Package leaflet: Information for the user

Isotretinoina difa 40 mg Soft Capsules

Isotretinoina
WARNING
CAN CAUSE SEVERE HARM TO THE UNBORN CHILD
Women must use effective contraceptive methods
Do not use if you are or think you may be pregnant
This medicine is under additional monitoring. This will allow rapid 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.
Read this leaflet carefully before taking this medicine

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 personally. Never give it to others. It may be harmful to other people, even if their symptoms are the same as yours.
If any of the side effects worsen, or if you notice any side effect not listed in this leaflet, inform your doctor or pharmacist.

Contents of this leaflet:

What Isotretinoina difa is and what it is used for
What you need to know before taking Isotretinoina difa
How to take Isotretinoina difa
Possible side effects
How to store Isotretinoina difa
Further information

1. What Isotretinoina difa is and what it is used for

Isotretinoina difa contains the active substance isotretinoin, a derivative of Vitamin A, belonging to the class of retinoids.
Isotretinoina difa is used for the treatment of severe forms of acne (such as nodular acne, conglobate acne, or acne with risk of permanent scarring) that are resistant to appropriate standard therapies with oral antibiotics and topical treatment.

2. What you need to know before using Isotretinoina difa

Isotretinoina must be prescribed and monitored by a dermatologist (a doctor
specialized in treating skin conditions), who is aware of the risks associated with
treatment with isotretinoin and the need for monitoring.
Your doctor will inform you about the precautions to follow when taking Isotretinoina
difa. In addition, your doctor will provide you with an informational guide.
If these guides have not been provided or if the precautionary measures have not
been explained or fully understood, speak with your doctor before starting treatment
with Isotretinoina difa.

Do not use Isotretinoina difa

If you are pregnant or breastfeeding
If there is any possibility that you could become pregnant, you must follow the precautions outlined in the “Pregnancy Prevention Programme” described in the “Warnings and precautions” section.
If you have hypersensitivity (allergy) to isotretinoin, soya, peanuts, or any of the excipients
If you have liver disease
If you have excessively high levels of lipids in the blood (cholesterol, triglycerides)
If you have excessively high levels of vitamin A in the body (hypervitaminosis A)
If you are taking tetracyclines (antibiotics)

Warnings and precautions
Pregnancy Prevention Programme
Pregnant women must not use Isotretinoina difa
This medicine can severely harm the unborn baby (it is said to be “teratogenic”) – it
can cause birth defects affecting the brain, face, ears, eyes, heart, and certain glands
(thymus and parathyroid glands). It may also increase the risk of spontaneous
abortion. This can occur even if Isotretinoina difa is used for only a short time during
pregnancy.

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

For women who could become pregnant, Isotretinoina difa is prescribed under
very strict rules due to the risk of serious 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 give you 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 take a pregnancy test. The test must confirm that you are not pregnant when starting treatment with Isotretinoina difa.

Women must use effective contraception before, during, and after taking
Isotretinoina difa

You must agree to use at least one highly reliable contraceptive method (e.g. an intrauterine device or contraceptive implant) or two effective methods that work in different ways (e.g. hormonal oral contraceptive and a condom). Discuss with your doctor which method may be suitable for you.
- You must use contraception for one month before starting Isotretinoina difa, 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
taking Isotretinoina difa

You must agree to attend regular follow-up visits, preferably every month.
You must agree to undergo regular pregnancy tests, preferably every month during treatment and, since some medicines may remain in your body, one month after stopping Isotretinoina difa (unless your doctor decides otherwise in your case).
You must agree to take additional pregnancy tests if requested by your doctor.
You must not become pregnant during treatment or within one month after stopping 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 rules outlined above. If you become pregnant while taking Isotretinoina difa, 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 Isotretinoina difa, 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 Isotretinoina difa are too low to harm their partner’s unborn baby. However, you must never share your medicine with anyone else.
Additional precautions
Never give this medicine to anyone else. At the end of treatment, return any unused capsules to the pharmacist.
Do not donate blood during treatment with this medicine and for 1 month after stopping Isotretinoina difa, as if a pregnant woman were to receive your blood, it could harm the unborn baby.

