Active ingredients: Isotretinoin
AISOSKIN 10 mg soft capsules
AISOSKIN 20 mg soft capsules
Why is Aisoskin used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Retinoids for the treatment of acne.
THERAPEUTIC INDICATIONS
AISOSKIN is indicated in the treatment of severe forms of acne (such as nodular or conglobate acne or acne with the risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.
Contraindications When Aisoskin should not be used
Hypersensitivity to the active substance or to any of the excipients
Isotretinoin is contraindicated in pregnant or lactating women (see pregnancy and lactation section).
Isotretinoin is contraindicated in women of childbearing potential unless all conditions of the Pregnancy Prevention Program are met (see Precautions for use). AISOSKIN contains soybean oil, partially hydrogenated soybean oil.
Therefore, AISOSKIN is contraindicated in patients allergic to soy. Furthermore, Isotretinoin is contraindicated in patients:
- with liver failure
- with excessively high plasma lipid values
- with hypervitaminosis A.
- under concomitant treatment with tetracyclines (see Interactions section).
Precautions for use What you need to know before taking Aisoskin
AISOSKIN should only be prescribed by or under the supervision of physicians who are experienced in the use of systemic retinoids for the treatment of severe acne and who fully understand the risk of isotretinoin treatment and the need for monitoring.
Pregnancy prevention program.
This medicine is TERATOGEN.
Isotretinoin is contraindicated in women of childbearing potential unless the patient meets all of the following conditions of the Pregnancy Prevention Program:
- She must have severe acne (such as nodular or conglobate acne or acne with risk of permanent scarring) resistant to an adequate course of standard therapy with systemic antibacterials and topical therapy. (see section Therapeutic indications).
- He understands the teratogenic risk.
- He understands the need for rigorous monitoring on a monthly basis.
- Understands and accepts the need for effective contraception, without interruption, from 1 month before the start of treatment, for the duration of treatment and up to 1 month after the end of treatment. At least one, and preferably two, should be used. forms of contraception including a barrier method.
- Even in the case of amenorrhea, the patient must follow all the indications for effective contraception.
- She must be able to comply with effective contraceptive measures.
- She is informed and understands the potential consequences of pregnancy and the need to consult with her doctor quickly if there is a risk of pregnancy.
- He understands the need and agrees to undergo a pregnancy test immediately before starting treatment, during treatment and 5 weeks after the end of treatment.
- He confirmed that he understood 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 prescribing physician believes there are valid reasons indicating the absence of a risk of pregnancy.
Contraception
Patients should be provided with comprehensive information on pregnancy prevention and counseling on contraception if they are not using an effective method of contraception.
At a minimum, patients at potential pregnancy risk should use at least one effective method of contraception. Patients should preferably use two complementary methods of contraception, including a barrier method. Contraception should be continued for at least 1 month after termination of isotretinoin treatment, even in patients with amenorrhea.
Pregnancy test
It is recommended that a pregnancy test be performed in the first three days of the menstrual cycle, under medical supervision.
Before starting therapy:
Before starting therapy, in order to exclude the possibility of pregnancy, it is recommended that a pregnancy test be performed, with medical supervision, the date of execution and the result recorded. In patients with irregular menstruation, the time of this Pregnancy test should reflect the patient's sexual activity and should be performed approximately 3 weeks after the last unprotected intercourse. The prescribing physician should explain the concepts of contraception to the patient.
A physician-supervised pregnancy test should also be performed at the initial prescription or in the 3 days prior to the prescription visit, and should be performed after the patient has used effective contraception for at least 1 month. This pregnancy test should provide assurance that the patient is not pregnant at the time of initiation of isotretinoin therapy.
Control visits
Subsequent visits must be scheduled every 28 days. The need for a physician-supervised monthly repeat pregnancy test should be determined based on local regulations, considering the patient's sexual activity and recent menstrual history (irregular periods, missed periods or amenorrhea). If indicated, subsequent pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the prescribing visit.
End of treatment
Five weeks after the end of treatment, patients must undergo a final pregnancy test to rule out pregnancy.
Dispensation Prescription and Restrictions
The prescription of isotretinoin to women of childbearing age is limited to 30 days of therapy and the continuation of therapy requires a new prescription. Pregnancy testing, prescription delivery and isotretinoin dispensing should preferably take place on the same day. Dispensing of isotretinoin must take place within a maximum of 7 days from the date of prescription.
Male patients
Available data suggest that the level of maternal exposure to semen of patients taking isotretinoin is not of such a magnitude as to be associated with the teratogenic effects of isotretinoin.
However, male patients should remember never to give this medicine to other people, particularly women. Additional precautions for use Patients should be instructed never to give this medicine to other people and to dispose of unused capsules at the end of treatment, using the special containers for separate collection of medicines. Patients should not donate blood during treatment and for 1 month after discontinuation of isotretinoin due to the potential risk to the fetus of a pregnant woman receiving such blood.
Educational material
All patients, men and women, must be given complete information by the physician on the risk of teratogenicity and strict pregnancy prevention measures, as detailed in the Pregnancy Prevention Program.
Psychiatric disorders
Depression, aggravated depression, anxiety, aggression, mood alteration, psychotic symptoms, and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients receiving isotretinoin (see section Undesirable effects).
Particular attention should be paid to patients with a history of depression and signs of depression should be sought in all patients who, if necessary, should be referred for appropriate treatment. Discontinuation of treatment, however, may not be sufficient to reduce psychiatric symptoms and may therefore require "further psychiatric or psychological evaluation.
