Isotretinoin 10mg capsules

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Isotretinoin
Available from:
DE Pharmaceuticals
ATC code:
D10BA01
INN (International Name):
Isotretinoin
Dosage:
10mg
Pharmaceutical form:
Capsule
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF:
Authorization number:
; PL 14894/0161

Isotretinoin 10/20 mg Capsules (PIL)

UK

180 x 580 mm (Folded size: 180 x 35 mm)

0000000 5179440

00000

26.07.2018/ 15.03.2019/ 18.03.2019/ 22.03.2019

Ref.

Blue

It is very common to experience dryness of the skin, especially

of the lips and face. You may get an inflamed skin (dermatitis),

chapped and inflamed lips (cheilitis), a rash, some mild itching

and slight peeling. This dryness can be relieved by the regular

use of a good moisturising cream from the start of treatment.

If you develop a rash or these skin symptoms, stop taking

isotretinoin and contact your doctor immediately.

Serious skin rashes (erythema multiforme, Stevens-Johnson

syndrome, and toxic epidermal necrolysis), which are

potentially life-threatening and require immediate medical

attention. These appear initially as circular patches often with

central blisters usually on arms and hands or legs and feet,

more severe rashes may include blistering of the chest and

back. Additional symptoms such as infection of the eye

(conjunctivitis) or ulcers of the mouth, throat or nose may

occur. Severe forms of rash may progress to widespread

peeling of the skin which can be life threatening. These serious

skin rashes are often preceded by headache, fever, body aches

(flu-like symptoms). These side effects have been reported with

unknown frequency.

Skin problems

Contact your doctor straight away if you get signs of any of

these mental problems. Your doctor may tell you to stop taking

Isotretinoin Capsules. That may not be enough to stop the

effects: you may need more help and your doctor can arrange

this.

As mental problems can be caused by many different factors, it

is important to tell your doctor if you have ever had any mental

illness including depression, suicidal behaviour or psychosis

(psychosis means a loss of contact with reality, such as hearing

voices or seeing things that are not there). Also tell your doctor

if you take medicines for any of these conditions.

Signs of psychosis: a loss of contact with reality, such as

hearing voices or seeing things that are not there.

Unusual behaviour.

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

Some people have had thoughts or feelings about hurting

themselves or ending their own lives (suicidal thoughts), have

tried to end their own lives (attempted suicide), or have ended

their lives (suicide). These people may not appear to be

depressed.

It is common for the inside of your nose to become dry or

bleed; throat and nose to get sore or inflamed and very rarely,

Nose and throat

In very rare cases patients may not be able to hear as well as

they used to.

Ear disorders

In very rare cases, patients have experienced other sight

problems (vision disturbances), such as blurred vision, corneal

opacities and cataracts (clouding of the surface of the eye). If

your sight is affected at all by this medicine tell your doctor as

soon as possible.

Sensitivity to light may increase and you may find that you need

to wear sunglasses to protect your eyes from too bright

sunlight.

Isotretinoin can cause colour blindness and some patients are

less able to distinguish colours.

Very rarely, your night vision may be affected by this medicine

making it harder to see at night.

Inflammation of the eye (conjunctivitis) and eyelid area

(blepharitis) is very common. It is very common for your eyes

to feel dry and slightly irritated. Ask your pharmacist to suggest

some suitable eye drops to help. Very rarely, contact lens

wearers may have to wear glasses for the duration of treatment

due to dryness of the eyes.

Eye disorders

Headache is a common side effect associated with isotretinoin

treatment. Convulsions, dizziness and drowsiness have been

reported very rarely.

Very rarely benign intracranial hypertension has been reported,

particularly when isotretinoin is taken together with some

antibiotics (tetracyclines). If you experience a persistent

headache with nausea, vomiting and blurred vision, this may

mean that you have developed a benign intracranial

hypertension. Stop taking Isotretinoin Capsules as soon as

possible and contact your doctor.

Neurological disorders

It is very common for patients to develop blood disorders,

which affect different cells in the blood. The cells involved in

clotting may be affected, which means you may bruise or bleed

more easily. If the red blood cells are affected you may develop

anaemia. If the white cells in the blood, which fight infection, are

affected you may become more susceptible to infection. Your

blood will be regularly monitored throughout your treatment.

Very rarely your lymph glands may become swollen.

Blood disorders

If you have any allergic reaction, stop taking isotretinoin and

contact your doctor.

If you have a serious reaction, get emergency medical help

immediately.

Rarely allergic reactions such as skin rashes and itchiness have

been reported in patients receiving isotretinoin. Serious

reactions (anaphylactic reactions) may be associated with a

tightness in your chest and difficulty breathing. If you experience

an allergic reaction stop taking Isotretinoin Capsules and

contact your doctor.

Allergic reactions

You may very rarely experience local bacterial infections of the

tissue around the base of the nail, swellings discharging pus,

changes in the nails, thickened scarring after surgical

interventions and increased levels of body hair.

Occasionally your acne may get worse during the first weeks of

treatment. Your skin can in very rare cases appear inflamed and

swollen, with increased facial pigmentation. However, your acne

and other symptoms should improve with continued treatment.

Very rarely, you may experience excess sweating, itching or

develop increased sensitivity to light.

It is very common for your skin to become more fragile and

redder than usual, particularly on the face.

Rare effects (may affect up to 1 in every 1000 people)

Mental problems

Some of the side effects associated with the use of isotretinoin

are related to the dose. The side effects are generally reversible

after changing the dose or stopping treatment, however some

may continue after treatment has stopped.

Like all medicines, this medicine can cause side effects,

although not everybody gets them. These effects often wear off

as your treatment continues or after treatment has stopped.

Your doctor can help you to deal with them.

4. Possible side effects

If you have any further questions on the use of this medicine,

ask your doctor or pharmacist.

If you stop taking the medicine your symptoms may return. You

should check with your doctor or pharmacist if you are not sure.

If you stop taking Isotretinoin Capsules

If you miss a dose, take it as soon as possible. However if it is

nearly time for your next dose, skip the missed dose and carry

on as before. Do not take a double dose to make up for a

forgotten dose.

If you forget to take Isotretinoin Capsules:

If you take more Isotretinoin Capsules than you should:

If you take too many capsules or someone else accidentally

takes your medicine, contact your doctor, pharmacist or nearest

hospital immediately.

Please return any unused capsules to your pharmacist at the

end of treatment. Only keep it if your doctor tells you to.

Remember this medicine is for you. Only a doctor can prescribe

it for you. Never give it to others. It may harm them even if their

symptoms look similar to yours.

A course of treatment usually lasts for 16 to 24 weeks. Your

acne may continue to improve for up to 8 weeks after the

treatment finishes. Therefore, a further course of treatment

should not be started until at least this period has elapsed. Most

patients only need a single course of treatment.

Depression or related disorders. Signs of this include sad or

altered mood, anxiety, feelings of emotional discomfort.

Existing depression getting worse.

Becoming violent or aggressive.

5th floor, Hyde Park, Hayes 3

Ranbaxy (UK) Limited

Marketing Authorization Holder:

Not all pack sizes may be marketed.

