Active ingredients: Isotretinoin
ISOTRETINOIN STIEFEL Isotretinoin 0.05% cream
Why is Isotretinoin Cream - Generic Drug used? What is it for?
The name of your medicine is Isotretinoin Stiefel 0.05% cream. Isotretinoin Stiefel contains an active substance called isotretinoin.
Isotretinoin Stiefel is used to treat acne (boils) in young people who are about to or have entered puberty, and in adults. It is not intended for use in children who have not entered puberty. Isotretinoin Stiefel helps to:
- soften blackheads and whiteheads so they can come out easier
- prevent the formation of new blackheads, whiteheads and boils
- reduce the number of red and inflamed acne boils.
It is particularly suitable if you have dry skin.
Contraindications When Isotretinoin Cream - Generic Drug should not be used
Do not use Isotretinoin Stiefel:
- if you are allergic (hypersensitive) to isotretinoin or any of the other ingredients of Isotretinoin Stiefel (listed in section 6).
- if you are pregnant, think you are pregnant or are planning to become pregnant
- if you are breastfeeding.
→ tell your doctor if any of these apply to you. Do not use Isotretinoin Stiefel.
Precautions for use What you need to know before taking Isotretinoin Cream - Generic Drug
Before using Isotretinoin Stiefel your doctor needs to know:
- if you or any of your close relatives have had skin cancer
- if you have had problems tolerating this or similar medicines in the past (found them too irritating for your skin)
- if you have: o eczema o redness of the skin, broken capillaries and small pimples which are usually found in the center of the face (rosacea) o redness and dryness around the mouth (perioral dermatitis
Isotretinoin Stiefel can further accentuate these conditions.
- if you have skin reactions to sunlight
→ Check with your doctor if you think any of these apply to you.
Take care not to use too much cream especially where it can run into your eyes or build up in the corners of the nose, skin folds or other areas of the skin that don't need to be treated.
Only use Isotretinoin Stiefel on the skin.
Keep it away from areas such as your mouth, lips and eyes.
Do not use Isotretinoin Stiefel on any irritated area of the skin. For example if you have cuts, grazes, or sunburn.
Do not use too much Isotretinoin Stiefel on sensitive areas of the skin, such as the neck.
Sunlight
Using Isotretinoin Stiefel can make the skin more sensitive to sunlight.
While using Isotretinoin Stiefel you need to:
- protect the skin from the sun. You can do this by using sunscreen and wearing clothing that protects you from sunburn.
- avoid using sun beds (sun lamps) or spending long periods in the sun.
→ If you get sunburn, stop using Isotretinoin Stiefel until your skin improves.
Interactions Which drugs or foods can modify the effect of Isotretinoin Cream - Generic Drug
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This also includes medicines bought without a prescription.
In particular, tell your doctor or pharmacist:
- if you are using benzoyl peroxide (another acne treatment). If used at the same time, it can make Isotretinoin Stiefel less effective. You may need to use these drugs at different times of the day (for example, one in the morning and the other in the morning). bedtime).
- if you use any other acne treatment. If used at the same time, it can worsen skin irritation. If your skin becomes very irritated, you may need to use Isotretinoin Stiefel less often or stop using it for a short time to allow your skin to recover and then restart treatment. Stop treatment and consult your doctor if skin irritation does not improve.
→ Check with your doctor if you think any of these apply to you.
Warnings It is important to know that:
Pregnancy and breastfeeding
Do not use Isotretinoin Stiefel if you are pregnant.
- Tell your doctor if you are pregnant or planning to become pregnant.
- Use a reliable method of contraception correctly to prevent pregnancy while you are using Isotretinoin Stiefel.
- If you become pregnant while taking Isotretinoin Stiefel, please inform your doctor.
Do not breast-feed if you are using Isotretinoin Stiefel. Ask your doctor for advice on whether to breast-feed or use Isotretinoin Stiefel.
Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breastfeeding.
Important information about some of the ingredients of Isotretinoin Stiefel
- Isotretinoin Stiefel contains butylated hydroxytoluene (BHT). It can cause local skin reactions. In addition, it can cause irritation to the eyes and mucous membranes, such as the inside of the nose.
- Isotretinoin Stiefel contains cetostearyl alcohol. It can cause local skin reactions (eg contact dermatitis).
