PACKAGE LEAFLET: INFORMATION FOR THE USER

Isodifa 5 mg soft capsules, 10 mg soft capsules, 20 mg soft capsules, 30 mg soft capsules

Isotretinoin
Generic medicine
Isotretinoin WARNING
Generic medicine
CAN CAUSE SEVERE HARM TO THE UNBORN CHILD
Women must use effective contraception
Do not use if you are or think you may be pregnant
This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you experience while taking this medicine.
See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Isodifa is and what it is used for
What you need to know before taking Isodifa
How to take Isodifa
Possible side effects
How to store Isodifa
Contents of the pack and other information

1. What Isodifa is and what it is used for

Isodifa contains the active substance isotretinoin. This is a substance similar to
Vitamin A and belongs to a class of medicines called retinoids (for the
treatment of acne).
Isodifa is used to treat severe forms of acne (such as nodular acne, conglobate acne, or acne with risk of permanent scarring) that are resistant to other anti-acne therapies, such as oral antibacterial agents and topical therapy.
Treatment with Isodifa must be supervised by a dermatologist (a doctor
specialized in treating skin disorders).

2. What you should know before taking Isodifa

Do not use Isodifa

If you are pregnant or breastfeeding.
If there is any possibility you could become pregnant, you must follow the precautions outlined in the "Pregnancy Prevention Programme" in the section "Warnings and Precautions".
If you are allergic to isotretinoin, Ponceau 4R (E124), soy, peanuts, or any of the other ingredients of this medicine (listed in section 6).
If you have liver problems.
If you have high levels of lipids (cholesterol, triglycerides) in your blood.
If you have high levels of vitamin A in your body (hypervitaminosis A).
If you are taking tetracyclines (a type of antibiotic).

Warnings and precautions
Pregnancy Prevention Programme
Women who are pregnant must not use Isodifa
This medicine can seriously harm the unborn baby (it is said to be "teratogenic") – it may cause birth defects affecting the brain, face, ears, eyes, heart, and certain glands (thymus and parathyroid glands). It may also very likely cause miscarriage. This can occur even if Isodifa is used for only a short time during pregnancy.

Do not use Isodifa if you are pregnant or think you might be pregnant.
- Do not use Isodifa if you are breastfeeding. The medicine can pass into breast milk and harm the newborn baby.
- Do not use Isodifa if you can become pregnant during treatment.
- Do not become pregnant for one month after stopping this treatment, as some medicines may remain in your body.

For women who could become pregnant, Isodifa is prescribed under very strict rules.
This is due to the risk of harm to the unborn baby.
These are the rules:

Your doctor must explain the risk of harm to the unborn baby – you must understand that you must not become pregnant and what is required to prevent pregnancy.
Your doctor must discuss contraception (birth control) with you. Your doctor will provide information on how to avoid pregnancy. Your doctor may refer you to a specialist for contraceptive counselling.
Before starting treatment, your doctor will instruct you to have a pregnancy test. The test must confirm that you are not pregnant when starting treatment with Isodifa.

Women must use effective contraception before, during, and after using Isodifa

You must agree to use at least one highly reliable method of contraception (for example, an intrauterine device or contraceptive implant) or two effective methods that work in different ways (for example, hormonal contraceptive pills and a condom). Discuss with your doctor which method may be suitable for you.
- You must use contraception for one month before starting Isodifa, during treatment, and for one month after stopping treatment.
- You must use contraception even if you do not have periods or are not sexually active (unless your doctor tells you it is not necessary).

Women must agree to undergo pregnancy tests before, during, and after using Isodifa

You must agree to regular check-ups, preferably every month.
You must agree to regular pregnancy tests, preferably every month during treatment and, since some medicines may remain in your body, one month after stopping Isodifa (unless your doctor decides this is not necessary in your case).
You must agree to additional pregnancy tests if requested by your doctor.
You must not become pregnant during treatment or within one month after treatment, as some medicines may remain in your body.
- Your doctor will discuss all these points with you, using a checklist, and will ask you (or a relative/guardian) to sign it. This document confirms that the risks have been explained to you and that you agree to follow the above rules. If you become pregnant while taking Isodifa, stop taking this medicine immediately and contact your doctor. Your doctor may refer you to a specialist for consultation. Additionally, if you become pregnant within one month after stopping Isodifa, you must contact your doctor. Your doctor may refer you to a specialist for consultation.