Isotretinoin 20 mg Capsules are available as blister strips in

pack sizes of 30, 50, 56, 60 and 100 capsules.

Isotretinoin 10 mg Capsules are available as blister strips in

pack sizes of 30, 50, 56 and 60 capsules.

Isotretinoin 20 mg Capsules are oval-shaped, maroon coloured

soft capsules and contain 20 mg of isotretinoin as the active

ingredient.

Isotretinoin 10 mg Capsules are oval shaped, light pink coloured

soft capsules and contain 10 mg of isotretinoin as the active

ingredient.

The capsule shell contains gelatin, glycerol, titanium dioxide

(E171), methyl parahydroxybenzoate and propyl

parahydroxybenzoate. The colourant that has been used in

the capsules is either ferric oxide red (E172) for the 10 mg

capsules or FD&C Red No 3, FD&C Blue No 1 and Brilliant

Blue FCF (E133) for the 20 mg capsules. The (Opacode S-1-

17823 Black) printing ink contains shellac glaze, ferric oxide

black (E172) and propylene glycol.

What Isotretinoin Capsules look like and contents of the pack

The other ingredients are soyabean oil hydrogenated,

hydrogenated vegetable oil (Type II USNF), beeswaxwhite,

disodium edetate, butyl hydroxyanisole, soyabean oil refined

and polysorbate 80.

The active substance is isotretinoin

Terapia S.A.

124 Fabricii Street

What Isotretinoin Capsules contain

6. Contents of the pack and other information

400632 Cluj-Napoca

Romania

This leaflet was last revised in March 2019.

Detailed and updated information on this product is available by

scanning the QR code included in the PL with a smartphone.

The same information is also available on the following URL:

http://www.sunpharma.com/united-kingdom/products and

www.mhra.gov.uk.

2132 JH Hoofddorp

The Netherlands

Polarisavenue 87

Sun Pharmaceutical Industries Europe B.V.

Manufacturer:

United Kingdom

Hayes, UB3 4AZ

11 Millington Road

Do not throw away any medicines via wastewater or household

waste. Ask your pharmacist how to throw away medicines you

no longer use. These measures will help protect the

environment.

Do not store above 25C. Store in the original package. Keep the

container in the outer carton in order to protect from light and

moisture

Do not use this medicine after the expiry date which is stated on

the carton and blister after EXP. The expiry date refers to the last

day of that month.

Keep this medicine out of the sight and reach of children.

5. How to store Isotretinoin Capsules

If you get any side effects, talk to your doctor, pharmacist or

nurse. This includes any possible side effects not listed in this

leaflet. You can also report side effects directly via the Yellow

Card Scheme at: www.mhra.gov.uk/yellowcard or search for

MHRA Yellow Card in the Google Play or Apple App Store. By

reporting side effects you can help provide more information on

the safety of this medicine.

Reporting of side effects

If any of the side effects get serious or if you notice any side

effects not listed in this leaflet, please tell you doctor or

pharmacist.

Breast swelling with or without tenderness in males

Lower libido

Problems getting or maintaining an erection

Dark or cola-coloured urine

Unknown frequency: (frequency cannot be estimated from the

available data)

Very rare effects include generally feeling unwell, high levels of

uric acid in the blood, bacterial infections and inflammation of

the blood vessels (sometimes with bruising, red patches).

Common reported side effects are higher levels of cholesterol in

the blood, protein or blood in the urine.

Very commonly changed levels of fats in the blood (including

HDL or triglycerides) have been reported.

Other adverse reactions

In addition, on some very rare occasions, it has been reported

that you may develop arthritis, muscle weakness, bone

disorders (including delayed growth, exostoses and changes to

bone density), calcifications in soft tissues, occasional

soreness of the tendons and an abnormal level of muscle

degradation products in your blood if you exercise vigorously

while taking your medication. Bones that have not finished their

normal growth may stop growing prematurely.

Back pain, muscle pain and pain of the joints have been very

commonly reported during isotretinoin treatment (particularly in

children and teenagers).

To avoid making any bone or muscle problems worse, care

should be taken to reduce intensive physical activity during

isotretinoin therapy.

Bones and muscles

You may notice some changes to your hair (either a loss or,

rarely an increase) after taking this medicine for a while. This is

usually only temporary and persistent hair thinning is rare. Your

hair should return to normal after the treatment ends.

Hair problems

On very rare occasions patients have developed diabetes,

symptoms include excessive thirst and a frequent need to

urinate or your blood tests may show an increase in your blood

sugar levels.

Diabetes

In very rare cases, patients may experience inflammation of

their kidneys. Symptoms include feeling excessively tired,

difficulty urinating as well as swollen and puffy eyelids. If this

occurs while you are taking your medicine, stop the therapy and

contact your doctor.

Kidney problems

It is very common for patients to experience increase in the level

of liver enzymes. These are identified by the blood tests that are

taken throughout your treatment. Very rarely patients have

developed more serious liver problems (hepatitis). If you

experience yellowing of the skin or eyes with tiredness, stop

taking your medication as soon as possible and contact your

doctor.

Liver problems

If you experience severe abdominal pain with or without severe

bloody diarrhoea, nausea and vomiting, stop taking isotretinoin

as soon as possible and contact your doctor. There have been

very rare reports of patients experiencing serious

gastrointestinal disturbances, such as pancreatitis,

gastrointestinal haemorrhage, colitis, ileitis and inflammatory

bowel disease.

Gastrointestinal disorders

you may experience dryness of the throat which may cause

hoarseness or sudden chest tightness with shortness of breath

and wheezing (bronchospasm), particularly in patients with

asthma.

0000000

isotretinoin

ISOTRETINOIN 10 MG CAPSULES

ISOTRETINOIN 20 MG CAPSULES

Package leaflet: Information for the patient

You must use contraception even if you do not have periods

or you are not sexually active (unless your doctor decides

this is not necessary).

You must agree to regular follow-up visits, ideally every

month.

Women must agree to pregnancy testing before, during and

after taking Isotretinoin

You must agree to have regular pregnancy tests, ideally every

month during treatment and, because some medicine may

still be left in your body, 1 month after stopping Isotretinoin

(unless your doctor decides this is not necessary in your

case).

You must agree to extra pregnancy tests if your doctor asks

you.

You must not get pregnant during treatment or for a month

afterwards because some medicine may still be left in your

body.

Your doctor will discuss all these points with you, using a

checklist and will ask you (or a parent/guardian) to sign it.

This form confirms that you have been told about the risks

and that you will follow the rules above.

if you are planning a pregnancy

if you are breastfeeding

You must use contraception for a month before taking

Isotretinoin, during treatment and for a month afterwards

You must agree to use at least one very reliable method of

contraception (for example an intra uterine device or

contraceptive implant) or, two effective methods that work in

different ways (for example a hormonal contraceptive pill and

a condom). Discuss with your doctor which methods would

be suitable for you.

Women must use effective contraception before, during and

after taking Isotretinoin.

Before you start treatment, your doctor will ask you to take a

pregnancy test. The test must show that you are not pregnant

when starting treatment with Isotretinoin.