Other precautions

Isotretinoina difa may increase levels of fats such as triglycerides or cholesterol in the blood. Your doctor will perform blood tests to monitor these values before starting, during, and at the end of treatment with Isotretinoina difa. 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.
Isotretinoina difa may increase liver enzyme levels. Your doctor will perform blood tests before starting, during, and at the end of treatment with Isotretinoina difa to monitor liver function. If liver enzyme levels remain high, your doctor may reduce the dose or discontinue treatment with Isotretinoina difa.
Isotretinoina difa may increase blood sugar levels and, in rare cases, diabetes mellitus has been diagnosed. Your doctor will monitor 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 Isotretinoina difa.

Talk to your doctor before taking Isotretinoina difa

If you have a history of mental health problems, including depression, aggressive tendencies, or mood changes. This includes thoughts of self-harm or suicide. This is because your mood may change while taking Isotretinoina difa. Mental health problems: 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 promptly.
If you have kidney impairment. In this case, treatment should start with a lower dose.
Isotretinoina difa may affect night vision. Dry eyes or vision problems may occur during treatment with Isotretinoina difa, 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 Isotretinoina difa. If you experience any vision problems, inform your doctor immediately, as treatment with Isotretinoina difa may need to be suspended and your vision monitored.

Patients must immediately stop treatment and promptly consult their doctor if they experience any of the following symptoms:

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

What to avoid when taking Isotretinoina difa:

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

Taking other medicines
Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those obtained without a prescription. Do not take vitamin preparations containing vitamin A or tetracyclines (a type of antibiotic) during treatment with Isotretinoina difa, due to an increased risk of adverse effects. Do not use any other acne treatments during treatment with Isotretinoina difa to avoid increased local irritation.

Pregnancy and breastfeeding
Pregnancy

Isotretinoina difa must not be taken during pregnancy, as isotretinoin,
the active ingredient in Isotretinoina difa, is highly teratogenic. Even if
precautions are taken (Pregnancy Prevention Programme), if pregnancy
occurs during treatment or within one month afterwards, there is a high
risk of severe and serious fetal malformations.
Fetal malformations associated with isotretinoin treatment include
central nervous system abnormalities (hydrocephalus, cerebellar malformations/anomalies, microcephaly), facial dysmorphism, cleft palate, external ear abnormalities (absent external ear, small or absent external auditory canals), ocular abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of the great vessels, septal defects), and thymus and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortions.
If pregnancy occurs during treatment with isotretinoin, treatment must
be stopped immediately and the patient must be referred to a
specialist doctor.
Breastfeeding
Isotretinoina difa must not be taken during breastfeeding, as isotretinoin
is likely to pass into breast milk and may harm the infant.
For further information on pregnancy and contraception, see section 2 of the
“Pregnancy Prevention Programme”.

Driving and using machines
Isotretinoina difa has a moderate effect on the ability to drive or use machines.
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.
Confusion and visual disturbances have been reported very rarely. Patients should be warned that if they experience these side effects, they must not drive, operate machinery, or participate in activities where these symptoms could put themselves or others at risk.

Important information about some ingredients of Isotretinoina difa
Isotretinoina difa contains soya oil. If you are allergic to peanuts or soya, do not use this medicine.
Isotretinoina difa contains sorbitol. If your doctor has diagnosed you with an intolerance to certain sugars, contact your doctor before taking this medicine.
Isotretinoina difa contains the colour sunset yellow (E110), which may cause allergic reactions.

