccutane® with topical keratolytic or exfoliative agents for the treatment of acne should be avoided due to possible increased local irritation (see section “Interaction with other medicinal products and other types of interactions”).
Patients receiving Roaccutane® are advised to use moisturizing ointments or body creams, lip balm to reduce dryness of the skin and lips at the beginning of treatment.
In the post-marketing period, cases of severe skin reactions (erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Since these reactions can be difficult to distinguish from other possible skin reactions (see section 4.8), patients should be warned about the symptoms of these diseases and be closely monitored for severe skin reactions. If severe skin reactions are suspected, isotretinoin treatment should be discontinued.
Allergic reactions
Anaphylactic reactions have been reported rarely, in some cases after topical retinoids. Allergic skin reactions have been reported infrequently. Serious cases of allergic vasculitis of the extremities, often with purpura (bruising and red spots), and non-cutaneous manifestations, have been reported. Serious allergic reactions require discontinuation of therapy and careful monitoring of the patient.
Vision disorders
Dry eyes, corneal clouding, night vision impairment and keratitis usually resolve after discontinuation of the drug. Cases of dry eyes that did not resolve after discontinuation of therapy have been reported. In case of dryness of the mucous membrane of the eye, moisturizing eye ointment or artificial tears can be used. In case of intolerance to contact lenses, glasses should be used during treatment.
Some patients may experience a decrease in twilight vision, sometimes occurring suddenly (see section "Ability to affect the speed of reactions when driving vehicles or other mechanisms"). If there are complaints about vision, such patients should be referred to an ophthalmologist and the issue of discontinuing the drug should be considered.
Patients receiving isotretinoin have experienced muscle and joint pain and increased serum creatine phosphokinase, particularly during strenuous exercise (see section 4.8). In some cases, progression to rhabdomyolysis, which is potentially life-threatening, has been reported.
Several years after the use of Roaccutane® for the treatment of dyskeratosis at very high doses, bone changes developed, including premature closure of the epiphyseal growth plates, hyperostosis, and calcification of ligaments and tendons. The doses, duration of treatment, and total cumulative dose in these patients generally exceeded those recommended for the treatment of acne.
Sacroiliitis has been reported in patients receiving isotretinoin. To differentiate sacroiliitis from other causes of back pain, patients with clinical manifestations of sacroiliitis may require additional evaluation, including imaging techniques such as MRI. In cases reported in the post-marketing setting, sacroiliitis resolved after discontinuation of the drug and appropriate treatment.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been described, sometimes caused by concomitant use with tetracyclines (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions"). Symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and swelling of the optic nerve head. Patients who develop benign intracranial hypertension should immediately discontinue the drug.
Hepatobiliary disorders
It is recommended to monitor liver enzymes before treatment, 1 month after its initiation, and then every 3 months, unless there is a clinical indication for more frequent monitoring. Transient and reversible increases in liver transaminase levels have been observed, in most cases within the normal range, which returned to baseline values during treatment. If transaminase levels exceed the normal range, the dose of the drug should be reduced or the drug should be discontinued.
Kidney failure
Renal impairment or renal failure does not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be administered to patients with renal failure. However, it is recommended to start with a low dose and titrate it to the maximum tolerated dose (see section "Method of administration and dosage").
Lipid metabolism
Fasting serum lipid levels should be measured (prior to treatment, 1 month after initiation, then every 3 months unless clinically indicated for more frequent monitoring). Elevated serum lipids usually resolve after dose reduction or discontinuation and with diet. Isotretinoin has been associated with increases in triglycerides. Isotretinoin should be discontinued in the event of uncontrolled hyperlipidemia or symptoms of pancreatitis. Elevated triglycerides above 800 mg/dL, or 9 mmol/L, may be associated with the development of acute pancreatitis, which may be fatal.
Gastrointestinal disorders
Inflammatory bowel disease (including regional ileitis) may develop during treatment with isotretinoin. Patients with severe (hemorrhagic) diarrhea should immediately discontinue the drug.
High-risk groups
Patients with diabetes mellitus, obesity, alcoholism or lipid metabolism disorders may require more frequent monitoring of serum glucose and/or lipids during treatment with isotretinoin. Increased fasting blood sugar levels and new cases of diabetes mellitus have been reported during treatment with isotretinoin.
Excipients
This medicine contains 2-3.05 mg of sorbitol (E 420) in each 10 mg capsule.
This medicine contains 3.2–4.86 mg of sorbitol (E 420) in each 20 mg capsule.
The additive effect of concomitantly used medicinal products containing sorbitol (or fructose) and the consumption of sorbitol (or lactose) with food should be taken into account.
The sorbitol content of oral medicinal products may affect the bioavailability of other oral medicinal products when used concomitantly.
Use during pregnancy or breastfeeding
Pregnancy
Pregnancy is an absolute contraindication to the use of Roaccutane® (see section "Contraindications"). Women of childbearing potential should use effective contraception during treatment and for one month after treatment. If, despite precautions, pregnancy occurs while a woman is taking Roaccutane® or within one month after stopping therapy, there is a very high risk of severe and serious fetal malformations.
If pregnancy occurs in a woman receiving isotretinoin treatment, therapy should be discontinued and a physician specializing and experienced in teratology should be consulted for evaluation and advice.
Breast-feeding.
Due to the high lipophilicity of isotretinoin, it is likely that it will be excreted in breast milk. Due to the possible side effects in the child associated with the action of the drug through breast milk, the use of Roaccutane® is contraindicated in women during breastfeeding (see section "Contraindications").