- Isotretinoin Stiefel contains chlorine cresol. It can cause allergic reactions.
- Isotretinoin Stiefel contains propylene glycol. It can cause skin irritation.
Dose, Method and Time of Administration How to use Isotretinoin Cream - Generic Drug: Posology
Always use Isotretinoin Stiefel exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
- Use Isotretinoin Stiefel once or twice a day. Your doctor will tell you how to use the medicine.
- It may take 6-8 weeks before you have any noticeable effects with Isotretinoin Stiefel.
- You must continue to use the medicine until your doctor tells you otherwise.
How to apply Isotretinoin Stiefel
- Wash your hands.
- Remove makeup completely
- Wash the area with a mild soap and warm water and dry gently.
- Put a thin layer of Isotretinoin Stiefel cream on the affected skin, using your fingertips and massage.
- Apply to the entire area of acne-prone skin, not just individual pimples.
- Wash your hands after using the cream.
Overdose What to do if you have taken too much Isotretinoin Cream - Generic Drug
If you use more Isotretinoin Stiefel than you should
If you use too much Isotretinoin Stiefel or more frequently than you should, it may cause redness, peeling or skin irritation. If this happens, use the cream less often or stop using it for a few days and then start again. Using more Isotretinoin Stiefel than you should will not help your boils heal faster.
If you accidentally swallow Isotretinoin Stiefel
The components of Isotretinoin Stiefel are not expected to be harmful if ingested in small quantities.
- If you accidentally get Isotretinoin Stiefel in your mouth, rinse immediately with plenty of water.
- Consult a doctor if you ingest a large amount of Isotretinoin Stiefel.
If you forget to use Isotretinoin Stiefel
Do not use a double dose of cream to make up for a forgotten dose. Apply the next dose at the usual time.
Side Effects What are the side effects of Isotretinoin Cream - Generic Drug
Like all medicines, Isotretinoin Stiefel can cause side effects, although not everybody gets them.
Severe allergic reactions:
- severe burning, peeling or itching of the skin
→ Stop using Isotretinoin Stiefel and see a doctor immediately, if you notice any of the above side effects - you may need urgent medical treatment.
Very common side effects (may affect at least 1 in 10 people):
These effects can occur in the area of the skin where the cream was used. If they cause you problems, try to use Isotretinoin Stiefel cream less often, or stop using it for a few days until the irritation resolves, then start using it again.
Stop using Isotretinoin Stiefel cream if irritation persists:
- redness or peeling of the skin, especially during the first few weeks of use
- mild itching or pain of the skin
- irritation or soreness of the skin
- burning sensation of the skin
- dry skin
- itch
Other side effects
These side effects have occurred in a small number of people but their exact frequency is not known:
- skin that becomes darker or lighter
- increased sensitivity to sunlight.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at the address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep Isotretinoin Stiefel out of the sight and reach of children
- Do not store Isotretinoin Stiefel above 25 ° C.
- Do not use Isotretinoin Stiefel after the expiry date which is stated on the tube and carton
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Isotretinoin Stiefel contains
- The active ingredient is 0.05% weight / weight isotretinoin
- The other ingredients are light liquid paraffin, di-n-butyl adipate, macrogol stearyl ether, propylene glycol, cetostearyl alcohol, benzyl alcohol, PEG-5 glyceryl stearate, carbomer, chlorocresol, sodium hydroxide, butylated hydroxytoluene (BHT), purified water .
What Isotretinoin Stiefel looks like and contents of the pack
- Isotretinoin Stiefel is a pale yellow cream
- Isotretinoin Stiefel is sold in tubes of 15 grams, 25 grams, 30 grams, 40 grams or 50 grams of cream.
- Not all pack sizes may be marketed.
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
ISOTRETINOIN DIFA COOPER SOFT CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Isotretinoin Difa Cooper 10 mg soft capsule
Each soft capsule contains 10 mg of isotretinoin
Isotretinoin Difa Cooper 20 mg soft capsule
Each soft capsule contains 20 mg of isotretinoin
Excipients:
Soybean oil, Ponceau 4R (E 124), sorbitol
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Soft capsules
Isotretinoin Difa Cooper 10 mg soft capsules: pale purple oblong soft capsules containing an opaque yellow / orange viscous liquid.