You must have talked about contraception (birth control) with

your doctor. The doctor will give you information on how not

to get pregnant. The doctor may send you to a specialist for

contraception advice.

Your doctor must explain the risk of harm to the unborn baby

- you must understand why you must not get pregnant and

what you need to do to prevent getting pregnant.

These are the rules:

Women who could get pregnant are only prescribed

Isotretinoin under strict rules. This is because of the risk of

serious harm to the unborn baby.

You must not get pregnant for one month after stopping this

treatment because some medicine may still be left in your

body.

You must not take Isotretinoin if you could get pregnant

during treatment.

You must not take Isotretinoin if you are breastfeeding. The

medicine is likely to pass into your milk and may harm your

baby.

You must not take Isotretinoin if you are pregnant or if you

think you might be pregnant.

if you have very high levels of vitamin A in your body

(hypervitaminosis A)

if you have very high levels of lipids (cholesterol,

triglycerides) in your blood

This medicine can seriously harm an unborn baby (the medicine

is said to be 'teratogenic') – it can cause serious abnormalities

of the unborn baby's brain, face, ear, eye, heart and certain

glands (thymus gland and parathyroid gland). It also makes a

miscarriage more likely. This may happen even if Isotretinoin is

taken only for a short time during pregnancy.

You may not notice some changes in your mood and behaviour

and so it is very important that you tell your friends and family

that you are taking this medicine. They may notice these

changes and help you quickly identify any problems that you

need to talk to your doctor about.

Important advice for women

Women who are pregnant must not take Isotretinoin

Mental health problems

If you have ever had any kind of mental health problems. This

includes depression, aggressive tendencies or mood changes. It

also includes thoughts about hurting yourself or ending your

life. This is because your mood may be affected while taking

Isotretinoin.

if you have liver disease

if you are allergic to isotretinoin or any of the other

ingredients of this medicine (listed in section 6).

if there is any chance you could become pregnant, you must

follow the precautions under “Pregnancy and prevention

programme”, see section on "Warnings and precautions”.

if you are taking tetracyclines (a type of antibiotic medicine)

Warnings and Precautions

Talk to your doctor or pharmacist before taking Isotretinoin

Capsules:

The name of your medicine is Isotretinoin 10 mg or 20 mg

Capsules (also referred to as Isotretinoin Capsules or

Isotretinoin throughout this leaflet).

What is in this leaflet:

1. What Isotretinoin Capsules are and what they are used for

2. What you need to know before you take Isotretinoin Capsules

3. How to take Isotretinoin Capsules

4. Possible side effects

5 How to store Isotretinoin Capsules

6. Contents of the pack and other information

1. What Isotretinoin Capsules are and what they are used for

Isotretinoin treatment must be supervised by a dermatologist (a

doctor specialised in the treatment of skin problems).

Isotretinoin capsules are not used to treat acne occurring before

puberty, or in children younger than 12 years of age.

Isotretinoin Capsules contain the active ingredient isotretinoin.

This is a vitamin A derivative, belonging to the retinoid class of

medicines. Isotretinoin is used to treat severe forms of acne

(such as nodular or conglobate acne, or acne at risk of

permanent scarring) which has not got better after other

treatments, including oral antibiotics.

2. What you need to know before you take Isotretinoin

Capsules

Do not take Isotretinoin Capsules:

if you are pregnant

If you get pregnant while taking Isotretinoin, stop taking the

medicine straight away, and contact your doctor. Your doctor

may send you to a specialist for advice.

Also, if you become pregnant within one month after you stop

taking Isotretinoin, you should contact your doctor. Your doctor

may send you to a specialist for advice.

Prescriptions are limited to 30 days treatment for women of

childbearing potential. Continuation of treatment requires a new

prescription, and each prescription is only valid for seven days.

Advice for men

The levels of oral retinoid in the semen of men taking

Isotretinoin are too low to harm their partners' unborn baby.

However, you must never share your medication with anyone.

Isotretinoin Capsules may increase the levels of fats such as

triglycerides or cholesterol in your blood. Your doctor will do

some blood tests in order to monitor these levels before, during

and at the end of your treatment with isotretinoin. Please tell

your doctor if you already have high levels of these substances

in your blood or if you have diabetes, are overweight, or are an

alcoholic, as you may need to get the blood tests more

frequently.

Advice for all patients

Isotretinoin Capsules may increase your liver enzyme levels.

Your doctor will do some blood tests before, during and at the

end of your treatment with isotretinoin to check your liver

values. In cases where liver enzyme values remain high your

doctor may reduce your dose or stop your isotretinoin therapy.

Isotretinoin Capsules may increase your blood sugar levels and

in rare cases diabetes mellitus has been diagnosed. Your doctor

may monitor your blood sugar levels during your treatment,

particularly if you have diabetes, are overweight, or are an

alcoholic.

Use a skin moisturising ointment or cream and a lip balm during

treatment as you may experience skin or lips dryness or both

during isotretinoin therapy.

Rare cases of depression, worsening depression, anxiety, mood

changes, psychotic symptoms and very rarely suicidal

thoughts, suicide attempts and suicide have been reported. If

you have any kind of mental problems, or, if you think you have

signs of depression while taking isotretinoin, such as feeling

very sad for no reason, crying spells, difficulty concentrating or

you become withdrawn from your friends or family, please

inform your doctor. Your doctor may refer you for appropriate

treatment if necessary. Discontinuation of your isotretinoin

therapy may not be enough to relieve symptoms and you may

require further psychiatric or psychological help.

If you experience an allergic reaction (skin redness, itching) or a

serious anaphylactic reaction, please stop your therapy

immediately and contact your doctor as soon as possible.

Isotretinoin Capsules have been very rarely associated with a

condition called benign intercranial hypertension. If you

experience a persistent headache, nausea, vomiting and blurred

vision, please stop your therapy immediately and contact your

doctor as soon as possible.

Isotretinoin Capsules have on very rare occasions been

associated with inflammatory bowel disease. If you experience

severe hemorrhagic diarrhoea (e.g. blood in your stool), please

stop therapy immediately and contact your doctor as soon as

possible.

Isotretinoin therapy may affect your night vision. You may

develop dry eyes or sight problems during isotretinoin therapy

which normally returns to normal once treatment is stopped.

Always be cautious when driving or operating machinery at

night because these sight changes can happen quite suddenly.

If you wear contact lenses and experience dry eyes you may

need to wear glasses for the duration of isotretinoin treatment. If

you experience any problems with your sight, please inform

your doctor immediately, as your Isotretinoin Capsules may

need to be stopped and your sight monitored.

Your skin may become more sensitive to sunlight during

isotretinoin therapy. Avoid too much sun and do not use a sun-

lamp or sun-bed. Before going out in the sun apply a sun-

protection product with a high protection factor of at least SPF 15.

Isotretinoin may make your skin more fragile. Cosmetic

procedures such as dermabrasion or laser treatments (removal

of horny skin or scars) and wax depilation should be avoided

during and for at least 6 months after treatment as this could

cause scarring or irritation of the skin.

Because muscle and joint pain have been observed during

isotretinoin treatment, care should be taken to reduce intensive

physical activity during isotretinoin therapy.