Skin and subcutaneous tissue disorders
Worsening of acne may occasionally occur in the initial period of therapy, but resolves with continued therapy, usually within 7-10 days, and usually does not require dose adjustment. Avoid prolonged exposure to sunlight or UV radiation. If necessary, use an anti-sun product with a high protection factor (at least 15).
Avoid aggressive dermabrasion or laser therapy in patients treated with isotretinoin for a period of 5 - 6 months after the end of treatment due to the risk of hypertrophic scarring in atypical areas and, more rarely, post inflammatory hypo- or hyper-pigmentation in areas treated.
Avoid using depilatory wax in patients treated with isotretinoin for a period of at least 6 months after the end of treatment due to the risk of skin tears. Avoid concomitant administration of isotretinoin and topical anti-acne products with keratolytic or exfoliating action as there may be an increase in local irritation (see Interactions section). The use of a greasy ointment and lip balm is recommended. "initiation of treatment as isotretinoin can cause dry skin and lips.
Eye disorders
Dry eyes, corneal opacities, decreased night vision, and keratitis usually resolve after stopping treatment. Dry eyes can be prevented by applying mild eye ointment or artificial tears. During the treatment, intolerance to contact lenses may occur and the patient may be forced to wear glasses.
Reduction in night vision which occurred suddenly in some patients has also been reported (see section Effects on ability to drive and use machines). Patients with visual impairment should be referred for an eye examination and taken the possibility of discontinuing isotretinoin is being examined.
Musculoskeletal and connective tissue disorders
Cases of myalgia, arthralgia and increased serum creatine phosphokinase have been reported in patients receiving isotretinoin, especially among those engaging in strenuous physical activity (see section Undesirable effects). Bone changes have occurred including premature epiphyseal welding, hyperostosis, and calcification of tendons and ligaments after several years of high-dose administration for the treatment of keratinization disorders. Dosages, treatment duration and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines (see section Contraindications and Interactions). Signs and symptoms of benign intracranial hypertension are headache, nausea and vomiting, visual disturbances and papilledema. In patients who develop benign intracranial hypertension, isotretinoin treatment should be discontinued immediately.
Hepatobiliary disorders
Liver enzymes should be monitored prior to initiation of therapy and 1 month after, and every 3 months thereafter unless more frequent monitoring is indicated for clinical reasons. Transient and reversible elevations of liver transaminases have been reported. In many cases these changes remained within the normal range and the values returned to initial levels during the course of treatment.
However, in the event of persistent elevated transaminase levels, dose reduction or discontinuation of treatment should be considered.
Kidney failure
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be administered to patients with renal insufficiency. It is recommended, however, that in these patients treatment is started with a reduced dose and then increased up to maximum tolerated dose (see section Dose, method and time of administration).
Lipid metabolism
Serum lipids (fasting values) should be checked prior to initiation of therapy and 1 month after, and every 3 months thereafter unless more frequent monitoring is indicated for clinical reasons. Serum lipids usually return to normal values reducing the dose or discontinuing treatment and may also resolve with a modification of diet. Since isotretinoin has been linked to an increase in triglyceride levels, it should be discontinued if it is not possible to maintain triglyceridemia at an acceptable level or in the presence of symptoms of pancreatitis (see section Undesirable Effects) Levels above 800 mg / dL or 9 mmol / L are sometimes associated with acute pancreatitis, which can sometimes be fatal.
Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients with no medical history of bowel disorders. Patients who experience severe (haemorrhagic) diarrhea should immediately discontinue treatment with isotretinoin.
Allergic reactions
Rare cases of anaphylactic reaction have been reported, in some cases after topical exposure to retinoids. Cases of allergic skin reactions are not frequently reported. Severe cases of allergic vasculitis have been reported, often with purpura (ecchymosis and red patches) in the limbs and with involvement not only of the skin. Severe allergic reactions involve discontinuation of therapy and careful monitoring of the patient.
High Risk Patients
In patients with diabetes, obesity, alcoholism, or lipid metabolism disorders treated with isotretinoin, more frequent checks of serum lipids (fasting values) and / or blood glucose may be necessary. Cases of elevated fasting blood glucose have been reported and new cases of diabetes have been diagnosed during treatment with isotretinoin.
Interactions Which drugs or foods can modify the effect of Aisoskin
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.
Concomitant use of isotretinoin and vitamin A should be avoided, as there is a risk of developing symptoms of hypervitaminosis A.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported during concomitant use of isotretinoin and tetracyclines. Therefore concomitant treatment with tetracyclines should be avoided (see Contraindications and Precautions for use).
Avoid concomitant administration of isotretinoin and topical anti-acne products with keratolytic or exfoliating action as there may be an increase in local irritation (see section Precautions for use).
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine
Pregnancy is an absolute contraindication to isotretinoin treatment (see Contraindications section). If pregnancy does occur despite these precautions during treatment with isotretinoin or in the following month, there is a high risk of very serious and serious fetal malformations.
Fetal malformations associated with isotretinoin treatment include central nervous system abnormalities (hydrocephalus, cerebellar malformations / abnormalities, microcephaly), facial dysmorphism, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), ocular anomalies (microphthalmia), cardiovascular anomalies (malformations of the cone-trunk, such as the tetralogy of Fallot, transposition of the great vessels, septal defects), anomalies of the thymus and anomalies of the parathyroid glands. There is also an "increased incidence of spontaneous abortions. Should pregnancy occur during treatment with isotretinoin, treatment should be discontinued and the patient should be referred to a medical specialist or experienced in teratology for evaluation and consultation."