Isotretinoin Difa Cooper 20 mg soft capsules: Oblong soft, reddish brown capsules containing an opaque yellow / orange viscous liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Severe forms of acne (such as nodular acne or acne conglobata 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 initiated at a dose of 0.5 mg / kg per day. The therapeutic response to isotretinoin and some of the adverse events of isotretinoin are dose related and vary from patient to patient. Therefore, individual dose adjustment is required during therapy. For most patients the dose is between 0.5 and 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. A treatment course of 16-24 weeks is normally sufficient to achieve remission.
In most patients, complete resolution of acne is achieved with a single course of treatment. In the event of a certain recurrence, an additional course of treatment with isotretinoin at the same daily dose and with the same cumulative treatment dose can be considered. Since further improvement in acne can be observed up to 8 weeks after the end of treatment, no further treatment course should be considered before this period has elapsed.
Patients with severe renal insufficiency
In patients with severe renal insufficiency, treatment should be started with a lower 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 4.4 "Special warnings and precautions for use").
Children
Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended for patients under 12 years of age.
Patients with intolerance
In patients with severe intolerance to the recommended dose, treatment can be continued at a lower dose with the consequence of a longer duration of treatment and a higher risk of relapse. To achieve the maximum possible efficacy in these patients the dose should normally be continued at the maximum tolerated dose.
04.3 Contraindications
Isotretinoin is contraindicated in women who are pregnant or breastfeeding (see section 4.6 "Pregnancy and lactation")
Isotretinoin is contraindicated in women of childbearing potential unless all conditions of the Pregnancy Prevention Program are met (see section 4.4 "Special warnings and precautions for use").
Furthermore, isotretinoin is contraindicated in patients
• With liver failure
• With excessively high plasma lipid values
• With hypervitaminosis A
• With hypersensitivity to isotretinoin, soy, peanut, Ponceau 4R (E 124) or to any of the excipients
• In concomitant treatment with tetracyclines (see section 4.5 "Interactions with other medicinal products and other forms of" interaction ")
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 (nodular acne or acne conglobata or acne with risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy (see section 4.1 "Therapeutic indications").
- Understands the teratogenic risk.
- Understands the need for rigorous monthly follow-up.
- Understands and accepts the need for effective contraception, without interruption, from 1 month before the start of treatment, for the entire duration of treatment until 1 month after the end of treatment. At least one and preferably two should be used complementary 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 quickly with the doctor in case of 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.
- He acknowledged that he understood the risks and necessary precautions associated with the use of isotretinoin.
These conditions also affect women who are not currently sexually active, unless the prescribing physician believes there are compelling reasons that indicate that there is no risk of pregnancy.
The prescribing physician must ensure that:
- The patient complies with the previously reported pregnancy prevention conditions, including confirmation of an adequate level of understanding.
- The patient has recognized the aforementioned requirements.
- The patient has used at least one and preferably two methods of effective contraception, including a barrier method for at least 1 month prior to the start of treatment, and is continuing to use effective contraception throughout the treatment period and for at least 1 month. month after the end of the 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 effective contraception.
At a minimum, patients at potential pregnancy risk should use at least one effective method of contraception. Patients should preferably use two complementary forms 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
According to medical practice, it is recommended to perform the pregnancy test with a minimum sensitivity of 25 mIU / ml in the first three days of the menstrual cycle, under the supervision of the doctor, as follows.
Before starting therapy
Before starting contraception, in order to exclude the possibility of pregnancy, it is recommended that an initial pregnancy test be performed, under the supervision of the physician, with the date of execution and the result recorded. In patients with irregular menstruation, the time to perform The 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 inform the patient about contraception.
A physician-supervised pregnancy test should also be performed at or within 3 days of the initial prescription, and should be performed after the patient has used effective contraception for at least 1 month. This pregnancy test should ensure that the patient is not pregnant at the time of initiating isotretinoin therapy.
Follow up visits
Follow-up visits should be scheduled at 28-day intervals. The need for repeated, physician-supervised monthly pregnancy tests should be determined on the basis of local practice, considering the patient's sexual activity and recent menstrual history (irregular periods, missed periods or amenorrhea). When indicated, follow-up pregnancy tests should be performed on or within 3 days of the prescribing visit.