Advice for men
Levels of oral retinoids in the semen of men taking Isodifa are too low to harm their partner's unborn baby. However, you must never share your medicine with anyone.
Additional precautions
Never give this medicine to anyone else. At the end of treatment, return any unused capsules to your pharmacist.
Do not donate blood during treatment with this medicine and for 1 month after stopping Isodifa, as if a pregnant woman were to receive your blood, it could harm the unborn baby.

Other precautions

Isodifa may increase levels of fats such as triglycerides or cholesterol in the blood. Your doctor will perform blood tests to monitor these levels before starting, during, and at the end of treatment with Isodifa. Inform your doctor if you already have high levels of these substances in your blood, or if you have diabetes, are overweight, or suffer from alcoholism, as more frequent blood tests may be needed in these cases.
Isodifa may increase liver enzyme levels. Your doctor will perform blood tests before starting, during, and at the end of treatment with Isodifa to monitor liver function. If liver enzyme levels remain high, your doctor may reduce the dose or stop treatment with Isodifa.
Isodifa may increase blood sugar levels and, in rare cases, diabetes mellitus has been diagnosed. Your doctor will monitor your blood sugar levels during treatment, especially if you have diabetes, are overweight, or suffer from alcoholism.
Use a moisturizing ointment or cream and a lip balm during treatment, as skin and lip dryness may occur during treatment with Isodifa.

Talk to your doctor before taking Isodifa

If you have a history of mental health problems, including depression, aggressive tendencies, or mood changes. This includes thoughts of self-harm or ending your life. Your mood may change while taking Isodifa. You may notice changes in your mood and behaviour, and it is very important that you inform your friends and family that you are taking this medicine. They may notice these changes and help you identify problems that need to be discussed with your doctor.
If you have kidney failure. In this case, treatment should start with a lower dose.
Isodifa may affect night vision. Dry eyes or vision problems may occur during treatment with Isodifa, which usually resolve after treatment ends. Be cautious when driving or operating machinery at night, as these symptoms may appear suddenly. If you wear contact lenses and experience dry eyes, you may need to wear glasses during treatment with Isodifa. If you experience any vision problems, inform your doctor immediately, as treatment with Isodifa may need to be stopped and your vision monitored.
If you have had severe skin reactions (e.g., erythema multiforme (EM), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN)) reported with isotretinoin use. The rash may progress to widespread blistering or skin peeling. Also monitor for mouth, throat, nose, or genital ulcers and conjunctivitis (red, swollen eyes).

Stop treatment and contact your doctor promptly if you experience:

Allergic reaction (redness or skin rash) or a severe anaphylactic reaction.
Persistent headache, nausea, vomiting, and visual disturbances. Isodifa has very rarely been associated with a condition called benign intracranial hypertension.
Haemorrhagic diarrhoea (e.g., blood in stools). Isodifa has very rarely been associated with inflammatory bowel disorders.

What to avoid when taking Isodifa:

Avoid prolonged sun exposure and do not use UV radiation lamps or sunbeds. Your skin may become more sensitive to light during treatment with Isodifa. Before sun exposure, apply a high-protection sunscreen with a minimum SPF of 15.
Avoid cosmetic procedures such as dermabrasion, laser treatments (removal of moles or scars), and waxing during treatment and for at least 6 months after treatment ends. Isodifa may make your skin more fragile, which could lead to scarring or irritation.
Reduce intense physical activity during treatment with Isodifa, as muscle and joint pain have been observed during treatment.
Do not donate blood either during or for one month after stopping treatment with Isodifa. If a pregnant woman were to receive this blood, the child could be born with severe birth defects.

Children and adolescents
Isodifa is not indicated for the treatment of acne in prepubertal children, and use is not recommended in children under 12 years of age.
Other medicines and Isodifa
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Do not take vitamin supplements containing vitamin A or tetracyclines (a type of antibiotic) during treatment with Isodifa, due to an increased risk of adverse effects.
Do not use any other acne treatments during treatment with Isodifa to avoid increased local irritation.
Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
Pregnancy
Isodifa must not be taken during pregnancy. If there is a possibility you could become pregnant, use effective contraception during treatment and for one month after stopping Isodifa.
If you become pregnant or suspect pregnancy during treatment or within one month after treatment with Isodifa, stop treatment immediately and contact your doctor promptly.
If used during pregnancy, Isodifa may harm the unborn baby (medically termed teratogenic). It also increases the risk of miscarriage.
Isodifa may cause severe malformations in the unborn baby’s brain, face, ears, eyes, heart, and certain glands (called the thymus gland and parathyroid glands).
Breastfeeding
Isodifa must not be taken during breastfeeding because it is likely to pass into breast milk and may harm the baby.
For further information on pregnancy and contraception, see section 2 of the "Pregnancy Prevention Programme".
Driving and using machines
Isodifa has a low to moderate influence on the ability to drive or operate machinery.
Night vision may be affected during treatment, and this may occur without warning. In rare cases, this problem may persist after treatment ends. Be cautious when driving or operating machinery.
Somnolence, dizziness, and visual disturbances have been reported very rarely. If you experience these side effects, do not drive, operate machinery, or engage in activities where these symptoms could put you or others at risk.
Isodifa contains