Breastfeeding: Since isotretinoin is highly lipophilic, passage of the drug into breast milk is very likely. Due to the possibility of side effects for the baby exposed through breast milk, the use of isotretinoin is contraindicated in breastfeeding women.
Important information about some of the ingredients
Aisoskin contains sorbitol. In cases of known intolerance to some sugars, contact your doctor before taking this medicine.
Effects on ability to drive and use machines
A number of cases of decreased night vision have occurred during treatment with isotretinoin, on rare occasions which lasted after treatment (see sections Precautions for use and Undesirable effects). Since in some patients the onset was sudden, Patients should be warned of this possible occurrence and advised to exercise caution while driving and using machines. Very rarely, somnolence, dizziness and visual disturbances have been reported. Patients should be warned that if they experience these effects, they should not drive , operate machinery or take part in any other activity where symptoms may put themselves or others at risk.
Dosage and method of use How to use Aisoskin: Dosage
The capsules should be taken with food once or twice a day.
Adults including adolescents and the elderly:
Treatment with isotretinoin should be initiated at a dose of 0.5 mg / kg per day. The therapeutic response and some of the adverse events to isotretinoin are dose related and vary from patient to patient. Therefore, individual dose adjustment is required during therapy. For most patients the dose ranges from 0.5 to 1.0 mg / kg per day.
Long-term remission and relapse frequency are more closely related to the total dose administered than to the duration of treatment or daily dose. It has been shown that substantial additional benefits are not to be expected beyond a cumulative treatment dose of 120-150 mg / kg. The duration of treatment will depend on the individual daily dose. In general, complete remission of acne is achieved with a treatment course of 16-24 weeks.
In most patients, complete resolution of acne is achieved with a single course of treatment. In the event of certain recurrence, a new course of treatment with isotretinoin should be administered at the same daily dose and with the same cumulative dose. Improvements in acne can be observed for up to 8 weeks after the end of treatment, a new course of treatment should not be started before this period has elapsed.
Patients with severe renal insufficiency In patients with severe renal insufficiency treatment should be initiated with a reduced dose (e.g. 10 mg / day). The dose should then be increased up to 1 mg / kg / day or up to the maximum tolerated dose by the patient (see section Precautions for use).
Children Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended for use in patients under 12 years of age.
Patients with intolerance In patients who have severe intolerance reactions to the recommended dose, it is possible to continue treatment at a reduced dose with the consequence of a longer duration of treatment and a higher risk of relapse. To obtain the maximum possible efficacy in these patients, therapy should normally be continued at the maximum tolerated dose. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Aisoskin
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.
Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and itching. Signs and symptoms of accidental or deliberate isotretinoin overdose are likely similar. Symptoms are expected to be reversible and do not require treatment. In case of accidental intake of an excessive dose of the medicine, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Aisoskin
Like all medicines, this can cause side effects, although not everybody gets them.
Some of the side effects associated with the use of isotretinoin are dose related.
Undesirable effects are generally reversible after dose reduction or discontinuation of treatment, however some may persist after discontinuation of treatment.
The following symptoms are the most commonly reported side effects of isotretinoin: dry skin, dry mucous membranes, e.g. of the lips (cheilitis), nasal mucosa (epistaxis) and eyes (conjunctivitis).
* frequency cannot be estimated from the available data.The incidence of adverse events was calculated from the pool of clinical trial data on 824 patients and post-marketing data.
** Skin and hair problems with frequency not known * Serious skin rashes (erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), which are potentially life-threatening for the patient and require immediate medical attention. These initially appear as circular patches often with central blisters usually on the arms and hands or legs and feet, more severe rashes may include blistering on the chest and back. Additional symptoms may also appear such as infection of the eye (conjunctivitis) or ulcers of the mouth, throat or nose. Severe forms of rash can progress to diffuse peeling of the skin which can be life-threatening. These severe skin rashes are often preceded by headache, fever, body aches (flu-like symptoms). If you get a rash or these skin symptoms, stop taking AISOSKIN and contact your doctor immediately.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Store at a temperature not exceeding 25 ° C.
Store in the original package and keep the blister in the outer carton in order to protect it from moisture and light.
Expiry: see the expiry date indicated on the package.
Warning: do not use the medicine after the expiry date indicated on the package.
The expiry date indicated on the package refers to the product in intact packaging, correctly stored.
Dispose of unused capsules at the end of treatment, using the special containers for the separate collection of medicines.
Composition and pharmaceutical form
COMPOSITION
AISOSKIN 10 mg soft capsules - each capsule contains:
Active ingredient: isotretinoin 10 mg
Excipients: Soybean oil, DL-alpha-tocopherol, edetate disodium, butylhydroxyanisole, Lipodan HP-100 (Grinsted PS 101 hydrogenated triglycerides), yellow wax, partially hydrogenated soybean oil. Constituents of the gelatinous shell: gelatin, glycerol, 70% sorbitol (not crystallizable), purified water, Ponceau 4R (E 124), black iron oxide (E 172), titanium dioxide (E 171).
AISOSKIN 20 mg soft capsules - each capsule contains:
Active ingredient: isotretinoin 20 mg
Excipients: Soybean oil, DL-alpha-tocopherol, edetate disodium, butylhydroxyanisole, Lipodan HP-100 (Grinsted PS 101 hydrogenated triglycerides), yellow wax, partially hydrogenated soybean oil. Constituents of the gelatinous shell: gelatin, glycerol, 70% sorbitol (not crystallizable), purified water, Ponceau 4R (E 124), indigo carmine (E 132), titanium dioxide (E 171).