End of treatment
Five weeks after the end of treatment, patients must undergo a final pregnancy test to rule out pregnancy.
Restrictions on Prescribing and Dispensing
Prescribing isotretinoin to women of childbearing potential should be limited to 30 days of treatment and continued treatment requires a new prescription. Ideally, the pregnancy test, prescription delivery and isotretinoin dispensing should occur on the same day. Dispensing of isotretinoin must take place within a maximum of 7 days of the prescription.
Male patients
Available data suggest that the level of maternal exposure from sperm of patients receiving isotretinoin is not large enough to be associated with teratogenic effects of isotretinoin. Male patients should remember never to share this medicine with other people, particularly with women. women.
Additional precautions
Patients should be instructed to never give this medicine to other people and return unused capsules to the pharmacist at the end of treatment.
Patients should not donate blood during treatment and for one month after drug discontinuation 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 will provide educational material aimed at reinforcing warnings about the teratogenicity of isotretinoin, providing advice on contraception before starting therapy and to advise on the need for a pregnancy test.
Full information on the risk of teratogenicity and strict pregnancy prevention measures as specified in the Pregnancy Prevention Program should be given by the physician to all male and female patients.
Psychiatric disorders
Depression, worsening of depression, anxiety, aggression, mood alteration, psychotic symptoms and, very rarely, suicidal thoughts, suicide attempts and suicide have been reported in patients treated with isotretinoin (see section 4.8 "Undesirable effects").
Particular attention should be paid to patients with a history of depression. All patients should be monitored for signs of depression and, if necessary, referred to appropriate treatment. Discontinuation, however, may not be sufficient. to relieve symptoms, and "further psychiatric or psychological evaluation may be required."
Skin and subcutaneous tissue disorders
Worsening of acne is occasionally observed in the initial period of therapy, but resolves with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.
In the post-marketing period, cases of severe skin reactions (eg erythema multiforme (EM), Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with the use of isotretinoin have been reported. As these events can be difficult to distinguish. from other skin reactions that may occur (see section 4.8), patients should be warned of these signs and symptoms and monitored closely for severe skin reactions. If there is a suspicion of a severe skin reaction, Isotretinoin treatment should be discontinued .
Avoid intense exposure to sunlight or UV radiation. When necessary, an anti-sun product with a high protection factor (at least 15) should be used.
Avoid aggressive chemical dermabrasion and skin 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 treatment due to the risk of skin lacerations.
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 4.5 "Interactions with other medicinal products and other forms of" interaction ")
Recommend patients to use a skin moisturizer or cream and lip balm from the start of treatment as isotretinoin can cause dry skin and lips.
Eye disorders
Dry eyes, corneal opacities, decreased night vision, and keratitis usually resolve after discontinuation of therapy. Dry eyes can be relieved by applying a lubricating eye ointment or artificial tears. Contact lens intolerance may occur and the patient may be forced to wear glasses during treatment.
Decreased night vision has also been reported and in some subjects the onset was sudden (see section 4.7 "Effects on ability to drive and use machines"). Patients who experience visual problems should be referred to an eye examination It may be necessary to discontinue treatment with isotretinoin.
Musculoskeletal and connective tissue disorders
Myalgia, arthralgia and increased serum creatinine phosphokinase have been reported in patients receiving isotretinoin, especially among those who engage in strenuous physical activity (see section 4.8 "Undesirable effects").
Bone changes have occurred including premature epiphyseal welding, hyperostosis, and calcification of tendons and ligaments after several years of administration at very high doses 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 the concomitant use of tetracyclines (see sections 4.3 "Contraindications" and 4.5 "Interactions with other medicinal products and other forms of interaction"). The signs and symptoms of benign intracranial hypertension are headache, nausea and vomiting, visual disturbances and papilledema.
Patients who develop benign intracranial hypertension should immediately discontinue isotretinoin treatment.
Hepatobiliary disorders
Liver enzymes should be checked prior to treatment, 1 month after initiation of treatment and every 3 months thereafter unless more frequent monitoring is clinically indicated. Transient and reversible elevations in hepatic transaminases have been reported.In many cases these changes remained within the normal range and values returned to baseline during the course of treatment. However, in case of persistent, clinically relevant increase in transaminase levels, dose reduction or the suspension of the treatment.
