Active ingredients: Atomoxetine
Strattera 10, 18, 25, 40, 60, 80 and 100 mg hard capsules
Strattera package inserts are available for pack sizes:- Strattera 10, 18, 25, 40, 60, 80 and 100 mg hard capsules
- Strattera 4 mg / ml oral solution
Why is Strattera used? What is it for?
What is it for
Strattera contains atomoxetine and is used to treat attention deficit hyperactivity disorder (ADHD). It is used
- in children over 6 years of age
- in young people
- in adults.
It is used only as part of a general disease treatment that also requires non-drug interventions, such as psychological and behavioral support therapy.
It should not be used as a treatment for ADHD in children under 6 years of age, as it is not known whether this drug works or is safe in these people.
In adults Strattera is used to treat ADHD when the symptoms are very distracting and affect your work or social life and when you have had symptoms of the disease as a child.
How does it work
Strattera increases the levels of norepinephrine in the brain. Norepinephrine is a naturally produced chemical that increases alertness and reduces impulsivity and hyperactivity in ADHD patients. This medicine has been prescribed to help control the symptoms of ADHD. This medicine is not a stimulant and therefore is not addictive. It may take a few weeks after starting treatment with this medicine for your symptoms to improve completely.
About ADHD
Children and young people with ADHD find:
- difficult to stand still e
- difficult to concentrate.
It is not their fault that they cannot do these things. Many children and young people strive to do these things. However, with ADHD they can have problems with everyday life. Children and young people with ADHD can have difficulty learning and doing homework. They struggle to perform well at home, at school, or elsewhere. ADHD does not affect the intelligence of a child or young person.
Adults with ADHD find it difficult to do all those things that children find difficult to do; however this can lead to them having problems with:
- the job
- interpersonal relationships
- low self-esteem
- education
Contraindications When Strattera should not be used
DO NOT take Strattera if:
- you are allergic (hypersensitive) to atomoxetine or any of the other ingredients of Strattera
- have taken a medicine known as a monoamine oxidase inhibitor (MAOI), such as phenelzine, within the last two weeks.A MAOI medicine is sometimes used to treat depression and other mental disorders; if you take Strattera together with a MAOI medicine you may experience serious or life-threatening side effects. You also need to wait at least 14 days after stopping Strattera treatment before you start taking an MAOI medicine.
- have an eye disease called narrow-angle glaucoma (increased eye pressure)
- have severe heart problems which may be affected by an increase in heart rate and / or blood pressure, as this could be an effect of Strattera
- have severe blood vessel problems in the brain such as a stroke, a swelling or weakening of part of a blood vessel (aneurysm) or a narrowing or blockage of blood vessels
- have adrenal gland tumor (pheochromocytoma).
Do not take Strattera if any of the above conditions apply to you. If you are not sure, talk to your doctor or pharmacist before taking Strattera. This is because Strattera can make these problems worse.
Precautions for use What you need to know before you take Strattera
Both adults and children should be informed of the following warnings and precautions. Before treatment with Strattera, tell your doctor if you have:
- suicidal thoughts or attempting suicide
- heart problems (including heart defects) or an increase in heart rate. Strattera can increase the rate of the heartbeat (pulse). Sudden death has been reported in patients with heart defects
- high blood pressure. Strattera can increase blood pressure
- low blood pressure. Strattera can cause dizziness or fainting in people with low blood pressure
- problems with sudden changes in blood pressure or heart rate
- a cardiovascular disease or a previous medical history of stroke
- liver problems. A lower dose may be needed
- psychotic symptoms including hallucinations (such as hearing voices or seeing things that aren't there), believing things that aren't true, or being suspicious
- mania (feeling elated or overexcited with unusual behavior) and agitation
- aggression
- unfriendly and angry feelings (hostility)
- history of epilepsy or seizures for any other reason. Strattera could induce an increase in the frequency of seizures
- different moods than usual (mood swings) or feeling very unhappy
- difficulty controlling yourself, repeated spasms of some part of the body or repeating sounds and words.
Before starting treatment, contact your doctor or pharmacist if any of the above applies to you. This is because Strattera can make these problems worse. Your doctor will want to check how the medicine works on you.
Check your doctor will do before you start taking Strattera
These checks are used to decide if Strattera is the right medicine for you.