PHARMACEUTICAL FORM AND CONTENT
Soft capsule
AISOSKIN 10 mg: soft capsules - 30 capsules of 10 mg
AISOSKIN 20 mg: soft capsules - 30 capsules of 20 mg
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AISOSKIN
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active principle
AISOSKIN 10 mg soft capsules
One soft capsule contains: active ingredient: isotretinoin 10 mg
AISOSKIN 20 mg soft capsules
One soft capsule contains: active ingredient: 20 mg isotretinoin
For the full list of excipients, see 6.1
03.0 PHARMACEUTICAL FORM
Soft capsule
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Severe forms of acne (such as nodular or conglobate acne or acne with risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.
04.2 Posology and method of administration
Isotretinoin should only be prescribed by or under the supervision of physicians who are experienced in the use of systemic retinoids for the treatment of severe acne and who fully understand the risk of isotretinoin treatment and the need for monitoring.
The capsules should be taken with food once or twice a day.
Adults including adolescents and the elderly
Treatment with isotretinoin should be started at a dose of 0.5 mg / kg per day. The therapeutic response and some of the adverse events to isotretinoin are dose related and vary from patient to patient. Therefore, individual dose adjustment is required during therapy. For most patients the dose ranges from 0.5 to 1.0 mg / kg per day.
Long-term remission and relapse frequency are more closely related to the total dose administered than to the duration of treatment or daily dose. It has been shown that substantial additional benefits are not to be expected beyond a cumulative treatment dose of 120-150 mg / kg. The duration of treatment will depend on the individual daily dose. In general, complete remission of acne is achieved with a treatment course of 16-24 weeks.
In most patients, complete resolution of acne is achieved with a single course of treatment. In the event of certain recurrence, a new course of treatment with isotretinoin should be administered at the same daily dose and with the same cumulative dose. Improvements in acne can be observed for up to 8 weeks after the end of treatment, a new course of treatment should not be started before this period has elapsed.
Patients with severe renal insufficiency
In patients with severe renal insufficiency, treatment should be started with a reduced dose (e.g. 10 mg / day). The dose should then be increased up to 1 mg / kg / day or up to the maximum tolerated patient dose (see section 4.4).
Children
Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended for use in patients less than 12 years of age.
Patients with intolerance
In patients who have severe intolerance reactions to the recommended dose, it is possible to continue treatment at a reduced dose with the consequence of a longer duration of treatment and a higher risk of relapse. To obtain the maximum possible efficacy in these patients, therapy should normally be continued at the maximum tolerated dose.
04.3 Contraindications
Isotretinoin is contraindicated in pregnant or lactating women (see section 4.6).
Isotretinoin is contraindicated in women of childbearing potential unless all conditions of the Pregnancy Prevention Program are met (see section 4.4).
Isotretinoin is also contraindicated in patients with hypersensitivity to isotretinoin or to any of the excipients. AISOSKIN contains soybean oil, partially hydrogenated soybean oil. Therefore, AISOSKIN is contraindicated in patients allergic to soy.
Furthermore, Isotretinoin is contraindicated in patients:
- with liver failure
- with excessively high values of plasma lipids
- with hypervitaminosis A
- in concomitant treatment with tetracyclines (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Pregnancy prevention program
This medicine is TERATOGEN.
Isotretinoin is contraindicated in women of childbearing potential unless the patient meets all of the following conditions of the Pregnancy Prevention Program:
• You must have severe acne (such as nodular or conglobate acne or acne with risk of permanent scarring) resistant to an adequate course of standard therapy with systemic antibacterials and topical therapy (see section 4.1).
• Understands the teratogenic risk.
• Understands the need for rigorous monitoring on a monthly basis.
• Understands and accepts the need for effective contraception, without interruption, from 1 month before the start of treatment, for the duration of treatment and up to 1 month after the end of treatment. At least one, and preferably two, should be used. , forms of contraception including a barrier method.
• Even in the case of amenorrhea, the patient must follow all the instructions for effective contraception.
• Must be able to comply with effective contraceptive measures.
• She is informed and understands the potential consequences of pregnancy and the need to consult with her doctor quickly if there is a risk of pregnancy.
• Understands the need and agrees to undergo a pregnancy test immediately before starting treatment, during treatment and 5 weeks after the end of treatment.
• Confirmed that he understood 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 prescribing physician believes there are valid reasons indicating the absence of a risk of pregnancy.
The prescribing physician must ensure that:
• The patient meets the pregnancy prevention requirements listed above, including confirmation of an adequate level of understanding.
• The patient has confirmed that she has understood the above requirements.
• The patient has used at least one and preferably two methods of effective contraception, including a barrier method for at least 1 month before the start of therapy, throughout the treatment period and for at least 1 month after the end of treatment.
• Negative pregnancy test results were obtained before, during and 5 weeks after the end of treatment. Test dates and results must be documented.
Contraception
Patients should be provided with comprehensive information on pregnancy prevention and counseling on contraception if they are not using an effective method of contraception.
At a minimum, patients at potential pregnancy risk should use at least one effective method of contraception. Patients should preferably use two complementary methods of contraception, including a barrier method. Contraception must be continued for at least 1 month after the end of isotretinoin treatment, even in patients with amenorrhea.
Pregnancy test
According to medical practice, it is recommended to perform pregnancy tests with a minimum sensitivity limit of 25mIU / ml in the first three days of the menstrual cycle, under medical supervision, as follows.