Additional precautions

You should not donate blood during treatment with this

medicine and for 1 month after stopping Isotretinoin because

an unborn baby could be harmed if a pregnant patient

receives your blood.

Other medicines and Isotretinoin Capsules:

You should never give this medicinal product to another

person. Please take any unused capsules to your pharmacist

at the end of treatment.

Tell your doctor or pharmacist if you are taking, have recently

taken or might take any other medicines, including herbal

products, even those not prescribed. Do not take vitamin A

supplements or tetracyclines (a type of antibiotic) or use any

skin treatments for acne during isotretinoin therapy.

Occasionally your acne may get worse during the first weeks

of treatment. It should improve with continued treatment.

The capsules should be taken with food once or twice daily.

Swallow the capsules whole, do not chew or suck them.

If you do not tolerate the recommended dose, your doctor may

continue your treatment at a lower dose with the consequence

of a longer therapy duration and a higher risk of relapse.

If you have severe kidney problems, Isotretinoin Capsules

should be started at a lower dose such as 10 mg/day and then

increased to highest tolerated dose.

The usual starting dose is 0.5 mg per kilogram bodyweight per

day (0.5 mg/Kg/day). After a few weeks your doctor may adjust

your dose. This will depend on how you are getting on with your

medicine. For most of the patients dose will be between 0.5 and

1.0 mg/Kg/day. If you have the impression that the effect of

isotretinoin is too strong or too weak, talk to your doctor or

pharmacist.

Always take this medicine exactly as your doctor or pharmacist

has told you. Check with your doctor or pharmacist if you are

not sure.

3. How to take Isotretinoin Capsules

Isotretinoin capsules contain soya oil. If you are allergic to

peanut or soya, do not use this medicinal product. This

medicinal product contains methyl parahydroxybenzoate and

propyl parahydroxybenzoate which may cause allergic reactions

(possibly delayed).

Isotretinoin Capsules contain soya oil, methyl

parahydroxybenzoate and propyl parahydroxybenzoate

Your night vision may get worse during your treatment. This can

happen suddenly. In rare cases this has continued after the

treatment has stopped. Drowsiness and dizziness have been

reported very rarely. If this happens to you, you should not drive

or operate machinery.

Driving and using machines

For more information on pregnancy and contraception, see

section 2 “Pregnancy and prevention programme”

DO NOT take Isotretinoin if you are pregnant or thinking of

becoming pregnant. Your doctor can give you more information.

Pregnancy and Breast-feeding

Isotretinoin Capsules with food and drink

Isotretinoin Capsules should be taken with food.

Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

If you have any further questions, ask your doctor or

pharmacist.

Keep this leaflet. You may need to read it again.

This medicine has been prescribed for you only. Do not

pass it on to others. It may harm them, even if their signs

of illness are the same as yours.

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

Font Size: 9 pt

WARNING

CAN SERIOUSLY HARM AN UNBORN BABY.

Women must use effective contraception.

Do not use if you are pregnant or you 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 may get. See the end of

section 4 for how to report side effects.

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Isotretinoin 10mg Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains isotretinoin 10 mg.

Excipient(s) with known effect:

For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Capsules, Soft

Oval shaped, light pink coloured, opaque soft gelatin capsules imprinted with `RR` in

black edible ink containing orange-yellow coloured oily suspension.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Severe forms of acne (such as nodular or conglobate acne or acne at risk of

permanent scarring) resistant to adequate courses of standard therapy with systemic

antibacterials and topical therapy.

4.2

Posology and method of administration

Isotretinoin should only be prescribed by or under the supervision of physicians with

expertise in the use of systemic retinoids for the treatment of severe acne and a full

understanding of the risks of isotretinoin therapy and monitoring requirements.

The capsules should be taken with food once or twice daily.

Adults including adolescents and the elderly:

Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic

response to isotretinoin and some of the adverse effects are dose-related and vary

between patients. This necessitates individual dosage adjustment during therapy. For

most patients, the dose ranges from 0.5-1.0 mg/kg per day.

Long-term remission and relapse rates are more closely related to the total dose

administered than to either duration of treatment or daily dose. It has been shown that

no substantial additional benefit is 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 the majority of patients, complete clearing of the acne is obtained with a single

treatment course. In the event of a definite relapse a further course of isotretinoin

therapy may be considered using the same daily dose and cumulative treatment dose.

As further improvement of the acne can be observed up to 8 weeks after

discontinuation of treatment, a further course of treatment should not be considered

until at least this period has elapsed.

Patients with severe renal insufficiency

In patients with severe renal insufficiency treatment should be started at a lower dose

(e.g. 10 mg/day). The dose should then be increased up to 1 mg/kg/day or until the

patient is receiving the maximum tolerated dose (see section 4.4).

Children

Isotretinoin is not indicated for the treatment of prepubertal acne and is not

recommended in patients less than 12 years of age.

Patients with intolerance

In patients who show severe intolerance to the recommended dose, treatment may be

continued at a lower dose with the consequences of a longer therapy duration and a

higher risk of relapse. In order to achieve the maximum possible efficacy in these

patients the dose should normally be continued at the highest tolerated dose.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section

6.1.

Isotretinoin is contraindicated in women who are pregnant or breastfeeding (see

section 4.6).

Isotretinoin is contraindicated in women of childbearing potential unless all of the

conditions of the Pregnancy Prevention Programme are met (see section 4.4).

Isotretinoin 10 mg Capsules contain refined soyabean oil and hydrogenated soyabean

oil. Therefore, Isotretinoin 10 mg Capsules are contraindicated in patients allergic to

peanut or soya.

Isotretinoin is also contraindicated in patients:

With hepatic insufficiency

With excessively elevated blood lipid values

With hypervitaminosis A

Receiving concomitant treatment with tetracyclines (see section 4.5)

4.4

Special warnings and precautions for use

Teratogenic effects

Isotretinoin is a powerful human teratogen inducing a high frequency of severe and life

threatening birth defects.

Isotretinoin is strictly contraindicated in:

- Pregnant women

-Women of childbearing potential unless all of the conditions of the Pregnancy Prevention

Programme are met

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC

Isotretinoin is contraindicated in women of childbearing potential unless all of the following

conditions of the Pregnancy Prevention Programme are met:

She has severe acne (such as nodular or conglobate acne or acne at risk of permanent

scarring) resistant to adequate courses of standard therapy with systemic

antibacterials and topical therapy (see section 4.1 “Therapeutic indications”).

The potential for pregnancy must be assessed for all female patients.

She understands the teratogenic risk.

She understands the need for rigorous follow-up, on a monthly basis.

She understands and accepts the need for effective contraception, without

interruption, 1 month before starting treatment, throughout the duration of treatment

and 1 month after the end of treatment. At least one and preferably two

complementary forms of contraception including a barrier method should be used.

Individual circumstances should be evaluated in each case, when choosing the

contraception method, involving the patient in the discussion, to guarantee her

engagement and compliance with the chosen measures.

Even if she has amenorrhea she must follow all of the advice on effective

contraception.

She is informed and understands the potential consequences of pregnancy and the

need to rapidly consult if there is a risk of pregnancy.