Your doctor will measure them:
- your blood pressure and heart rate (pulse) before and during the time you take Strattera
- your height and weight if you are a child or a teenager while taking Strattera.
Your doctor will talk to you:
- any other medicines you are taking
- if there is any family history of unexplained sudden death
- any other health problems (such as heart problems) that you or your family may have.
It is important that you provide as much information as possible. This will help your doctor decide if Strattera is the right medicine for you. Your doctor may decide that other medical tests are needed before you start taking this medicine.
Interactions What medications or foods may change the effect of Strattera
Tell your doctor or pharmacist if you are taking or have recently taken or plan to take any other medicines, including those obtained without a prescription. Your doctor will decide whether you can take Strattera with these other medicines and in some cases you may need to adjust the dose or increase it much more slowly.
Do not take Strattera with medicines called MAOIs (monoamine oxidase inhibitors) used for depression. See section 2 "Do not take Strattera".
If you are taking other medicines, Strattera may affect how well they work or cause side effects. If you are taking any of the following medicines, consult your doctor or pharmacist before taking Strattera:
- medicines that raise blood pressure or are used to control blood pressure
- medicines such as antidepressants, for example imipramine, venlafaxine, mirtazapine, fluoxetine and paroxetine
- some cough and cold remedies that contain medicines that can affect blood pressure. It is important that you check with your pharmacist when purchasing any of these products
- some medicines used to treat mental disorders
- medicines that are known to increase the risk of seizures
- some medicines where Strattera stays in the body longer than normal (such as quinidine and terbinafine)
- salbutamol (an asthma medicine) which when taken by mouth or by injection may make you feel like your heart is beating faster, but this is not related to worsening asthma.
The medicines listed below may cause an increased risk of abnormal heart rhythm if they are taken with Strattera:
- medicines used to control heart rhythm
- medicines that change the concentration of salts in the blood
- medicines for the prevention and treatment of malaria
- some antibiotic medicines (such as erythromycin and moxifloxacin).
If you are not sure if any of the medicines you are taking are included in the list above, ask your doctor or pharmacist before taking Strattera.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
It is not known whether Strattera can affect an unborn baby or if it passes into breast milk.
- Strattera should not be used during pregnancy unless advised by your doctor.
- You should also avoid taking Strattera while breastfeeding or stop breastfeeding.
Self:
- you are pregnant or breastfeeding
- suspect that you are pregnant or are planning to become pregnant
- plan to breastfeed ask your doctor or pharmacist for advice before taking Strattera.
Driving and using machines
You may feel tired, sleepy or dizzy after taking Strattera. You should be careful driving or using machines until you know how Strattera affects your abilities. If you feel tired, sleepy or dizzy, you should not drive or operate any dangerous machinery.
Important information on the contents of the capsules
Do not open the Strattera capsules as the contents of the capsule may irritate the eyes. If the contents of the capsules come into contact with the eyes, the affected eye should be washed immediately with water and medical attention should be sought. Hands and any other parts of the body that may have come into contact with the contents of the capsules should be wash as soon as possible.
Dose, Method and Time of Administration How to use Strattera: Posology
- Always take Strattera as your doctor has told you. It is usually taken once or twice a day (the first dose in the morning and the second in the late afternoon or early evening).
- If you are taking Strattera once a day and feel sleepy and nauseous, your doctor may change your medicine to twice a day.
- The capsules should be swallowed whole, regardless of meals.
- The capsules must not be opened and the internal contents of the capsules must not be removed and taken in some other way.
- Taking the medicine at the same time each day can help you remember to take it.
How much to take
If you are a child or adolescent (aged 6 years or older): Your doctor will tell you the dose of Strattera to take and calculate the dose based on your body weight. Normally he will start making you take a lower dose before increasing the dose of Strattera you need to take based on your body weight.
- Body weight up to 70 kg: a starting total daily dose of 0.5 mg per kg body weight for at least 7 days. The doctor may then decide to increase it to the usual maintenance dose of 1.2 mg per kg of body weight per day.
- Body weight over 70 kg: a starting total daily dose of 40 mg for at least 7 days. The doctor may then decide to increase it to the usual maintenance dose of 80 mg per day. The maximum daily dose that your doctor will prescribe is 100 mg.
Adults
- Strattera should be started with a total daily dose of 40 mg for at least 7 days. The doctor may then decide to increase it to the usual maintenance dose of 80-100 mg per day. The maximum daily dose that your doctor will prescribe is 100 mg.