Soybean seed oil. If you are allergic to peanuts or soy, do not use this medicine. This medicine contains 3.5 mg of sorbitol in each 5 mg capsule (15.23 mg of sorbitol in each 30 mg capsule) (5.31 mg of sorbitol in each 10 mg capsule) (15.98 mg of sorbitol in each 20 mg capsule). This medicine contains less than 1 mmol of sodium (23 mg) per capsule, i.e., essentially "sodium-free".
(10 mg and 20 mg:) Isodifa contains the colouring agent Ponceau 4R (E124), which may cause allergic reactions.

3. How to use Isodifa

Always use Isodifa exactly as directed by your doctor. If in doubt, consult your doctor or pharmacist.

The capsules should be taken with food once or twice daily.
Swallow the capsules whole; do not chew or suck them.

Occasionally, acne may worsen during the first weeks of treatment, but it should improve with continued use.
Dosage
Your doctor will prescribe an individual dose based on body weight and other clinical parameters such as renal impairment, etc.
Specific individual doses may be optimized by combining the different available strengths (capsules of 10 mg, 20 mg, or 30 mg).
Adults including adolescents and elderly
The usual starting dose is 0.5 mg per kg of body weight per day (0.5 mg/kg/day).
After several weeks, your doctor may adjust the dose depending on your response to treatment. For most patients, the dose ranges between 0.5 and 1.0 mg/kg/day.
If you feel that the effect of Isodifa is too strong or too weak, inform your doctor or pharmacist.
Patients with severe renal impairment
If you suffer from severe renal impairment, treatment with Isodifa should be initiated at a reduced dose, e.g., 10 mg/day, and then gradually increased up to the maximum tolerated dose.
Children under 12 years of age
Isodifa is not indicated in children under 12 years of age.
Patients with intolerance
If you do not tolerate the recommended dose, your doctor may decide to continue treatment at a reduced dose. In such cases, treatment duration will be longer and the risk of relapse higher.
Duration of treatment
A treatment cycle usually lasts from 16 to 24 weeks.
Acne may continue to improve for up to 8 weeks after the end of treatment.
Therefore, a new treatment cycle should not be started until at least this period has passed. Most patients require only a single course of treatment.
Remember that this medicine has been prescribed for you!
Only a doctor can prescribe it. Do not give this medicine to others. This medicine could be dangerous for other individuals, even if their symptoms are similar to yours.
If you take more Isodifa than you should
The following symptoms may occur: severe headache, nausea or vomiting, drowsiness, irritability, and flushing.
If you take too many capsules or if someone else accidentally takes this medicine, contact your doctor or pharmacist immediately or go to the nearest hospital.
If you forget to take Isodifa
If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and continue with your regular schedule. Do not take a double dose to make up for the missed one.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although
not everyone will experience them.
Side effects requiring immediate medical attention:
Stop taking the capsules and contact your doctor IMMEDIATELY if you experience any of
the following side effects:
Rare (may affect up to 1 in 1,000 people):

Severe (anaphylactic) reactions: difficulty breathing or swallowing due to sudden swelling of the throat, face, lips, and mouth. Sudden swelling of the hands, feet, and ankles may also occur.

Very rare (may affect up to 1 in 10,000 people):

Sudden feeling of tightness in the chest, shortness of breath, and labored breathing, especially if you have asthma.
Yellowing of the skin or eyes and fatigue. These may be signs of hepatitis.
Difficulty urinating, swollen eyelids, excessive tiredness. These may be signs of kidney inflammation.
Persistent headache, with malaise (nausea), malaise (vomiting), and changes in vision, including blurred vision. These may be signs of benign intracranial hypertension, especially if Isodifa is taken together with antibiotics known as tetracyclines.
Severe abdominal pain (stomach), with or without severe bloody diarrhea, feeling unwell (nausea), and malaise (vomiting). These may be signs of serious intestinal conditions.
Muscle weakness that may potentially be life-threatening, possibly associated with problems moving arms or legs, pain, swelling, bruising of body parts, dark urine, reduced or absent urine output, confusion, or dehydration. These are signs of rhabdomyolysis, a breakdown of muscle tissue that may lead to kidney failure. This may occur if you are engaging in intense physical activity during treatment with Isodifa.