3. How to use Isotretinoina difa

Always use Isotretinoina difa 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 therapy.
Dosage
Your doctor will prescribe an individual dose based on body weight and other
clinical parameters such as renal impairment, etc.
Adults, including adolescents and elderly patients
The usual starting dose is 0.5 mg per kg of body weight per day (0.5
mg/kg/day). After a few weeks, your doctor may adjust the dose. This
depends on the response to treatment and the occurrence of adverse effects. For most
patients, the dose ranges between 0.5 and 1.0 mg/kg per day.
If you feel that the effect of Isotretinoina difa is too strong or too weak,
inform your doctor or pharmacist.
Patients with severe renal impairment
In patients with severe renal impairment, treatment with Isotretinoina difa should
be initiated at a reduced dose, for example 10 mg/day. The dose should then be
increased up to the maximum dose tolerated by the patient.
Children
Isotretinoin is not indicated in children due to insufficient safety data.
Patients with intolerance
In patients who 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 there may be a higher risk of relapse.
If the recommended dose cannot be achieved with 40 mg capsules,
another isotretinoin-containing formulation should be selected.
Duration of treatment
A treatment cycle usually lasts 16–24 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 before at least this period has
elapsed. Most patients require only a single treatment cycle.
Remember that this medicine has been prescribed for you!
Only a doctor can prescribe it. Do not give this medicine to others, as it may be
dangerous for other individuals, even if their symptoms are similar to yours.
If you use more Isotretinoina difa 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 Isotretinoina difa
If you miss a dose, take it as soon as possible. If it is almost time for the next dose,
skip the missed dose and continue with your regular dosing schedule. Do not take a
double dose to make up for the missed dose.
If you have any doubts about how to use this medicine, consult your doctor or
pharmacist.

4. Possible side effects

Like all medicines, Isotretinoina difa can cause side effects,
although not everyone will experience them.
Some of the side effects associated with isotretinoin use are dose-dependent.
Side effects are generally reversible after dose reduction or discontinuation of
treatment, although some may persist after stopping therapy.
The following frequency data form the basis for assessing side effects:
Very common: may occur in more than 1 in 10 people
Common: may occur in up to 1 in 10 people
Uncommon: may occur in up to 1 in 100 people
Rare: may occur in up to 1 in 1,000 people
Very rare: may occur in up to 1 in 10,000 people
Not known: frequency cannot be estimated from the available data

The following symptoms are the most commonly reported side effects of isotretinoin:
dry skin, dryness of mucous membranes such as lips, nasal mucosa, and eyes.

Other side effects may also occur.

Diagnostic examinations
Very common: Increased blood levels of fats (triglycerides), decreased HDL cholesterol (high-density lipoproteins)
Common: Increased blood cholesterol, increased blood sugar (glycaemia), blood in urine, protein excretion in urine
Very rare: Increased blood levels of creatine phosphokinase

Blood and lymphatic system disorders
Very common: Anaemia (reduced red blood cells), increased erythrocyte sedimentation rate, increased or decreased platelet count
Common: Decreased neutrophil leucocytes (a type of white blood cell)
Very rare: Lymph node disease (lymphadenopathy)

Nervous system disorders
Common: Headache
Very rare: Benign intracranial hypertension, seizures, confusion

Eye disorders
Very common: Inflammation of the periocular area, eye inflammation, dry eyes, eye irritation
Very rare: Night blindness, clouding of the eye lens (cataract), colour blindness (colour vision deficiency), intolerance to contact lenses, corneal opacity, reduced night vision, keratitis, optic disc swelling (papilledema, as a sign of benign intracranial hypertension), light sensitivity, visual disturbances

Ear and labyrinth disorders
Very rare: Hearing loss

Respiratory, thoracic and mediastinal disorders
Common: Nosebleeds, dry nose, inflammation of nasal mucosa, particularly pharyngeal mucosa
Very rare: Airway constriction (bronchospasm), especially in asthmatic patients, hoarseness

Gastrointestinal disorders
Very rare: Inflammation of the colon and intestinal mucosa, dry throat, gastrointestinal bleeding, haemorrhagic diarrhoea, inflammatory bowel disease, nausea, pancreatitis (see section 2. Before taking Isotretinoina difa)

Renal and urinary disorders
Very rare: Kidney inflammation
Frequency not known: Dark urine

Skin and subcutaneous tissue disorders
Very common: Chapped lips (cheilitis), skin inflammation, dry skin, localized peeling, itching, red rash, skin fragility (risk of friction injuries)
Rare: Hair loss
Very rare: Severe acne (acne fulminans), worsening of acne (acne exacerbation), skin redness, particularly on the face, skin rash, hair disorders, increased body hair growth, nail changes, infection of tissue around the nail base, light sensitivity, pus-forming eruptions (pyogenic granuloma), increased skin pigmentation, increased sweating

Skin and hair disorders
Frequency not known:
Severe skin rashes (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), which may be life-threatening and require immediate medical attention. These symptoms initially appear as circular spots, often with central blisters, usually on arms and hands or legs and feet; more severe rashes may include blisters on the chest and neck. Additional symptoms may include eye infections (conjunctivitis) or ulcers in the mouth, throat, or nose. Severe forms of rash may progress to widespread skin peeling, which can be fatal. These are often preceded by headache, fever, muscle pain (influenza-like symptoms).
If you develop a rash or these skin symptoms, stop treatment with Isotretinoina difa and contact your doctor immediately.