If you have liver problems, your doctor may prescribe a lower dose.
Long-term treatment
Strattera doesn't have to be taken forever. If you have been taking Strattera for more than a year, your doctor will re-evaluate your treatment to see if the medicine is still needed.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
If you forget to take Strattera
If you forget to take a dose of Strattera, you should take this dose as soon as possible, but within 24 hours you should not take more than the total daily dose. Do not take a double dose to make up for forgotten doses.
If you stop using Strattera
If you stop using Strattera usually no side effects will occur, but ADHD symptoms may return. You should speak to your doctor before stopping treatment.
Overdose What to do if you have taken too much Strattera
If you take more Strattera than you should contact your doctor or the nearest hospital emergency department immediately and tell how many capsules you have taken. The most commonly reported symptoms of overdose are gastrointestinal symptoms, sleepiness, dizziness, tremor and abnormal behavior.
Side Effects What are the side effects of Strattera
Like all medicines, Strattera can cause side effects, although not everybody gets them. Although some people have side effects, most find Strattera to help. Your doctor will discuss these side effects with you.
Possible side effects
- Side effects are unwanted things that can happen when you take a medicine. If any of the following side effects occur, speak to a trusted adult right away. He will then discuss it with the doctor. The main things that could happen are:
- Your heart beating faster than normal
- Being very depressed and unhappy or wanting to hurt yourself
- Feeling aggressive
- Feeling unhappy or having a different mood than usual (mood swings)
- Show signs of an allergic reaction such as a "rash, itching or hives, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty in breathing
- Convulsions
- Seeing, feeling or hearing things that other people don't see, feel or hear
- Liver damage: belly pain that hurts when pressing (tenderness) on the right side just below the ribs
Because the medicine can make you sleepy, it is important not to engage in outdoor sports, such as horseback riding or cycling, swimming or climbing trees. You could harm yourself and others.
Some side effects could be serious. If you have any of the side effects listed below, contact a doctor immediately.
Uncommon (affects less than 1 in 100 people)
- feeling or having a rapid heartbeat, changes in heart rhythm
- suicidal thoughts or feelings
- aggression
- unfriendly and angry feelings (hostility)
- mood swings or changes
- severe allergic reaction with symptoms of:
- swelling of the face and tongue
- respiratory difficulties
- hives (small, raised, itchy patches of skin)
- convulsions
- psychotic symptoms including hallucinations (such as hearing voices or seeing things that aren't there), believing things that aren't true, or being suspicious.
Children and young people under the age of 18 have an increased risk of side effects (affecting less than 1 in 100 people) of side effects such as:
- suicidal thoughts or feelings (may affect up to 1 in 100 people)
- mood changes or swings (may affect up to 1 in 10 people)
Adults have a reduced risk of side effects (affecting less than 1 in 10,000 people) such as:
- convulsions
- psychotic symptoms including hallucinations (such as hearing voices or seeing things that aren't there), believing things that aren't true, or being suspicious.
Rarely (affects less than 1 in 1000 people)
- liver damage
You should stop taking Strattera and contact your doctor immediately if you experience any of the following symptoms:
- dark urine
- yellowing of the skin or eyes
- belly pain that hurts when pressing the right side of the abdomen just below the ribs
- unexplained feeling of being sick (nausea)
- tiredness
- itch
- feeling of having the flu.
Other side effects that have been reported are listed below. If these get worse, contact your doctor or pharmacist.
- headache
- pain in the stomach (abdomen)
- decreased appetite (not being hungry)
- feeling sick (nausea) or
- being sick (vomiting)
- drowsiness
- increased blood pressure
- increased heart rate (pulsation).
- nausea
- dry mouth
- headache
- decreased appetite (not being hungry)
- problems falling asleep, staying asleep and waking up early
- increased blood pressure
- increased heart rate (pulse)
- being irritable or agitated
- sleep disturbances including early awakening
- depression
- feeling sad or hopeless
- feel anxious
- tic
- dilation of the pupils (the black center of the eye)
- dizziness
- constipation
- loss of appetite
- stomach pain, indigestion
- swelling, redness and itching of the skin - rash
- feeling sluggish (lethargy)
- chest pain
- tiredness
- weight loss.