Not known (frequency cannot be estimated from available data):

Severe skin rashes (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), potentially life-threatening and requiring immediate medical attention. These initially appear as circular areas, often with central blisters, typically on arms and hands or legs and feet; more severe rashes may include blisters on the chest and back. Additional symptoms may include eye infection (conjunctivitis) or mouth, throat, or nose ulcers. Severe forms of rash may progress to widespread skin peeling, which can be life-threatening. These serious skin reactions are often preceded by headache, fever, and body aches (flu-like symptoms).

Mental health problems
Rare (may affect up to 1 in 1,000 people):

Depression or related disorders. Symptoms include sadness or mood changes, anxiety, and feelings of emotional discomfort.
Worsening of pre-existing depression.
Aggression or violent behavior.

Very rare (may affect up to 1 in 10,000 people):

Some people have had thoughts or intentions of harming themselves or ending their life (suicidal ideation), have attempted suicide, or died by suicide. These individuals may not appear depressed.
Unusual behavior.
Signs of psychosis: loss of contact with reality, such as hearing voices or seeing things that are not there.

Contact your doctor immediately if you experience symptoms of any of these
mental health problems. Your doctor may tell you to stop taking Isodifa. This may not
be sufficient to stop the effects: you may need further help, and your doctor can ensure
this is provided.
Some of the side effects associated with isotretinoin use are dose-related. Side effects
are generally reversible after dose reduction or discontinuation of treatment; however,
some may persist after treatment is stopped.
Other side effects:
Very common (may affect more than 1 in 10 people):

Dry skin, particularly of the lips and face; inflamed skin, chapped and inflamed lips, rash, mild itching, and mild skin peeling. Use a moisturizing cream from the start of treatment.
Skin becomes more fragile and redder than usual, especially on the face.
Back pain; muscle pain; joint pain, particularly in children and adolescents. To avoid worsening bone or muscle problems, reduce intense physical activity during treatment with Isodifa.
Inflammation of the eye (conjunctivitis) and eyelid area; eyes feel dry and irritated. Ask your pharmacist for suitable eye drops. If you experience dry eyes and wear contact lenses, you may need to wear glasses instead.
Increased liver enzymes in the blood.
Changes in blood fat levels (including HDL or triglycerides).
Increased risk of bleeding, bruising, or clotting – if clotting cells are affected.
Anemia – weakness, dizziness, pale skin – if red blood cells are affected.

Common (may affect up to 1 in 10 people):

Headache.
Higher levels of cholesterol in the blood.
Blood tests show increased blood sugar levels.
Protein or blood in the urine.
Increased susceptibility to infections if white blood cells are affected.
Dryness and crusting inside the nose, causing mild discomfort.
Inflamed throat and nose.

Rare (may affect up to 1 in 1,000 people):

Hair loss (alopecia). This is usually temporary. Hair should regrow after treatment ends.
Allergic reactions such as rash and itching. If you experience allergic reactions, stop taking Isodifa and contact your doctor.

Very rare (may affect up to 1 in 10,000 people):

Reduced night vision; changes in color vision.
Increased sensitivity to light; you may need to wear sunglasses to protect your eyes from strong sunlight.
Other vision problems, including blurred vision, distorted vision, cloudy surface of the eye (corneal opacity, cataract).
Excessive thirst; frequent need to urinate. These may be signs of diabetes.
Acne may worsen during the first weeks, but symptoms should improve over time.
Skin inflammation, swelling, and darker-than-usual skin, especially on the face.
Excessive sweating or itching.
Arthritis; bone disorders (delayed growth, extra bone growth, and changes in bone density); growing bones may stop growing.
Calcium deposits in soft tissues, painful tendons, elevated levels of muscle metabolism products in the blood in case of excessive physical exertion.
Increased sensitivity to light.
Bacterial infections at the base of the nails, nail changes.
Swelling, rashes, pus.
Thick scarring after surgical procedures.
Increased body hair.
Seizures, drowsiness, dizziness.
Lymph glands may become swollen.
Dry throat, hoarseness.
Hearing difficulties.
General feeling of malaise.
High levels of uric acid in the blood.
Bacterial infections.
Inflammation of blood vessels (sometimes with bruising, red spots).