Kidney failure
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be administered to patients with renal insufficiency. However, it is recommended that treatment in patients is initiated with a reduced dose and then increased to the maximum tolerated dose (see section 4.2 "Posology and method of administration").
Lipid metabolism
Serum lipids (fasting values) should be checked prior to treatment, 1 month after initiation of treatment, and every 3 months thereafter unless more frequent monitoring is clinically indicated. Serum lipids usually return to within values. normal by reducing the dose or stopping treatment and may also respond to dietary measures.
Isotretinoin has been associated with increased plasma triglyceride levels.
Isotretinoin should be discontinued if triglyceridemia cannot be controlled to an acceptable level or if symptoms of pancreatitis occur (see section 4.8 "Undesirable effects"). Levels above 800 mg / dl or 9 mmol / l they are sometimes associated with acute pancreatitis, which can be fatal.
Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients with no previous history of bowel disease. Patients who experience severe (haemorrhagic) diarrhea should immediately discontinue isotretinoin treatment.
Allergic reactions
Anaphylactic reactions have been reported rarely, in some cases after previous topical exposure to retinoids. Allergic skin reactions are rarely reported. Severe cases of allergic vasculitis often with purpura (ecchymosis and red patches) in the limbs and extracutaneous involvement have been reported. Severe allergic reactions require discontinuation of therapy and careful patient monitoring.
High Risk Patients
In patients suffering from diabetes, obesity, alcoholism or lipid metabolism disorders treated with isotretinoin it may be necessary to carry out more frequent checks of serum lipids and / or blood glucose. Elevated fasting blood glucose has been reported and new cases of diabetes have been diagnosed during treatment with isotretinoin.
Metabolic and nutritional disorders
Isotretinoin Difa Cooper 10 mg / 20 mg soft capsule contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Patients should not take vitamin A as a concomitant drug due to the risk of developing 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 "Contraindications" and 4.4 "Special warnings 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 4.4 "Special warnings and precautions for use").
04.6 Pregnancy and lactation
Pregnancy
Pregnancy is an absolute contraindication to isotretinoin treatment (see section 4.3 "Contraindications"). 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 exposure include central nervous system abnormalities (hydrocephalus, cerebellar malformations / abnormalities, microcephaly), facial dimorphism, cleft palate, external ear abnormalities (absence of the external ear, small or absent), 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 parathyroid glands. There is also an increased incidence of spontaneous abortions.
Should pregnancy occur in a woman receiving isotretinoin, the treatment should be discontinued and the patient referred to a specialist or 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 adverse effects for the exposed infant through breast milk, the use of isotretinoin in nursing mothers is contraindicated.
04.7 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 lasting after treatment (see sections 4.4 "Special warnings and precautions for use" and 4.8 "Undesirable effects"). the onset was sudden, it is necessary to warn patients of this possible problem and instruct them to be careful when driving and using machines.
Somnolence, dizziness and visual disturbances have been reported very rarely.
Patients should be advised that if they have experienced these disorders, they should not drive, operate machinery or take part in other activities where these symptoms could 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 generally reversible after dose modification or discontinuation of treatment, some however may persist after discontinuation of therapy. 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).
Infections
Very rare (≤ 1/10.000)
Gram positive bacterial (mucocutaneous) infections
Disorders of the blood and lymphatic system
Very common (≥ 1/10)
Anemia, increased erythrocyte sedimentation rate, thrombocytopenia, thrombocytosis
Common (≥ 1/100,
Neutropenia
Very rare (≤ 1/10.000)
Lymphadenopathy
Disorders of the immune system
Rare (≥ 1/10.000,
Allergic skin reaction, anaphylactic reactions, hypersensitivity
Metabolism and nutrition disorders
Very rare (≤ 1/10.000)
Diabetes mellitus, Hyperuricemia
Psychiatric disorders
Rare (≥ 1/10.000,
Depression, aggravation of depression, anxiety, aggression, mood alteration.