- feeling agitated
- decreased sexual desire
- sleep disorders
- depression
- feeling sad or hopeless
- feel anxious
- dizziness
- an "anomaly or change in taste that won't go away."
- tremor
- tingling or numbness in the hands or feet
- drowsiness, being asleep, feeling tired
- constipation
- stomach ache
- indigestion
- air in the intestines (flatulence)
- He retched
- hot flashes or redness
- feel or have a very fast heartbeat
- swelling, redness and itching of the skin
- increased sweating
- rash
- problems when you have to pass urine, such as being unable to pass urine, frequent needing to pass urine or initial difficulty passing urine, pain in passing urine
- inflammation of the prostate (prostatitis)
- groin pain in men
- inability to get an "erection
- delay in orgasm
- difficulty maintaining an erection
- menstrual cramps
- lack of strength or energy
- tiredness
- feeling sluggish (lethargy)
- chills
- sensitivity, irritability, nervousness
- feeling thirsty
- weight loss
- fainting
- tremor
- migraine
- abnormal skin sensation, such as burning, stinging, itching or tingling
- tingling or numbness in the hands or feet
- convulsions
- feeling or having a rapid heartbeat (QT prolongation)
- wheezing
- increased sweating
- itchy skin
- lack of strength or energy.
- restlessness
- tic
- fainting
- migraine
- altered heart rhythm (QT prolongation)
- feeling of cold in the fingers and toes
- chest pain
- wheezing
- itchy red rash (hives)
- muscle spasms
- urge to urinate
- absent or abnormal orgasm
- irregular menstruation
- inability to ejaculate.
- poor blood circulation which makes the fingers and toes numb and pale (Raynaud's syndrome)
- problems when you have to urinate, such as frequent urination or difficulty starting urination, pain when urinating
- prolonged and painful erections
- groin pain in males.
- poor blood circulation which makes the fingers and toes numb and pale (Raynaud's syndrome)
- prolonged and painful erections.
Effects on growth
Some children have reported reduced growth (in weight and height) when they started taking Strattera. However, with long-term treatment, children regain their age-predicted weight and height. Your doctor will monitor your child's weight and height during the treatment period. If your baby is not growing or gaining weight as expected, your doctor may decide to change your baby's dose or temporarily stop Strattera.
Reporting of side effects
Talk to your doctor or pharmacist if:
- have any of these side effects and become bothersome or worsening
- get any side effects not listed in this leaflet.
You can also report side effects directly via the Italian Medicines Agency, Website: (www.agenziafarmaco.it/it/responsabili). By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep Strattera out of the reach and sight of children.
Do not use Strattera after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of the month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
Things your doctor will do when you are being treated with the medicine
The doctor will perform some tests:
- before starting treatment (to ensure Strattera is safe and beneficial)
- after starting treatment (they will be done at least every 6 months, but possibly more often)
Tests will be performed even if the dose is changed. These tests will include:
- measuring height and weight in children and young people
- measurement of blood pressure and heart rate
- check for any problems or if side effects have worsened while you are taking Strattera.
What Strattera 10, 18, 25, 40, 60, 80 and 100 mg hard capsules contains
- The active ingredient is atomoxetine hydrochloride. Each hard capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60, 80 and 100 mg of atomoxetine.
- The other ingredients are pregelatinised starch and dimethicone.
- The capsule shell contains sodium lauryl sulfate and gelatin. The capsule shell colors are: Yellow iron oxide E172 (18 mg, 60 mg, 80 mg and 100 mg) Titanium dioxide E171 (10 mg, 18 mg, 25 mg) , 40 mg, 60 mg, 80 mg and 100 mg) FD&C Blue 2 (indigo carmine) E132 (25 mg, 40 mg and 60 mg) Red iron oxide E172 (80 mg and 100 mg) Edible black ink (containing shellac and black iron oxide E172).
What Strattera looks like and contents of the pack
- Hard capsules 10 mg (white with Lilly 3227/10 mg)
- Hard capsules 18 mg (golden / white, imprinted with Lilly 3238/18 mg)
- Hard capsules 25 mg (blue / white, with Lilly 3228/25 mg)
- Hard capsules 40 mg (blue, marked Lilly 3229/40 mg)
- Hard capsules 60 mg (blue / gold colored, inscribed with Lilly 3239/60 mg)
- Hard capsules 80 mg (brown / white, imprinted with Lilly 3250/80 mg)
- Hard capsules 100 mg (brown, marked Lilly 3251/100 mg)
Strattera capsules are available in packs of 7, 14, 28 or 56 capsules. Not all pack sizes may be marketed.