Musculoskeletal and connective tissue disorders
Very common: Joint pain, muscle pain, back pain (particularly in children and adolescent patients)
Very rare: Joint inflammation, calcification of soft tissues (ligaments and tendons), premature fusion of growing bones, excessive bone tissue formation (exostosis/ hyperostosis), reduced bone density, tendonitis, muscle breakdown (rhabdomyolysis)

Metabolism and nutrition disorders
Very rare: Increased blood sugar levels (diabetes mellitus), increased blood uric acid levels

Infections
Very rare: Bacterial infections of the skin and mucous membranes

Vascular disorders
Very rare: Inflammation of blood vessels (e.g. Wegener's granulomatosis, allergic vasculitis)

General disorders and administration site conditions
Very rare: Increased tissue formation that may lead to excessive scarring (hypertrophic scarring) after surgical procedures, malaise

Immune system disorders
Rare: Allergic skin reaction, severe allergic reactions that may lead to shock (anaphylactic reactions), hypersensitivity

Hepatobiliary disorders
Very common: Increased liver enzyme levels (see section 2. Before taking Isotretinoina difa)
Very rare: Liver inflammation

Psychiatric disorders
Rare: Depression or related disorders. Symptoms include sadness or mood changes, anxiety, feelings of emotional distress. Worsening of pre-existing depression. Becoming violent or aggressive.
Very rare:
• Some people have had thoughts or intentions of harming themselves or ending their life (suicidal ideation), attempted suicide, or died by suicide. These individuals may not appear depressed.
• Unusual behaviour
• 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 advise you to stop taking Isotretinoina difa. This may not be sufficient to stop the effects: you may need further help, and your doctor can ensure this is provided.

Reproductive system disorders
Frequency not known: Problems achieving or maintaining erection, decreased libido

Soybean oil may very rarely 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 can also report side effects directly via the national reporting system at 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 Isotretinoin difa

KEEP THE MEDICINAL PRODUCT OUT OF SIGHT AND REACH OF
CHILDREN.
Do not use Isotretinoin difa after the expiry date stated on the outer carton and blister pack. The expiry date refers to the last day of the month.
Do not store above 25°C. Keep in the original packaging to protect the medicinal product from moisture and light.
IMPORTANT! Return unused capsules to the pharmacist at the end of treatment. Store only if instructed by the doctor.
Medicines must be disposed of through appropriate containers in order to protect the environment.

6. Other information

What Isotretinoina difa contains
The active substance is isotretinoina.
Each capsule contains 40 mg of isotretinoina.
The other ingredients are:
Capsule contents:
yellow wax, refined soybean seed oil, hydrogenated soybean seed oil, partially hydrogenated soybean seed oil, DL-alpha-tocopherol, disodium edetate, butylated hydroxyanisole.
Capsule shell:
gelatin, glycerol, non-crystalline liquid sorbitol (E420), sunset yellow (E110), titanium dioxide (E171).

Description of the appearance of Isotretinoina difa and contents of the pack:
The soft gelatin capsules are light orange, oval-shaped, and contain an opaque yellow/orange viscous liquid.
The capsules are packed in blisters of 15, 20, 30, 50 and 60 capsules.
Not all pack sizes may be marketed.

MARKETING AUTHORISATION HOLDER
Difa Cooper S.p.A.
Via Milano 160
21042 Caronno Pertusella (Varese)

MANUFACTURER
TOLL MANUFACTURING SERVICES SL
CALLE DE LOS ARAGONESES (P I ALCOBENDAS) 2
28108 ALCOBENDAS (MADRID) SPAIN

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Detailed and updated information on this medicinal product is available at the following URL: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home

Isotretinoin Difa