Before starting therapy
Before starting therapy, in order to exclude the possibility of pregnancy, it is recommended that a pregnancy test be performed, with medical supervision, the date of execution and the result recorded. In patients with irregular menstruation, the time of this Pregnancy test should reflect the patient's sexual activity and should be performed approximately 3 weeks after the last unprotected intercourse. The prescribing physician should explain the concepts of contraception to the patient.
A physician-supervised pregnancy test should also be performed at the initial prescription or in the 3 days prior to the prescription visit, and should be performed after the patient has used effective contraception for at least 1 month. This pregnancy test should provide assurance that the patient is not pregnant at the time of initiation of isotretinoin therapy.
Control visits
Subsequent visits must be scheduled every 28 days. The need for repetitive, physician-supervised monthly pregnancy tests should be determined based on local regulations, considering the patient's sexual activity and recent menstrual history (irregular periods, missed periods or amenorrhea). If indicated, subsequent pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the prescribing visit.
End of treatment
Five weeks after the end of treatment, patients must undergo a final pregnancy test to rule out pregnancy.
Dispensation Prescription and Restrictions
Prescribing isotretinoin to women of childbearing age is limited to 30 days of therapy and continuation of therapy requires a new prescription. Pregnancy testing, prescription delivery and isotretinoin dispensing should preferably take place on the same day. Dispensing of isotretinoin must take place within a maximum of 7 days from the date of prescription.
Male patients
Available data suggest that the level of maternal exposure to semen of patients taking isotretinoin is not of such a magnitude as to be associated with the teratogenic effects of isotretinoin.
However, male patients should remember never to give this medicine to other people, particularly women.
Additional precautions for use
Patients should be instructed never to give this medicine to other people and to return unused capsules to the pharmacist at the end of treatment.
Patients should not donate blood during treatment and for 1 month after discontinuation of isotretinoin due to the potential risk to the fetus of a pregnant woman receiving such blood.
Educational material
To help prescribers, pharmacists and patients avoid fetal exposure to isotretinoin, the marketing authorization holder provides educational material to reinforce warnings about the teratogenicity of isotretinoin, to advise on contraception before therapy is started and to advise on the need for a pregnancy test.
All patients, men and women, must be given complete information by the physician on the risk of teratogenicity and strict pregnancy prevention measures, as detailed in the Pregnancy Prevention Program.
Psychiatric disorders
Depression, aggravated depression, anxiety, aggression, mood changes, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients receiving isotretinoin (see section 4.8).
Particular attention should be paid to patients with a history of depression and signs of depression should be sought in all patients who, if necessary, should be referred for appropriate treatment. Discontinuation of treatment, however, may not be sufficient to reduce psychiatric symptoms and may therefore require "further psychiatric or psychological evaluation.
Skin and subcutaneous tissue disorders
Worsening of acne may occasionally occur in the initial period of therapy, but resolves with continued therapy, usually within 7-10 days, and usually does not require dose adjustment.
Avoid prolonged exposure to sunlight or UV radiation. If necessary, use a sunscreen product with a high protection factor (at least 15).
Avoid aggressive dermabrasion or laser therapy in patients treated with isotretinoin for a period of 5-6 months after the end of treatment due to the risk of hypertrophic scarring in atypical areas and, more rarely, post-inflammatory hypo- or hyper-pigmentation in treated areas . Avoid using depilatory wax in patients treated with isotretinoin for a period of at least 6 months after the end of treatment due to the risk of skin tears.
Avoid concomitant administration of isotretinoin and topical anti-acne products with keratolytic or exfoliating action as local irritation may increase (see section 4.5).
Recommend patients to use a greasy ointment and lip balm from the start of treatment as isotretinoin can cause dry skin and lips.
Post-marketing data have reported severe skin reactions such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with the use of isotretinoin.As these events may be difficult to distinguish from other skin reactions that may occur (see section 4.8), patients should be informed of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, isotretinoin treatment should be discontinued.
Allergic reactions
Rare cases of anaphylactic reactions have been reported, in some cases after topical exposure to retinoids. Cases of allergic skin reactions are not frequently reported. Severe cases of allergic vasculitis have been reported, often with purpura (bruising and red patches) in the limbs and involving not only the skin. Severe allergic reactions involve discontinuation of therapy and careful monitoring of the patient.
Eye disorders
Dry eyes, corneal opacities, decreased night vision, and keratitis usually resolve after stopping treatment. Dry eyes can be prevented by applying eye ointment or artificial tears. During the treatment, intolerance to contact lenses may occur and the patient may be forced to wear glasses.
Reduction in night vision which occurred suddenly in some patients has also been reported (see section 4.7). Patients with visual impairment should be referred for an eye examination and consideration should be given to discontinuing isotretinoin.
Musculoskeletal and connective tissue disorders
Cases of myalgia, arthralgia and increased serum creatine phosphokinase have been reported in patients receiving isotretinoin, especially among those engaging in strenuous physical activity (see section 4.8).
Bone changes have occurred including premature epiphyseal welding, hyperostosis, and calcification of tendons and ligaments after several years of high-dose administration for the treatment of keratinization disorders. Dosages, treatment duration and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines (see sections 4.3 and 4.5). Signs and symptoms of benign intracranial hypertension are headache, nausea and vomiting, visual disturbances and papilledema. Patients who develop benign intracranial hypertension should have isotretinoin discontinued immediately.
Hepatobiliary disorders
Liver enzymes should be monitored prior to initiation of therapy and 1 month after, and every 3 months thereafter unless more frequent monitoring is indicated for clinical reasons. Transient and reversible elevations of liver transaminases have been reported. In many cases these changes remained within the normal range and the values returned to initial levels during the course of treatment. However, in the event of persistent elevated transaminase levels, dose reduction or discontinuation of treatment should be considered.