Very rare (≤ 1/10.000)
Behavioral abnormalities, psychotic disorders, suicidal thoughts, suicide
Nervous system disorders
Common (≥ 1/100,
Headache
Very rare (≤ 1/10.000)
Benign intracranial hypertension, convulsions, somnolence, dizziness
Eye disorders
Very common (≥ 1/10)
Blepharitis, conjunctivitis, dry eyes, eye irritation
Very rare (≤ 1/10.000)
Blurred vision, cataracts, color blindness (color vision deficiency), contact lens intolerance, corneal opacity, reduced night vision, keratitis, papilledema (as a sign of benign intracranial hypertension), photophobia, visual disturbances
Ear and labyrinth disorders
Very rare (≤ 1/10.000)
Hearing impairment
Vascular pathologies
Very rare (≤ 1/10.000)
Vasculitis (e.g. Wegener's granulomatosis, allergic vasculitis)
Respiratory, thoracic and mediastinal disorders
Common (≥ 1/100,
Epistaxis, nasal dryness, nasopharyngitis
Very rare (≤ 1/10.000)
Bronchospasm (particularly in asthmatic patients), hoarseness
Gastrointestinal disorders
Very rare (≤ 1/10.000)
Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhea and inflammatory bowel disease, nausea, pancreatitis (see section 4.4 "Special warnings and precautions for use")
Hepatobiliary disorders
Very common (≥ 1/10)
Increased transaminases (see section 4.4 "Special warnings and precautions for use")
Very rare (≤ 1/10.000)
Hepatitis
Skin and subcutaneous tissue disorders
Very common (≥ 1/10)
Cheilitis, dermatitis, dry skin, localized exfoliation, pruritus, rash erythematous, skin fragility (risk of friction trauma)
Rare (≥ 1/10.000,
Alopecia
Very rare (≤ 1/10.000)
Fulminant acne, acne aggravation (acne exacerbation), erythema (facial), rash, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reactions, pyogenic granuloma, skin hyperpigmentation, increased sweating
Frequency not known (not estimable from available data): erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Very common (≥ 1/10)
Arthralgia, myalgia, back pain (particularly in children and adolescent patients)
Very rare (≤ 1/10.000)
Arthritis, calcinosis (calcification of ligaments and tendons), premature epiphyseal sealing, exostosis (hyperostosis), reduced bone density, tendonitis, rhabdomyolysis
Renal and urinary disorders
Very rare (≤ 1/10.000)
Glomerulonephritis
General disorders and administration site conditions
Very rare (≤ 1/10.000)
Granulation tissue (increased formation), malaise
Diagnostic tests
Very common (≥ 1/10)
Increase in triglyceridemia, decrease in high density lipoproteins
Common (≥ 1/100,
Increased cholesterol, increased blood sugar, hematuria, proteinuria
Very rare (≤ 1/10.000)
Increased blood levels of creatine phosphokinase.
The incidence of adverse events was calculated from the pool of data from clinical trials involving 824 patients and from post-marketing data.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 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. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itch. Signs and symptoms of accidental or deliberate isotretinoin overdose are likely similar. Symptoms are expected to be reversible and pass without the need for treatment.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-acne preparation for systemic use
ATC code: D10BA01
Mechanism of action
Isotretinoin is a stereoisomer of the all-trans retinoic (tretinoin). The exact mechanism of action of isotretinoin has not yet been clarified in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in size. of the sebaceous glands. Furthermore, an anti-inflammatory effect of isotretinoin on the skin has been demonstrated.
Effectiveness
Excessive cornification of the epithelial lining of the pilosebaceous unit leads to the deposition of horny cells inside the duct and to its blockage by keratin and excess sebum. This results in the formation of a blackhead and, possibly, lesions inflammatory.
Isotretinoin inhibits the proliferation of cells that produce sebum and appears to act against acne by restoring the normal differentiation process. The sebum is an important substrate for the growth of Propionibacterium acnes so the reduction of sebum production inhibits bacterial colonization of the duct.
05.2 "Pharmacokinetic properties
Absorption
Absorption of isotretinoin through the gastrointestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of isotretinoin has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from studies in dogs suggests a fairly low and variable systemic bioavailability. If isotretinoin is taken with food, the bioavailability doubles compared to fasting conditions.