Information for children and young people
This information will help you learn the most important things about the medicine called Strattera.
If you don't like reading, someone like your mom, dad or your carer can read it to you and answer any questions. It may be helpful to read it a little at a time.
Why was this medicine given to me?
- This medicine can help children and young people with ADHD.
- ADHD can:
- make you run too much
- don't be careful
- make you act fast without thinking about what will happen next (impulsiveness)
- It interferes with learning, relationships with friends and what you think about yourself. It's not your fault.
While you are taking this medicine
- In addition to taking this medicine, you will also receive other help in dealing with ADHD, such as talking to ADHD specialists.
- This medicine must help you. But it doesn't cure ADHD.
- You will have to go to the doctor several times a year for checkups. This is to make sure the medicine is working and that you are growing and developing well.
- Girls should tell the doctor immediately if they think they may be pregnant. We do not know how this medicine affects the fetus. If you are having sex, talk to your doctor about contraception.
Some people cannot take this medicine
You cannot take this medicine if:
- you have taken a medicine known as a monoamine oxidase inhibitor (MAOI), such as phenelzine, in the past two weeks
- you have an eye disease called narrow-angle glaucoma (increased eye pressure)
- you have severe heart problems
- you have severe blood vessel problems in the brain
- you have adrenal gland tumor
Some people need to talk to their doctor before starting to take this medicine
You need to speak to your doctor if:
- you are pregnant or breastfeeding
- you are taking other medicines - your doctor must be informed of all medicines you are taking
- you have thoughts of harming yourself or others
- you have problems with your heart beating too fast or skipping beats even though you are not exercising
- you hear voices or see things that other people neither see nor hear
- you get angry easily
How do I take this medicine (capsules)?
- Swallow this medicine with water, regardless of meals.
- The capsules must not be opened. If the capsules break and the contents inside the capsules come into contact with your skin or eyes, get help from an adult.
- Your doctor will tell you how many times a day you need to take this medicine.
- Taking this medicine at the same time each day can help you remember to take it.
- Do not stop taking the medicine without talking to your doctor first.
Possible side effects
- Side effects are unwanted things that can happen when you take a medicine. If any of the following side effects occur, speak to a trusted adult right away. He will then discuss it with the doctor. The main things that could happen are:
- Your heart beating faster than normal
- Being very depressed and unhappy or wanting to hurt yourself
- Feeling aggressive
- Feeling unhappy or having a different mood than usual (mood swings)
- Show signs of an allergic reaction such as a "rash, itching or hives, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty in breathing
- Convulsions
- Seeing, feeling or hearing things that other people don't see, feel or hear
- Liver damage: belly pain that hurts when pressing (tenderness) on the right side just below the ribs
Because the medicine can make you sleepy, it is important not to engage in outdoor sports, such as horseback riding or cycling, swimming or climbing trees. You could harm yourself and others.
If you feel any kind of discomfort while you are taking the medicine, immediately notify an adult you trust.
Other things to remember
- Make sure you keep the medicine in a safe place so that no one else takes it, especially younger brothers or sisters.
- The medicine is just for you - don't let anyone else take it. It can help you, but it could be bad for others.
- If you forget to take your medicine, do not take two tablets next time. Just take one tablet at the next regular time.
- If you take too much medicine, immediately notify your mom, dad, or carer.
- It is important not to take too much medicine or you will get sick.
- Don't stop taking the medicine until your doctor says it's okay.
Who should I ask if there is something I don't understand?
Your mom, your father, your carer, your doctor, nurse or pharmacist can help you.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
STRATTERS HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg of atomoxetine.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsules.
STRATTERA 10 mg capsules: white opaque hard capsules, imprinted with "Lilly 3227" and "10 mg" in black ink.
STRATTERA 18 mg capsules: golden (cap) and opaque white (body) hard capsules, imprinted with "Lilly 3238" and "18 mg" in black ink.
STRATTERA 25 mg capsules: opaque blue (cap) and opaque white (body) hard capsules, imprinted with "Lilly 3228" and "25 mg" in black ink.
STRATTERA 40 mg capsules: opaque blue hard capsules, imprinted with "Lilly 3229" and "40 mg" in black ink.