Kidney failure
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be administered to patients with renal insufficiency. It is recommended, however, that in these patients the treatment is started with a reduced dose and then increased up to maximum tolerated dose (see section 4.2).
Lipid metabolism
Serum lipids (fasting values) should be checked before initiation of therapy and 1 month after, and every 3 months thereafter unless more frequent monitoring is indicated for clinical reasons. Usually serum lipids return to normal values reducing the dose or stopping treatment and may also resolve with a modification of the diet.
Since it has been linked to increased triglyceride levels, isotretinoin should be discontinued if it is not possible to maintain triglyceridaemia at an acceptable level or if symptoms of pancreatitis are present (see section 4.8). Levels above 800 mg / dL or 9 mmol / L are sometimes associated with acute pancreatitis, which can sometimes be fatal.
Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients with no medical history of bowel disorders. Patients who experience severe (haemorrhagic) diarrhea should immediately discontinue treatment with isotretinoin.
Fructose intolerance
AISOSKIN contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
High Risk Patients
In patients with diabetes, obesity, alcoholism or lipid metabolism disorders treated with isotretinoin, more frequent checks of serum lipids (fasting values) and / or blood glucose may be necessary. Cases of elevated fasting blood glucose have been reported and new cases of diabetes have been diagnosed during treatment with isotretinoin.
04.5 Interactions with other medicinal products and other forms of interaction
Patients should not take vitamin A, as there is a risk of developing symptoms of hypervitaminosis A.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported during concomitant use of isotretinoin and tetracyclines. Therefore, concomitant treatment with tetracyclines should be avoided (see section 4.3 and section 4.4).
Avoid concomitant administration of isotretinoin and topical anti-acne products with keratolytic or exfoliating action as local irritation may increase (see section 4.4).
04.6 Pregnancy and lactation
Pregnancy is a contraindication absolute to treatment with isotretinoin (see section 4.3). If pregnancy does occur despite these precautions during treatment with isotretinoin or in the following month, there is a high risk of very serious and serious fetal malformations.
Fetal malformations associated with isotretinoin treatment include central nervous system abnormalities (hydrocephalus, cerebellar malformations / abnormalities, microcephaly), facial dysmorphism, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), ocular anomalies (microphthalmia), cardiovascular anomalies (malformations of the cone-trunk, such as the tetralogy of Fallot, transposition of the great vessels, septal defects), anomalies of the thymus and anomalies of the parathyroid glands. There is also an "increased incidence of spontaneous abortions.
Should pregnancy occur during treatment with isotretinoin, treatment should be discontinued and the patient should be referred to a specialist doctor or physician experienced in teratology for evaluation and consultation.
Feeding time
Since isotretinoin is highly lipophilic, passage of the drug into breast milk is very likely. Due to the possibility of side effects for the baby exposed through breast milk, the use of isotretinoin is contraindicated in breastfeeding women.
04.7 Effects on ability to drive and use machines
In a number of cases there has been a reduction in night vision during treatment with isotretinoin, sometimes persisting even after the end of therapy (see section 4.4 and section 4.8). Since in some cases the visual impairment has occurred suddenly, it is good to inform patients of this possible occurrence and ask them to be careful when driving vehicles or using machines at night.
Very rarely somnolence, dizziness and visual disturbances have been reported. Patients should be advised that if they experience these effects, they should not drive, operate machinery or take part in any other activity where the symptoms may put themselves or others at risk.
04.8 Undesirable effects
Some of the undesirable effects associated with the use of isotretinoin are dose related. Undesirable effects are usually reversible after dose reduction or discontinuation of treatment, however some may persist after discontinuation of treatment. The following symptoms are undesirable effects of isotretinoin most commonly reported: dry skin, dry mucous membranes, e.g. of the lips (cheilitis), nasal mucosa (epistaxis) and eyes (conjunctivitis).
* frequency cannot be estimated from the available data
The incidence of adverse events was calculated from the pool of clinical trial data on 824 patients and post-marketing data.
04.9 Overdose
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, symptoms of hypervitaminosis A may appear in the event of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and itching. . Signs and symptoms of accidental or deliberate isotretinoin overdose are likely similar.
Symptoms are expected to be reversible and do not require treatment.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Retinoids for the treatment of acne - ATC code: D10BA01
Mechanism of action
Isotretinoin, the active ingredient of AISOSKIN, is the synthetic stereoisomer of all-trans retinoic acid (tretinoin).
The exact mechanism of action of isotretinoin has not yet been clarified in detail, however it has been proven that the improvement observed in the clinical picture of severe acne is associated with the inhibition of the activity of the sebaceous glands and a histologically demonstrated reduction. the size of the glands themselves. It has also been demonstrated an "anti-inflammatory activity in the skin of isotretinoin".
Effectiveness
The excessive cornification of the epithelial lining of the pilosebaceous unit leads to an accumulation of horny cells inside the duct and the blocking of the latter due to keratin and excess sebum. This results in the formation of the blackhead and therefore the appearance of inflammatory lesions Isotretinoin inhibits the proliferation of sebum-producing cells and its efficacy in the treatment of acne appears to be related to the ability to restore the normal cell differentiation process.
Furthermore, since sebum is an important substrate for the growth of Propionibacterium acnes, by reducing the production of sebum, bacterial colonization of the sebaceous duct is fought.