Fertility
If a man takes isotretinoin in therapeutic doses, it does not affect the number, motility, and morphology of sperm and does not jeopardize the formation and development of the embryo.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug Roaccutane® has the potential to affect the ability to drive and use machines.
During treatment and rarely after it, some patients have experienced a decrease in twilight vision (see sections "Adverse reactions", "Special instructions for use"). Since in some individuals these phenomena occurred suddenly, patients should be informed of the possibility of this problem and warned about the need to be careful when driving vehicles and working with other mechanisms.
Very rarely, drowsiness, dizziness, and visual disturbances have been reported. Patients should be advised that if these symptoms occur, they should not drive, operate machinery, or engage in activities that could put themselves or others at risk.
Method of administration and doses
Standard dosage regimen.
Isotretinoin treatment should only be prescribed and administered by a physician who is experienced in the use of systemic retinoids for the treatment of severe acne and is fully aware of the risks of retinoid therapy and the requirements for monitoring patient conditions.
Capsules are taken with meals 1–2 times a day.
Adults (including adolescents and the elderly). Treatment should be initiated at a dose of 0.5 mg/kg/day. The therapeutic response to isotretinoin and some adverse reactions are dose-dependent and vary from patient to patient. Therefore, individual dose adjustment is necessary during treatment. In most patients, the dose ranges from 0.5 to 1 mg/kg/day.
Long-term remission and relapse rate are more related to the total dose than to the duration of treatment or daily dose. It has been shown that no additional benefit should be expected with a course dose above 120–150 mg/kg. The duration of therapy depends on the daily dose. A course of treatment of 16–24 weeks is usually sufficient to achieve remission.
In most patients, acne completely disappears after a single course of treatment. In case of severe relapse, a second course of treatment with Roaccutane® should be carried out at the same daily and course dose as the first. Since improvement may occur within 8 weeks after the end of treatment, a second course should be prescribed no earlier than the end of this period.
Dosage in special cases.
Patients with renal impairment: In patients with severe renal impairment, treatment should be initiated at a lower dose (e.g. 10 mg/day) and then increased to 1 mg/kg/day or the maximum tolerated dose (see section 4.4).
Patients with intolerance. Patients who develop severe intolerance to the recommended dose may be continued at a lower dose. In this case, the duration of therapy will be longer and the risk of relapse is higher. In order to achieve maximum efficacy, the highest tolerated dose should be used.
Children
Roaccutane® should not be used to treat acne in the prepubertal period, the drug is not recommended for children under 12 years of age due to the lack of data on efficacy and safety.
Before initiating treatment with isotretinoin in patients under 18 years of age, two independent prescribing physicians must agree that there is no other suitable effective treatment (see section “Indications”).
Overdose
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A may occur in the event of accidental overdose. Symptoms of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itching. Symptoms of accidental or intentional overdose of isotretinoin are likely to be similar. These symptoms are reversible and resolve without treatment.
Side effects
The following categories are used to describe the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infections: very rarely common - gram-positive bacterial infections of the skin and mucous membranes.
Blood and lymphatic system disorders: very common - anemia, erythrocyte sedimentation rate increased, thrombocytopenia, thrombocytosis; common - neutropenia; very rare - lymphadenopathy.
Immune system disorders: rarely - allergic skin reactions, anaphylactic reactions, hypersensitivity reactions.
Metabolic disorders: very rarely - diabetes mellitus, hyperuricemia.
Psychiatric disorders: rarely - aggression, anxiety, mood changes; very rarely - behavioral disorders, psychotic disorders; frequency unknown - depression, increased depression, suicide, suicide attempts, suicidal thoughts.
Nervous system disorders: common - headache; very rare - benign intracranial hypertension, convulsions, drowsiness, dizziness.
Eye disorders: very common - blepharitis, conjunctivitis, dry eyes, eye irritation; very rare - blurred vision, cataract, color vision impairment, contact lens intolerance, corneal opacity, decreased twilight vision, keratitis, optic nerve head swelling (as a manifestation of benign intracranial hypertension), photophobia, visual impairment.
Hearing and labyrinth disorders: very rare - hearing impairment.
Vascular disorders: very rare - vasculitis (e.g. Wegener's granulomatosis, allergic vasculitis).
Respiratory, thoracic and mediastinal disorders: common: epistaxis, dry nose, nasopharyngitis; very rare: bronchospasm (especially in patients with asthma), dysphonia.
Gastrointestinal disorders: very rarely - colitis, ileitis, dry throat, gastrointestinal bleeding, hemorrhagic diarrhea, inflammatory bowel disease, nausea, pancreatitis. Cases of severe diarrhea have also been reported (see section "Special warnings and precautions for use").
Hepatobiliary disorders: very common - increased transaminases (see section "Special warnings and precautions for use"); very rare - hepatitis.
Skin and subcutaneous tissue disorders: very common - cheilitis, dermatitis, dry skin, localized peeling, itching, erythematous rash, skin trauma (risk of injury from friction); rare - alopecia; very rare - acne fulminant, acne exacerbation (acne hyperemia), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency unknown - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Bone, muscle and connective tissue disorders: very common - arthralgia, myalgia, back pain (especially in children and adolescents); very rare - arthritis, calcinosis (calcification of ligaments and tendons), premature closure of epiphyseal growth plates, exostosis, hyperostosis, decreased bone density, tendonitis; frequency unknown - rhabdomyolysis, sacroiliitis.
Renal and urinary disorders: very rare - glomerulonephritis; frequency unknown - urethritis.
Reproductive system and breast disorders: frequency unknown - sexual dysfunction, including erectile dysfunction and decreased libido, gynecomastia, vulvovaginal dryness, orgasmic disorders, hypoesthesia