STRATTERA 60 mg capsules: opaque blue (cap) and gold (body) hard capsules, imprinted in black ink with "Lilly 3239" and "60 mg.
STRATTERA 80 mg capsules: opaque brown (cap) and opaque white (body) hard capsules, imprinted with "Lilly 3250" and "80 mg" in black ink.
STRATTERA 100 mg capsules: opaque brown hard capsules imprinted with "Lilly 3251" and "100 mg" in black ink.
4.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Strattera is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age, adolescents and adults as part of a multimodal treatment program. Treatment should be initiated by a physician specialist in the treatment of ADHD such as a pediatrician, a childhood and adolescent neuropsychiatrist or a psychiatrist. Diagnosis should be made according to criteria established by the current DSM or ICD guidelines.
In adults, the presence of ADHD symptoms that pre-existed in childhood should be confirmed. Third party confirmation is desirable and Strattera should not be initiated if testing for ADHD symptoms in childhood is uncertain. Diagnosis cannot be made solely on the basis of the presence of one or more symptoms of ADHD. Based on clinical evaluation, patients must have ADHD of at least moderate severity, as indicated by at least moderate functional impairment in 2 or more areas. (e.g. social, scholastic and / or occupational) affecting different aspects of an individual's life.
Additional information for the safe use of this drug:
A multimodal treatment program normally includes psychological, educational and social interventions with the aim of stabilizing patients with a behavioral disorder characterized by symptoms that may include: chronic history of poor concentration, inattention, emotional lability, impulsivity, hyperactivity moderate to severe, minor neurologic signs and abnormal EEG. Learning may or may not be impaired.
Pharmacological treatment is not indicated for all patients with this disorder and the decision to use the drug must be based on a very careful assessment of the severity of the symptoms and impairment of the patient in relation to his age and persistence of the symptoms.
04.2 Posology and method of administration
For oral use. Strattera can be administered in a single daily dose in the morning, regardless of meals. Patients who have not achieved a satisfactory clinical response (for tolerability [for example, nausea or drowsiness] or efficacy) taking Strattera in a single daily dose, may benefit by dividing the daily dose of the medicinal product into two equal doses, the first in the morning. and the second in the late afternoon or early evening.
Dosage in children / adolescents weighing up to 70 kg:
Strattera should be administered initially at a total daily dose of approximately 0.5 mg / kg.
The starting dose should be maintained for at least 7 days before progressively increasing it according to clinical response and tolerability. The recommended maintenance dose is approximately 1.2 mg / kg / day (based on patient weight and available atomoxetine dosages). Doses above 1.2 mg / kg / day have shown no additional benefit. The safety of single doses above 1.8 mg / kg / day and total daily doses above 1.8 mg / kg has not been systematically evaluated. In some cases it may be appropriate to continue treatment into adulthood.
Dosage in children / adolescents weighing more than 70 kg:
Strattera should be administered initially at a total daily dose of 40 mg. The starting dose should be maintained for at least 7 days before progressively increasing it according to clinical response and tolerability. The recommended maintenance dose is 80 mg. Doses above 80 mg have shown no additional benefit. The maximum recommended total daily dose is 100 mg. The safety of single doses greater than 120 mg and total daily doses greater than 150 mg has not been systematically evaluated.
Dosage in adults
Strattera should be administered initially at a total daily dose of 40 mg. The starting dose should be maintained for at least 7 days before progressively increasing it according to clinical response and tolerability. The recommended daily maintenance dose is 80 mg to 100 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses greater than 120 mg and total daily doses greater than 150 mg has not been systematically evaluated.
Additional information for the safe use of this medicine:
Pre-treatment screening:
An appropriate medical history and initial assessment of the patient's cardiovascular status, including blood pressure and heart rate, should be performed prior to prescribing (see sections 4.3 and 4.4).
Monitoring during treatment:
Cardiovascular status should be monitored regularly by recording blood pressure and heart rate after each dose adjustment and at least every six months thereafter. The use of a percentile graph is recommended for pediatric patients. Current guidelines for hypertension should be followed for adults. (See section 4.4).
Discontinuation of treatment
No clear discontinuation symptoms were described in the drug development program. In case of significant adverse effects, atomoxetine can be stopped abruptly; otherwise the medicine may be slowly tapered off over an appropriate period of time.