05.2 Pharmacokinetic properties
Absorption
Absorption of isotretinoin from the gastrointestinal tract is variable and dose linear beyond the therapeutic range. Absolute bioavailability has not been determined, as the active substance is not available as an intravenous injection for human use; however. extrapolating the data of the studies carried out on dogs, a very low and variable systemic bioavailability can be assumed.
When the drug is taken with food the bioavailability doubles compared to the fasting.
Distribution
Isotretinoin is largely bound to plasma proteins, mainly albumin, at 99.9%.
The volume of distribution of isotretinoin in humans has not been determined as the active substance is not available as an intravenous injection for human use.
There are few data on the distribution of isotretinoin in humans; epidermal concentrations of isotretinoin are only half of those in serum. Plasma concentrations of isotretinoin are approximately 1.7 times those of whole blood due to poor penetration of isotretinoin into red blood cells.
Metabolism
Following oral administration of isotretinoin, three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin, (all-trans retinoic acid), and 4-oxy-tretinoin. These metabolites have been shown to be biologically active in several studies in vitro.
A clinical study has shown that 4-oxo-isotretinoin contributes significantly to isotretinoin activity (significant reduction in the rate of sebaceous secretion, with no effect on plasma concentrations of isotretinoin and tretinoin). Other minor metabolites include glucuronate derivatives.
The most important is 4-oxo-isotretinoin, present with plasma concentrations at steady state 2.5 times higher than those of the parent compound.
Since reversible metabolism (interconversion) between isotretinoin and tretinoin (all-trans retinoic acid) is possible, the metabolism of tretinoin is related to that of isotretinoin. It is estimated that 20-30% of an administered dose of isotretinoin is metabolized by isomerization.
The enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.
In vitro metabolism studies have shown the involvement of several CYP enzymes (cytochrome P450 system) in the metabolic transformation of isotretinoin to 4-oxo-isotretinoin and tretinoin. It does not appear that a single isoenzyme plays a predominant role.
Isotretinoin and its metabolites do not significantly affect CYP activity.
Elimination
After oral administration of radiolabelled isotretinoin, approximately equivalent dose rates are found in faeces and urine. Following oral isotretinoin by acne patients, the terminal elimination half-life of the unchanged drug averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer (29 hours on average).
Isotretinoin is a physiological retinoid, and endogenous concentrations of retinoids are reached within approximately two weeks of the end of isotretinoin treatment.
Pharmacokinetics in particular patient groups
Since isotretinoin is contraindicated in patients with hepatic insufficiency, information on the kinetics of isotretinoin in this patient group is limited. Renal insufficiency does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.
05.3 Preclinical safety data
Acute toxicity
The acute oral toxicity of isotretinoin has been determined in several animal species. The LD50 is about 2000 mg / kg in rabbits, about 3000 mg / kg in mice and over 4000 mg / kg in rats.
Chronic toxicity
A long-term study in rats over 2 years (with isotretinoin dosages of 2, 8, 32 mg / kg / day) produced evidence of partial hair loss and elevated blood triglyceride levels in the dose group. higher. The spectrum of undesirable effects of isotretinoin in rodents therefore closely resembles that caused by vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A administration in rats. The changes observed in hepatocytes with vitamin A did not occur with isotretinoin.
All observed side effects of hypervitaminosis A were spontaneously reversible upon discontinuation of isotretinoin treatment. Experimental animals in poor general condition also recovered within 1-2 weeks.
Teratogenicity
Like other vitamin A derivatives, isotretinoin has been shown to be teratogenic and embryotoxic in experimental animals.
Given the teratogenic potential of isotretinoin, there are therapeutic consequences for its administration to patients of childbearing potential (see sections 4.3, 4.4 and 4.6).
Fertility
At therapeutic doses, isotretinoin does not affect the number, motility and morphology of spermatozoa and does not jeopardize the formation and development of the embryo for the male who takes isotretinoin.
Mutagenicity
Isotretinoin was not shown to be mutagenic in in vitro or in vivo tests on animals.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Soybean oil, DL-alpha-tocopherol, edetate disodium, butylhydroxyanisole, Lipodan HP-100 (Grinsted PS 101 hydrogenated triglycerides), yellow wax, partially hydrogenated soybean oil.
Constituents of the gelatinous shell: gelatin, glycerol, 70% sorbitol (not crystallizable), purified water, Ponceau 4R (E 124), titanium dioxide (E 171).
The gelatinous envelope also contains an additional different dye depending on the dose:
• AISOSKIN 10 mg - black iron oxide (E 172)
• AISOSKIN 20 mg - indigo carmine (E 132).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
A properly stored intact packaging: 3 years.
06.4 Special precautions for storage
Store at a temperature not exceeding 25 ° C.
Store in the original package and keep the blister in the outer carton in order to protect it from moisture and light.
06.5 Nature of the immediate packaging and contents of the package
The capsules are packaged in heat-sealed PVC / PVDC and aluminum blisters. The blisters are inserted, together with the package leaflet, inside a cardboard box.
AISOSKIN 10 mg 30 capsules.
AISOSKIN 20 mg 30 capsules.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
FIDIA Farmaceutici S.p.A. - Via Ponte della Fabbrica, 3 / A - 35031 Abano Terme (PD)
08.0 MARKETING AUTHORIZATION NUMBER
AISOSKIN 10 mg - A.I.C. 035258019
AISOSKIN 20 mg - A.I.C. 035258021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
07.10.2003
10.0 DATE OF REVISION OF THE TEXT
13-04-2013
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
March 2009
New prescribing modalities for isotretinoin-containing medicines for systemic use
Dear Doctor / Dear Doctor,
The Italian Medicines Agency wishes to provide you with a guide on the new ways of prescribing medicines containing isotretinoin for systemic use.