She understands the need and accepts to undergo pregnancy testing before, ideally

monthly during treatment and 1 month after stopping treatment.

She has acknowledged that she has understood the hazards and necessary precautions

associated with the use of isotretinoin.

These conditions also concern women who are not currently sexually active unless the

prescriber considers that there are compelling reasons to indicate that there is no risk of

pregnancy.

The prescriber must ensure that:

The patient complies with the conditions for pregnancy prevention as listed above,

including confirmation that she has an adequate level of understanding.

The patient has acknowledged the aforementioned conditions.

The patient understands that she must consistently and correctly use one highly

effective method of contraception (i.e. a user-independent form) or two

complementary user-dependent forms of contraception, for at least 1 month prior to

starting treatment and is continuing to use effective contraception throughout the

treatment period and for at least 1 month after cessation of treatment.

Negative pregnancy test results have been obtained before, during and 1 month after

the end of treatment. The dates and results of pregnancy tests should be documented.

If pregnancy occurs in a woman treated with isotretinoin, treatment must be stopped and the

patient should be referred to a physician specialised or experienced in teratology for

evaluation and advice.

If pregnancy occurs after stopping treatment there remains a risk of severe and serious

malformation of the foetus. This risk persists until the product has been completely

eliminated, which is within one month following the end of treatment.

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention

and should be referred for contraceptive advice if they are not using effective contraception. If

the prescribing physician is not in a position to provide such information the patient should be

referred to the relevant healthcare professional.

As a minimum requirement, female patients at potential risk of pregnancy must use at least

one effective method of contraception (i.e. a user-independent form) or two complementary

user-dependent forms of contraception. Contraception should be used for at least 1 month

prior to starting treatment, throughout treatment and continue for at least 1 month after

stopping treatment with isotretinoin, even in patients with amenorrhea.

Individual circumstances should be evaluated in each case, when choosing the contraception

method involving the patient in the discussion, to guarantee her engagement and compliance

with the chosen measures.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity

of 25mIU/mL are recommended to be performed as follows.

Prior to starting therapy:

At least one month after the patient has started using contraception, and shortly (preferably a

few days) prior to the first prescription, the patient should undergo a medically supervised

pregnancy test. This test should ensure the patient is not pregnant when she starts treatment

with isotretinoin.

Follow-up visits

Follow-up visits should be arranged at regular intervals, ideally monthly. The need for

repeated medically supervised pregnancy tests every month should be determined according

to local practice including consideration of the patient's sexual activity and recent menstrual

history (abnormal menses, missed periods or amenorrhea). Where indicated, follow-up

pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior

to the visit to the prescriber.

End of treatment

1 month after stopping treatment, women should undergo a final pregnancy test .

Prescribing and dispensing restrictions

For women of childbearing potential, the prescription duration of Isotretinoin should ideally

be limited to 30 days in order to support regular follow up, including pregnancy testing and

monitoring. Ideally, pregnancy testing, issuing a prescription and dispensing of Isotretinoin

should occur on the same day.

This monthly follow-up will allow ensuring that regular pregnancy testing and monitoring is

performed and that the patient is not pregnant before receiving the next cycle of medication.

Male patients:

The available data suggests that the level of maternal exposure from the semen of the patients

receiving Isotretinoin is not of a sufficient magnitude to be associated with the teratogenic

effects of isotretinoin.

Male patients should be reminded that they must not share their medication with anyone,

particularly not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to

return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 1 month following discontinuation of

isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to

isotretinoin the Marketing Authorisation Holder will provide educational material to reinforce

the warnings about the teratogenicity of isotretinoin, to provide advice on contraception

before therapy is started and to provide guidance on the need for pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention

measures as specified in the Pregnancy Prevention Programme should be given by the

physician to all patients, both male and female.

Psychiatric disorders

Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations,

psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have

been reported in patients treated with isotretinoin (see section 4.8). Particular care needs to be

taken in patients with a history of depression and all patients should be monitored for signs of

depression and referred for appropriate treatment if necessary. However, discontinuation of

isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or

psychological evaluation may be necessary.

Awareness by family or friends may be useful to detect mental health deterioration.

Skin and subcutaneous tissues disorders

Acute exacerbation of acne is occasionally seen during the initial period but this subsides with

continued treatment, usually within 7 - 10 days, and usually does not require dose adjustment.

Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-

protection product with a high protection factor of at least SPF 15 should be used.

Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in

patients on isotretinoin for a period of 5-6 months after the end of the treatment because of the

risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or

hypopigmentation in treated areas. Wax depilation should be avoided in patients on

isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal

stripping.

Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne

agents should be avoided as local irritation may increase (see section 4.5).

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from

the start of treatment as isotretinoin is likely to cause dryness of the skin and lips.

There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme

(EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated

with isotretinoin use. As these events may be difficult to distinguish from other skin reactions

that may occur (see section 4.8), patients should be advised of the signs and symptoms and

monitored closely for severe skin reactions. If a severe skin reaction is suspected, isotretinoin

treatment should be discontinued.

Eye disorders

Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after

discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye

ointment or by the application of tear replacement therapy. Intolerance to contact lenses may

occur which may necessitate the patient to wear glasses during treatment.

Decreased night vision has also been reported and the onset in some patients was sudden (see

section 4.7). Patients experiencing visual difficulties should be referred for an expert

ophthalmological opinion. Withdrawal of isotretinoin may be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in

patients receiving isotretinoin, particularly in those undertaking vigorous physical activity

(see section 4.8). In some cases, this may progress to potentially life threatening

rhabdomyolysis.

Bone changes including premature epiphyseal closure, hyperostosis, and calcification of

tendons and ligaments have occurred after several years of administration at very high doses

for treating disorders of keratinisation. The dose levels, duration of treatment and total

cumulative dose in these patients generally far exceeded those recommended for the treatment

of acne.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported, some of which involved

concomitant use of tetracyclines (see section 4.3 and section 4.5). Signs and symptoms of

benign intracranial hypertension include headache, nausea and vomiting, visual disturbances

and papilloedema. Patients who develop benign intracranial hypertension should discontinue

isotretinoin immediately.

Hepatobiliary disorders

Liver enzymes should be checked before treatment, 1 month after the start of treatment, and

subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated.

Transient and reversible increases in liver transaminases have been reported. In many cases

these changes have been within the normal range and values have returned to baseline levels

during treatment. However, in the event of persistent clinically relevant elevation of

transaminase levels, reduction of the dose or discontinuation of treatment should be

considered.

Renal insufficiency

Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin.

Therefore, isotretinoin can be given to patients with renal insufficiency. However, it is

recommended that patients are started on a low dose and titrated up to the maximum tolerated

dose (see section 4.2).

Lipid Metabolism

Serum lipids (fasting values) should be checked before treatment, 1 month after the start of

treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is

clinically indicated. Elevated serum lipid values usually return to normal on reduction of the

dose or discontinuation of treatment and may also respond to dietary measures.

Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin

should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or

if symptoms of pancreatitis occur (see section 4.8). Levels in excess of 800 mg/dL or

9mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders

Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis)

in patients without a prior history of intestinal disorders. Patients experiencing severe

(haemorrhagic) diarrhoea should discontinue isotretinoin immediately.