Distribution
Isotretinoin is highly bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of isotretinoin in humans has not been determined since isotretinoin is not available as an intravenous preparation for human use. Few data are available on the tissue distribution of isotretinoin in humans. isotretinoin in the epidermis are only half of those found 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) and 4-oxy-tretinoin. These metabolites have been shown to be biologically active in several studies in vitro. A clinical study showed that 4-oxy-tretinoin contributes significantly to isotretinoin activity (reduction in the rate of sebaceous secretion, despite no effect on plasma levels of isotretinoin and tretinoin). Other minor metabolites include glucuronate derivatives. The major metabolite is 4-oxo-isotretinoin with plasma concentrations at steady state 2.5 times higher than those of the parent compound.
Isotretinoin and tretinoin (all-trans retinoic) exhibit reversible metabolism (interconversion) and the metabolism of tretinoin is therefore related to that of isotretinoin. It has been estimated that 20-30% of a dose of isotretinoin is metabolised by isomerization.
The enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans. Metabolic studies in vitro have shown that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. There does not appear to be one predominant isomeric form over the others. Isotretinoin and its metabolites do not significantly affect CYP activity.
Elimination
After oral administration of radiolabelled isotretinoin, approximately equal dose fractions were found in urine and faeces. After oral administration of isotretinoin, the terminal elimination half-life of unchanged drug in acne patients averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached approximately two weeks after the end of isotretinoin treatment.
Pharmacokinetics in special populations
Since isotretinoin is contraindicated in patients with hepatic insufficiency, information on its kinetics in this patient population is limited. Renal insufficiency does not significantly reduce the plasma clearance of isotretinoin and 4-oxo-isotretinoin.
05.3 Preclinical safety data
Acute toxicity
The acute oral toxicity of isotretinoin has been determined in various 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 and 32 mg / kg / day) provided evidence of partial hair loss and elevated plasma triglyceride levels in the higher dose group. high. The spectrum of undesirable effects of isotretinoin in rodents therefore closely resembles that of 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 syndrome were spontaneously reversible after discontinuation of isotretinoin. Even experimental animals in general poor condition mostly recovered within 1-2 weeks.
Teratogenicity
As with 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 in patients of childbearing potential (see sections 4.3 "Contraindications", 4.4 "Special warnings and precautions for use" and 4.6 "Pregnancy and lactation").
Fertility
Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of spermatozoa and does not jeopardize the formation and development of the embryo by males who take isotretinoin.
Mutagenicity
Neither mutagenicity nor carcinogenicity of isotretinoin was shown in the tests in vitro or in tests in vivo on animals respectively.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule content:
Refined soybean oil, DL-alpha-tocopherol, edetate disodium, butylhydroxinisole, hydrogenated vegetable oil, partially hydrogenated soybean oil, yellow wax.
Capsule shell:
10 mg capsules: gelatin, 98-101% glycerol, 70% sorbitol, purified water, Ponceau 4R (E 124), black iron oxide (E 172) and titanium dioxide (E 171).
20 mg capsules: gelatin, 98-101% glycerol, 70% sorbitol, purified water, Ponceau 4R (E 124), indigo carmine (E 132) and titanium dioxide (E 171).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 30 ° C.
Store in the original package to protect from moisture and light.
06.5 Nature of the immediate packaging and contents of the package
PVC / PVDC / aluminum foil blisters.
Packs of 20, 30, 50, 60 or 100 soft capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Patients should be instructed to never give this medicine to other people and return unused capsules to their pharmacist at the end of treatment.
07.0 MARKETING AUTHORIZATION HOLDER
Difa Cooper S.p.A., Via Milano 160, 21042 Caronno Pertusella (Varese)
08.0 MARKETING AUTHORIZATION NUMBER
20 soft capsules of 10 mg AIC n ° 036083018
30 soft capsules of 10 mg AIC n ° 036083020
50 soft capsules of 10 mg AIC n ° 036083032
60 soft capsules of 10 mg AIC n ° 036083044
100 soft capsules of 10 mg AIC n ° 036083057 / M
20 soft capsules of 20 mg AIC n ° 036083069 / M
30 soft capsules of 20 mg AIC n ° 036083071 / M
50 soft capsules of 20 mg AIC n ° 036083083 / M
60 soft capsules of 20 mg AIC n ° 036083095 / M
100 soft capsules of 20 mg AIC n ° 036083107 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
AIC / UAC Decree n. 978 of 13/05/2004 - GU n. 168 of 20/07/2004
10.0 DATE OF REVISION OF THE TEXT
November 2014