Unknown frequency: (frequency cannot be estimated from available data)

Dark urine
Problems achieving or maintaining an erection
Decreased libido
Breast enlargement with or without tenderness in men
Vaginal dryness

Soybean oil may very rarely cause allergic reactions.
(10 mg and 20 mg: ) Ponceau 4R (124) may cause allergic reactions.
Reporting of side effects
If you experience any side effect, including those not listed in this
leaflet, talk to your doctor or pharmacist. You may also report side effects
directly via the national reporting system at
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.

5. How to store Isodifa

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and blister after EXP. The expiry date refers to the last day of the month.
Do not store above 30°C. Store in the original packaging to protect the medicine from light.
Return any unused Isodifa to your pharmacist at the end of treatment. Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Isodifa contains

The active substance is isotretinoin. Each capsule contains 5 mg of isotretinoin. Each capsule contains 10 mg of isotretinoin. Each capsule contains 20 mg of isotretinoin. Each capsule contains 30 mg of isotretinoin.
Other ingredients are:
Capsules 5 mg:
Capsule contents: yellow beeswax, refined soybean seed oil, partially hydrogenated soybean seed oil, hydrogenated vegetable oil, DL-alpha-tocopherol, disodium edetate, butylated hydroxyanisole
Capsule shell: gelatin, glycerol, non-crystalline liquid sorbitol (E420), titanium dioxide (E171)
Capsules 10 mg:
Capsule contents: yellow beeswax, refined soybean seed oil, partially hydrogenated soybean seed oil, hydrogenated vegetable oil, DL-alpha-tocopherol, disodium edetate, butylated hydroxyanisole
Capsule shell: gelatin, glycerol, non-crystalline liquid sorbitol (E 420),
titanium dioxide (E 171), ponceau 4R (E 124) and black iron oxide (E 172)
Capsules 20 mg:
Capsule contents: yellow beeswax, refined soybean seed oil, partially hydrogenated soybean seed oil, hydrogenated vegetable oil, DL-alpha-tocopherol, disodium edetate, butylated hydroxyanisole
Capsule shell: gelatin, glycerol, non-crystalline liquid sorbitol (E 420),
titanium dioxide (E 171), indigo carmine (E 132) and ponceau 4R (E 124)
Capsules 30 mg:
Capsule contents: yellow beeswax, refined soybean seed oil, hydrogenated soybean seed oil, hydrogenated vegetable oil, DL-alpha-tocopherol, disodium edetate, butylated hydroxyanisole
Capsule shell: gelatin, glycerol, non-crystalline liquid sorbitol (E 420),
titanium dioxide (E 171) and red iron oxide (E172)

Description of the appearance of Isodifa and package contents
Isodifa 5 mg capsules are soft gelatin capsules, oval-shaped, light pink/cream in colour, 8 mm x 5 mm, containing a viscous, opaque yellow/orange liquid.
Isodifa 10 mg capsules are soft gelatin capsules, oval-shaped, pale violet in colour, 10 mm x 7 mm, containing a viscous, opaque yellow/orange liquid.
Isodifa 20 mg capsules are soft gelatin capsules, oval-shaped, brown in colour, 13 mm x 8 mm, containing a viscous, opaque yellow/orange liquid.
Isodifa 30 mg capsules are soft gelatin capsules, oval-shaped, pink in colour, 11 mm x 7 mm, containing a viscous, opaque yellow/orange liquid.
Pack sizes of 20, 30, 50, 60 or 100 soft capsules.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Difa Cooper S.p.A.
Via Milano 160
21042 Caronno Pertusella (Varese)
Italy

Manufacturers

TOLL MANUFACTURING SERVICES, S.L., Aragoneses 2, 28108, Alcobendas, Madrid, España.
Industrial Farmacéutica Cantabria, S.A. C/ Pirita, 9 28850 Torrejón de Ardoz (Madrid) Spain

This medicinal product is authorized in the following EEA Member States with the
following names:
Denmark: Isotretinoin Difa
Italy: Isodifa
This patient information leaflet was last approved:
Detailed and up-to-date information on this medicinal product is available at the following URL: https://www.aifa.gov.it/hu/trova-farmaco