Allergic reactions

Anaphylactic reactions have been rarely reported, in some cases after previous topical

exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of

allergic vasculitis, often with purpura (bruises and red patches) of the extremities and

extracutaneous involvement have been reported. Severe allergic reactions necessitate

interruption of therapy and careful monitoring.

High Risk Patients

In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing

treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood

glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases

of diabetes have been diagnosed during isotretinoin therapy.

4.5

Interaction with other medicinal products and other forms of interaction

Patients should not take vitamin A as concurrent medication due to the risk of

developing hypervitaminosis A.

Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported

with concomitant use of isotretinoin and tetracyclines. Therefore, concomitant

treatment with tetracyclines must be avoided (see section 4.3 and section 4.4).

Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-

acne agents should be avoided as local irritation may increase (see section 4.4).

4.6

Fertility, pregnancy and lactation

Pregnancy is an absolute contraindication to treatment with isotretinoin (see section

4.3). Women of childbearing potential have to use effective contraception during and up

to one month after treatment. If pregnancy does occur in spite of these precautions

during treatment with isotretinoin or in the month following, there is a great risk of very

severe and serious malformation of the foetus.

The foetal malformations associated with exposure to isotretinoin include central nervous

system abnormalities (hydrocephalus, cerebellar malformation/abnormalities, microcephaly),

facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or

absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular

abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great

vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There

is also an increased incidence of spontaneous abortion.

If pregnancy occurs in a woman treated with isotretinoin, treatment must be stopped and the

patient should be referred to a physician specialised or experienced in teratology for

evaluation and advice.

Breastfeeding

Isotretinoin is highly lipophilic, therefore the passage of isotretinoin into human milk is very

likely. Due to the potential for adverse effects in the child exposed via mothers milk,

Isotretinoin is contraindicated during breast-feeding (see section 4.3).

Fertility

Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of

sperm and does not jeopardise the formation and development of the embryo on the part of

the men taking isotretinoin.

4.7

Effects on ability to drive and use machines

A number of cases of decreased night vision have occurred during isotretinoin

therapy and in rare instances have persisted after therapy (see section 4.4 and section

4.8). Because the onset in some patients was sudden, patients should be advised of

this potential problem and warned to be cautious when driving or operating machines.

Drowsiness, dizziness and visual disturbances have been reported very rarely.

Patients should be warned that if they experience these effects, they should not drive,

operate machinery or take part in any other activities where the symptoms could put

either themselves or others at risk.

4.8

Undesirable effects

Some of the side effects associated with the use of isotretinoin are related to the dose.

The side effects are generally reversible after changing the dose or stopping

treatment, however some may persist after treatment has stopped.

The following symptoms are the most commonly reported undesirable effects with

isotretinoin: dryness of the mucosa e.g. of the lips, cheilitis, the nasal mucosa,

epistaxis, and the eyes, conjunctivitis, dryness of the skin.

Infections:

Very Rare (

1/10 000)

Gram positive (mucocutaneous) bacterial infection

Blood and lymphatic system

disorders:

Very common (

1/10)

Common (

1/100, <1/10)

Very Rare (

1/10 000)

Anemia, red blood cell sedimentation rate increased,

thrombocytopaenia, thrombocytosis

Neutropenia

Lymphadenopathy

Immune system disorders:

Rare (

1/10 000,<1/1000)

Allergic skin reaction, anaphylactic reactions,

hypersensitivity

Metabolism and nutrition

disorders:

Very Rare (

1/10 000)

Diabetes mellitus, hyperuricaemia

Psychiatric disorders:

Rare (

1/10 000,<1/1000)

Very Rare (

1/10 000)

Depression, depression aggravated, aggressive tendencies,

anxiety, mood alterations

Abnormal behaviour, psychotic disorder, suicidal

ideation, suicide attempt, suicide

Nervous system disorders:

Common (

1/100, <1/10)

Very Rare (

1/10 000)

Headache

Benign intracranial hypertension, convulsions,

drowsiness, dizziness

Eye disorders:

Very common (

1/10)

Very Rare (

1/10 000)

Blepharitis, conjunctivitis, dry eye, eye irritation

Blurred vision, cataract, colour blindness (colour vision

deficiencies), contact lens intolerance, corneal opacity,

decreased night vision, keratitis, papilloedema (as sign of

benign intracranial hypertension), photophobia, visual

disturbances

Ear and labyrinth disorders:

Very Rare (

1/10 000)

Hearing impaired

Vascular disorders:

Very Rare (

1/10 000)

Vasculitis (for example Wegener’s granulomatosis,

allergic vasculitis)

Respiratory, thoracic and

mediastinal disorders:

Common (

1/100, <1/10)

Very Rare (

1/10 000)

Epistaxis, nasal dryness, nasopharyngitis

Bronchospasm (particularly in patients with asthma),

hoarseness

Gastrointestinal disorders:

Very Rare (

1/10 000)

Colitis, ileitis, dry throat, gastrointestinal haemorrhage,

haemorrhagic diarrhoea and inflammatory bowel disease,

nausea, pancreatitis (see section 4.4)

Hepatobiliary disorders:

Very common (

1/10)

Very Rare (

1/10 000)

Transaminase increased (see section 4.4)

Hepatitis

Skin and subcutaneous tissues

disorders:

Very common (

1/10)

Rare (

1/10 000,<1/1000)

Very Rare (

1/10 000)

Frequency unknown*

Cheilitis, dermatitis, dry skin, localised exfoliation,

pruritus, rash erythematous, skin fragility (risk of

frictional trauma)

Alopecia

Acne fulminans, acne aggravated (acne flare), erythema

(facial), exanthema, hair disorders, hirsutism, nail

dystrophy, paronychia, photosensitivity reaction,

pyogenic granuloma, skin

hyperpigmentation, sweating increased

Erythema multiforme, Stevens-Johnson Syndrome, toxic

epidermal necrolysis

Musculo-skeletal and

connective tissue disorders:

Very common (

1/10)

Very Rare (

1/10 000)

Arthralgia, myalgia, back pain (particularly in children

and adolescent patients)

Arthritis, calcinosis (calcification of ligaments and

tendons), epiphyses premature fusion, 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 of), malaise

Investigations:

Very common (

1/10)

Common (

1/100, <1/10)

Very Rare (

1/10 000)

Blood triglycerides increased, high density lipoprotein

decreased

Blood cholesterol increased, blood glucose increased,

haematuria, proteinuria

Blood creatine phosphokinase increased

Reproductive system and breast

disorders:

Frequency unknown *

Sexual dysfunction including erectile dysfunction and

decreased libido, gynaecomastia

* cannot be estimated from the available data

The incidence of the adverse events was calculated from pooled clinical trial data

involving 824 patients and from post-marketing data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product

is important. It allows continued monitoring of the benefit/risk balance of the

medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via the Yellow Card Scheme Website:

Public Assessment Report

UKPAR

Isotretinoin 10mg Capsules, soft

(isotretinoin)

UK Licence Number: PL 40739/0041

Ennogen Healthcare Limited

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

2

LAY SUMMARY

Isotretinoin 10mg Capsules, soft

(isotretinoin)

This is a summary of the Public Assessment Report (PAR) for Isotretinoin 10mg Capsules, soft

(PL 40739/0041). It explains how Isotretinoin 10mg Capsules, soft were assessed and their

authorisation recommended, as well as their conditions of use. It is not intended to provide

practical advice on how to use Isotretinoin 10mg Capsules, soft.