Isotretinoin is a medicine subject to the teratogenic risk prevention program approved by AIFA in 2005 (GU n.261 / 05 and subsequent amendments).
This Program, aimed at doctors, pharmacists and manufacturing companies, indicates the methods of prescribing, dispensing and distributing medicines containing isotretinoin for systemic use, information for patients on the risks associated with the use of the drug and on the need for contraceptive measures. adequate monitoring and management of any cases of pregnancy and / or suspected embryo-fetal exposure that have occurred.
The Technical Scientific Commission of the AIFA, in order to further strengthen the measures aimed at a more controlled and safe use of isotretinoin, has adopted a new method of prescribing medicines containing isotretinoin for systemic use (GU n ° 43/09) approving a specific "form for the prescription of" isotretinoin for systemic use "(see annex). This provision does not constitute a modification of the Risk Prevention Program.
The AIFA form for the prescription of isotretinoin for systemic use is divided into two parts, one for the dermatologist, who is entrusted with the first prescription, the other for the general practitioner (GP) or for the dermatologist himself in the case in which the patient is followed for the entire duration of the treatment by the specialist.
The dermatologist will have to:
• prescribe isotretinoin according to the authorized therapeutic indications such as severe forms of acne (such as nodular or conglobate acne or acne with the risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy;
• inform the patient of the teratogenic risk related to the use of isotretinoin;
• give the patient the guide to therapy and the guide to contraception;
• attach the patient's informed consent;
• verify that the patient has taken effective contraception one month before starting treatment with the drug.
If the patient agrees to undergo isotretinoin therapy, the dermatologist should recommend that the patient use effective contraception for at least one month before starting treatment; therapy should only be started after a negative pregnancy test has been performed. Date and test result must be recorded on the form. The test must be carried out during the first three days of the menstrual cycle following the visit to the doctor.
The GP or dermatologist will follow the patient for the entire duration of the therapy verifying that the patient has adopted effective contraception, without interruption, before the start of the treatment, for the entire duration and for at least 1 month after the end of the treatment.
The form includes a section in which the GP or dermatologist must indicate the date and outcome of the pregnancy test.
After four weeks of continuous adoption of the chosen method of contraception, the patient should go to the doctor again for a prescription for isotretinoin. Another pregnancy test should be performed immediately before starting treatment.
Visits and checks by the GP or dermatologist must be scheduled at 28-day intervals.
The last pregnancy test should be performed five weeks after the end of isotretinoin treatment.
The pharmacist must dispense drugs containing isotretinoin for systemic use only on presentation of a medical prescription (both SSN prescription and white prescription) to be used only once.
The pharmacist must:
• dispense a new pack of isotretinoin only following presentation of a new medical prescription.
• not accept telephone, fax or computerized requests for isotretinoin, requests for drug replenishment or distribution of samples.
The medical prescription (both on the SSN prescription and on the white prescription), which is valid for 7 days from the date of issue, must be indicated:
• the dosage;
• the certification date;
• the need for the drug for up to 30 days (expressed in mg / day).
The doctor is required to note on the prescription the date of the negative pregnancy test (date of certification) and that of the prescription, even when they coincide.
In the event that two different dates are placed on the prescription, the pharmacist should contact the doctor for clarification and, in any case, cautiously consider the 7-day validity of the prescription from the earliest date.
For male patients the risk management program should be followed for the applicable parts; for example, the limitations relating to the prescription (validity 7 days, therapy for a maximum of 30 days) and the acquisition of informed consent apply. In particular, the patient must be informed of the teratogenic risk of the drug and, therefore, not to be able to donate the own blood and not having to give isotretinoin to anyone.
The patient is required to return unused capsules to the pharmacist at the end of therapy.
Reports of suspected adverse drug reactions should be sent to the pharmacovigilance manager of the facility.
Attachment
AIFA FORM
BY PRESCRIPTION OF ISOTRETINOIN FOR SYSTEMIC USE
Dear Colleague,
I inform you that I intend to treat the patient with isotretinoin for systemic use for the treatment of severe forms of acne (such as nodular or conglobate acne or acne with risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.
I informed the patient of the teratogenic risk related to the use of isotretinoin
I gave the patient the therapy guide and the contraception guide
I enclose the patient's informed consent
Pregnancy test date: __________ result: __________ signature: _________
(one month before the start of isotretinoin treatment)
Name Surname of the dermatologist
________________________________________________________________ __
Address ___________________________________________ Tel ._____________
Patient (name, surname) _____________________________________________
age ________________________ health card n ° _______________________
Address ______________________________________________ Tel ._________
DOSE AND DURATION OF THE TREATMENT
Dose / day: _________________________
Expected duration of processing: _________________________
Maximum duration of treatment 16-24 weeks.
Indicate if:
• First prescription
• Continuation of treatment (reason: _________________________________________)
Date _____ / _____ / ______ Stamp and signature of the prescribing dermatologist
FOR THE GENERAL MEDICINE or DERMATOLOGIST
Pregnancy test date: __________ result: __________ signature: _________
(immediately before starting isotretinoin treatment)
Date of pregnancy test: ______________ result: ___________ signature: _________
Pregnancy test date: ______________ result: __________ signature: _________
Pregnancy test date: ______________ result: ______ ____ signature: _________
Date of pregnancy test: ______________ result: ___________ signature: _________
(one month after the end of isotretinoin treatment)
Date _____ / _____ / ______ Stamp and signature of the prescribing dermatologist