The product will be referred to as ‘Isotretinoin Capsules’ throughout the remainder of this lay

summary.

For practical information about using Isotretinoin Capsules, patients should read the package

leaflet or contact their doctor or pharmacist.

What are Isotretinoin Capsules and what are they used for?

Isotretinoin Capsules are a ‘generic medicine’. This means that Isotretinoin Capsules are

similar to a ‘reference medicine’ already authorised in the European Union (EU) called

Roaccutane 10mg soft gel Capsules authorised to (Roche Products Limited).

Isotretinoin soft capsules contain the active ingredient isotretinoin. Isotretinoin is used to treat

severe forms of acne (such as nodular or conglobate acne, or acne at risk of permanent

scarring) which has not got better after other anti-acne treatments, including oral antibiotics.

How do Isotretinoin Capsules work?

This medicine contains the active substance called isotretinoin. This is a vitamin A derivative,

belonging to the retinoid class of medicines. Isotretinoin is active against all four causes of

acne — excess oil production, clogged pores in the skin, too much of the bacteria P. acnes,

and inflammation.

How are Isotretinoin Capsules used?

The pharmaceutical form of this medicine is a soft gel capsule and the route of administration

is oral (by mouth). The capsule should be swallowed whole with a drink of water.

The patient should always take this medicine exactly as their doctor or pharmacist has told

them. The patient should check with their doctor or pharmacist if they are not sure.

The capsules should be taken with food once or twice daily.

The capsules should be swallowed whole, and not chewed or sucked.

Occasionally acne may get worse during the first weeks of treatment, but with continued

treatment should improve.

Dose

The patient’s doctor will prescribe an individual dose in accordance with their patient’s body

weight and other clinical parameters like renal insufficiency, etc.

The specific individual doses might be better matched by other available product strengths.

Please read section 3 of the package leaflet for detailed dosing recommendations, the route of

administration, and the duration of treatment.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

3

For further information on how Isotretinoin Capsules are used, refer to the package leaflet and

Summary of Product Characteristics available on the Medicines and Healthcare products

Regulatory Agency (MHRA) website.

This medicine can only be obtained with a prescription. Isotretinoin should only be prescribed

by or under the supervision of a dermatologist (a doctor specialised in the treatment of skin

problems) with understanding of the risks of isotretinoin therapy and monitoring requirements.

What benefits of Isotretinoin Capsules have been shown in studies?

Because Isotretinoin Capsules are a generic medicine, studies in patients have been limited to

tests to determine that Isotretinoin Capsules are considered to be bioequivalent to the

reference medicine Roaccutane 10mg soft gel Capsules authorised to (Roche Products

Limited).

Two medicines are bioequivalent when they produce the same levels of the active substance

in the body.

What are the possible side effects of Isotretinoin Capsules?

Because Isotretinoin Capsules are a generic medicine and they are considered to be

bioequivalent to the reference medicine Roaccutane 10mg soft gel Capsules authorised to

(Roche Products Limited), their benefits and possible side effect are taken as being the same

as those of the reference medicine.

For a full list of all the side effects reported with Isotretinoin Capsules see section 4 of the

package leaflet, available on the Medicines and Healthcare products Regulatory Agency

(MHRA) website.

For the full list of restrictions, see the package leaflet.

Why are Isotretinoin Capsules approved?

It was concluded that, in accordance with EU requirements, Isotretinoin Capsules have been

shown to have comparable quality and are considered to be bioequivalent Roaccutane 10mg

soft gel Capsules authorised to (Roche Products Limited). Their benefits are greater than the

risks and it was recommended that Isotretinoin Capsules can be approved for use.

What measures are being taken to ensure the safe and effective use of Isotretinoin

Capsules?

A risk management plan (RMP) has been developed to ensure that Isotretinoin Capsules are

used as safely as possible. Based on this plan, safety information has been included in the

Summary of Product Characteristics (SmPC) and the package leaflet for Isotretinoin Capsules

including the appropriate precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals reported by

patients/healthcare professionals will be monitored/ reviewed continuously.

Other information about Isotretinoin Capsules

A marketing authorisation was granted in the UK on 20 September 2018.

The full PAR for Isotretinoin Capsules follows this summary.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

4

For more information about treatment with Isotretinoin Capsules, read the package leaflet, or

contact your doctor or pharmacist.

This summary was last updated in November 2018.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

5

TABLE OF CONTENTS

INTRODUCTION

QUALITY ASPECTS

NON-CLINICAL ASPECTS

CLINICAL ASPECTS

USER CONSULTATION

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

TABLE OF CONTENT OF THE PAR UPDATE

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

6

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare

products Regulatory Agency (MHRA) granted Ennogen Healthcare Limited, a marketing

authorisation for the medicinal product Isotretinoin 10mg Capsules, soft (PL 40739/0041). This

product is a prescription-only medicine (POM) indicated for severe forms of acne (such as

nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate

courses of standard therapy with systemic antibacterials and topical therapy.

The application was submitted under Article 10(1) of Directive 2001/83/EC, as amended, as a

generic application. The reference product for this application is Roaccutane 10mg soft gel

Capsules authorised in the UK on 30 June 1983 to the marketing authorisation holder (MAH)

Roche Products Limited (PL 00109/0133).

Isotretinoin, a synthetic vitamin A derivative, is a retinoid that is effective against severe acne.

Its exact mechanism of action has not yet been elucidated 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 the size

of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has

been established.

Pregnancy is an absolute contraindication to treatment with isotretinoin (see section 4.3 of the

summary of product characteristics available on the MRHA website). Women of childbearing

potential must use effective contraception during and up to one month after treatment. If

pregnancy does occur in spite of these precautions during treatment with isotretinoin or in the

month following, there is a great risk of very severe and serious malformation of the fetus.

No new clinical or non-clinical studies were submitted, which is acceptable given that the

application was based on being a generic medicinal product of a reference product that has

been in clinical use for over 10 years. A bioequivalence study was not required as the basis for

a biowaiver was adequately justified.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice

(GMP) are in place for this product type at all sites responsible for the manufacture, assembly

and batch release of these products. For manufacturing sites within the Community, the MHRA

has accepted copies of current manufacturer authorisations issued by inspection services of

the competent authorities as certification that acceptable standards of GMP are in place at

those sites.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

7

II

QUALITY ASPECTS

II.1

Introduction

The finished product is a soft gelatin capsule containing 10mg isotretinoin per capsule. Other

ingredients consist of the pharmaceutical excipients refined soya-bean oil, All-rac-α-tocopherol,

disodium edetate, butylhydroxyanisole, partly hydrogenated soya bean oil, yellow beeswax,

and hydrogenated vegetable oil. The Capsule filling consists of gelatin, glycerol, non-

crystallising sorbitol solution 70% (E420), Erythrosine colourant soluble (E127), Titanium

dioxide (E171), purified water, and Black iron oxide (E172).

The product is packaged in polyvinyl chloride (PVC) / polyvinylidene chloride (PVdC) /

Aluminium (Alu) blister packs containing 28, 30, 56, and 60 capsules.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components. All primary packaging complies with the current European regulations concerning

materials in contact with food.

II.2

Drug Substance

INN:

Isotretinoin

Chemical name:

(13Z)-15-Apo-β-caroten-15-oic acid; (2Z,4E,6E,8E)-3,7-

Dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-

tetraenoic acid.

Structure:

Molecular formula:

Molecular mass:

300.4

Appearance:

A yellow or light orange crystalline powder.

Solubility:

Practically insoluble in water, soluble in methylene chloride,

and slightly soluble in 96 % ethanol.

All aspects of the manufacture and control of the active substance, isotretinoin, are covered by

the European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of

Suitability.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

8

II.3.

Medicinal Product

Pharmaceutical Development

The objective of the development programme was to develop a safe, efficacious, soft capsule

containing 10mg isotretinoin, that is a generic version of the reference product Roaccutane

10mg soft gel Capsules authorised to (Roche Products Limited). The development of the

product has been described, the choice of excipients is justified and their functions explained.

Comparative in-vitro dissolution and impurity profiles have been provided for the proposed and

reference products.

The excipients, included in the capsule fill are controlled by Ph Eur monographs, with the

exceptions of hydrogenated vegetable oil and partly hydrogenated soya-bean oil.

Hydrogenated vegetable oil complies with the British Pharmacopoeia (BP), while partly

hydrogenated soya-bean oil complies with the German Pharmacopoeia (DAB) except that the

melting point test (Ph. Eur. 2.2.15) may be replaced by the drop point test (Ph. Eur. 2.2.17).

The excipients included in the capsule shell are controlled by Ph Eur, with the exceptions of

iron oxide, black (E172) and Erythrosine colourant soluble (E127). Iron oxide, black and

Erythrosine colourant soluble (E127) are stated to be controlled by European Parliament and

Council Directive No. 2008/128/EC on Specific Purity Criteria Concerning Colours for Use in

Foodstuffs. Declarations are provided from suppliers of these colorants stating compliance

with Regulation (EU) No. 231/2012, applying from December 01, 2012 laying down

specifications for food additives listed in Annexes II and III to Regulation 1333/2008/EC.

Satisfactory specifications and Certificates of Analysis have been provided for the packaging

components.

With the exception of gelatin, none of the excipients contain materials of animal or human

origin. The suppliers of gelatin have provided Certificates of Suitability from the European

Directorate for the Quality of Medicines (EDQM) to show that they are manufactured in-line

with current European guidelines concerning the minimising of risk of transmission of Bovine

Spongiform Encephalopathy/transmissible Spongiform Encephalopathies (BSE/TSE).

This product does not contain or consist of genetically modified organisms (GMO).

Manufacture of the product

Satisfactory batch formulae have been provided for the manufacture of the product, together

with an appropriate account of the manufacturing process. Process validation data on

commercial batch sizes have been provided. The results are satisfactory.

Finished Product Specification

The finished product specification proposed is acceptable. Test methods have been described

that have been adequately validated. Batch data complying with the release specification have

been provided. Certificates of Analysis have been provided for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on

batches of the finished product in the packaging proposed for marketing. The data from these

studies support a shelf-life of 3 years with the storage conditions of “Do not store above 30°C.

Store in the original container. Keep container in the outer carton. Keep out of the sight and

reach of children”.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

9

Suitable post approval stability commitments to continue stability testing on batches of finished

product have been provided.

II.4

Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of this application from a pharmaceutical viewpoint.

III

NON-CLINICAL ASPECTS

III.1

Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of isotretinoin are

well-known, no new non-clinical studies are required and none have been provided. An

overview based on the literature review is, thus, appropriate.

The applicant’s non-clinical expert report has been written by an appropriately qualified person

and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,

pharmacokinetics and toxicology.

III.2

Pharmacology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.3

Pharmacokinetics

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.4

Toxicology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.5

Ecotoxicity/environmental risk assessment (ERA)

Since Isotretinoin 10mg Capsules, soft are intended for generic substitution, this will not lead to

an increase of the environmental exposure. An environmental risk assessment is therefore not

deemed necessary.

III.6

Discussion on the non-clinical aspects

There are no objections to the approval of this application from a non-clinical viewpoint.

IV

CLINICAL ASPECTS

IV.1

Introduction

The pharmacodynamic, pharmacokinetic, clinical efficacy and safety properties of isotretinoin

are well known. A comprehensive review of the published literature has been provided by the

applicant. The applicant’s clinical overview has been written by an appropriately qualified

person and is considered acceptable.

No new efficacy or safety studies have been performed and none are required for this type of

application. A comprehensive review of the published literature has been provided by the

applicant, citing the well-established clinical pharmacology, efficacy and safety of isotretinoin.

IV.2

Pharmacokinetics

No bioequivalence (BE) studies comparing the Isotretinoin 10mg soft gel Capsules with the

equivalent strength of the originator have been submitted. Instead the Applicant submitted the

findings of a BE study with a higher strength of product, Isotretinoin 20mg capsules and

requested a biowaiver which was accepted as the requirements of CPMP/EWP/QWP/1401/98

Rev. 1 were met.

PAR Isotretinoin 10mg Capsules, soft

PL 40739/0041

10

IV.3

Pharmacodynamics

No new pharmacodynamic data were submitted and none were required for an application of

this type.

IV.4

Clinical efficacy

No new efficacy data were submitted and none were required for an application of this type.

IV.5

Clinical safety

No new data on safety have been submitted and none are required for applications of this type.

IV.6

Risk Management Plan (RMP) and Pharmacovigilance System

The MAH has submitted a risk management plan, in accordance with the requirements of

Directive 2001/83/EC as amended.

There are no differences from the reference product in terms of proposed uses, maximum pack

size / strength or pharmaceutical form / formulation that would have any implications for safety.

In line with the reference product, the applicant proposes only routine pharmacovigilance and

routine risk minimisation measures for all safety concerns (labelling in the SmPC and the PIL),

which is acceptable.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed

subsequent updates of the RMP.

An updated RMP should be submitted:

At the request of the competent authority;

Whenever the risk management system is modified, especially as the result of new

information being received that may lead to a significant change to the benefit/risk

profile or as the result of an important (pharmacovigilance or risk minimisation)

milestone being reached.

If the dates for submission of a Periodic Safety Update Report and the update of an RMP

coincide, they can be submitted at the same time, but via different procedures.

IV.7

Discussion on the clinical aspects

The grant of a marketing authorisation is recommended for this application from a clinical

viewpoint.

V

User consultation

A user consultation with target patient groups on the package information leaflet (PIL) has

been performed on the basis of a bridging report making reference to called Isotretinoin 5mg

capsules (Ennogen Healthcare Limited). The bridging report submitted by the applicant has

been found acceptable.

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