Strattera treatment does not necessarily have to last indefinitely. A reassessment of the need to continue therapy for more than 1 year should be performed, particularly if the patient has achieved a stable and satisfactory response.
Special populations
Liver failure: In patients with moderate hepatic impairment (Child-Pugh Class B), initial and maintenance doses should be reduced to 50% of the usual dose. In patients with severe hepatic impairment (Child-Pugh Class C), initial and maintenance doses should be reduced to 25% of the usual dose. (see section 5.2).
Kidney failure: patients with end-stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (approximately 65% increase), but no difference was observed by correcting exposure for the mg / kg dose. Strattera can therefore be administered to ADHD patients with end stage renal disease or with a lesser degree of renal insufficiency using the usual posology. Atomoxetine may exacerbate hypertension in patients with end stage renal disease. (see section 5.2).
Approximately 7% of the Caucasian population has a genotype corresponding to a non-functional CYP2D6 enzyme (called CYP2D6 poor metabolisers).Patients with this genotype have several times higher exposure to atomoxetine than patients with a functional enzyme. Poor metabolisers are therefore at a higher risk of adverse events (see sections 4.8 and 5.2). In patients with known metabolizer genotype poor, a lower starting dose and slower dose titration should be considered.
Older people: the use of atomoxetine in patients over 65 years of age has not been systematically evaluated.
Children under 6 years of age: the safety and efficacy of Strattera in children under 6 years of age have not been established. Therefore, Strattera should not be used in children under 6 years of age (see section 4.4).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Atomoxetine must not be used in combination with monoamine oxidase inhibitors (MAOIs).
Atomoxetine should not be used for at least two weeks after stopping treatment with a MAOI. Treatment with a MAOI should not be started within two weeks after stopping treatment with atomoxetine.
Atomoxetine should not be used in patients with narrow-angle glaucoma as the use of atomoxetine has been associated with an increased incidence of mydriasis in clinical trials.
Atomoxetine should not be used in patients with severe cardiovascular or cerebrovascular disease (see section 4.4 Special warnings and precautions for use - Cardiovascular effects). Serious cardiovascular disease may include severe hypertension, heart failure, occlusive arterial disease, angina, haemodynamically significant congenital heart disease. , cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and canal disorders (diseases caused by ion channel dysfunction) Serious cerebrovascular disease can include brain aneurysm or stroke.
Atomoxetine should not be used in patients with pheochromocytoma or a history of pheochromocytoma (see section 4.4 Special warnings and precautions for use - Cardiovascular effects).
04.4 Special warnings and appropriate precautions for use
Suicidal behavior
Suicidal behavior (suicide attempts and suicidal thoughts) has been reported in patients treated with atomoxetine. In double-blind clinical trials cases of suicidal behavior were uncommon but observed more frequently among children and adolescents treated with atomoxetine than in those treated with placebo in which there were no cases. In double-blind clinical trials in adults there was no difference in the frequency of suicidal behavior between atomoxetine and placebo. Patients being treated for ADHD should be carefully monitored for the onset or worsening of suicidal behavior.
Sudden death and pre-existing cardiac abnormalities
Sudden death has been reported in patients with structural cardiac abnormalities who were taking atomoxetine at their usual doses. Although some severe structural cardiac abnormalities alone carry an increased risk of sudden death, atomoxetine should only be used with caution in patients with known structural cardiac abnormalities. severe and after consulting a cardiologist.
Cardiovascular effects
Atomoxetine can affect heart rate and blood pressure.
A modest increase in heart rate (mean blood pressure (mean
However, the pooled data from controlled and uncontrolled clinical trials in ADHD show that approximately 8-12% of children and adolescents and 6-10% of adults have a more marked change in heart rate (of 20 beats per minute or higher) and blood pressure (15-20 mm Hg or higher). Analysis of these clinical trial data showed that approximately 15-26% of children and adolescents and 27-32% of adults who experienced such changes in blood pressure and heart rate during treatment with atomoxetine had Prolonged or progressive increases Prolonged changes in blood pressure can potentially contribute, in the long term, to clinical consequences such as myocardial hypertrophy.
As a result of these findings, a "thorough medical history and physical examination to evaluate for heart disease should be done for patients being considered for treatment with atomoxetine, and such patients should receive further specialist cardiology evaluation if findings initials suggest a history of heart disease or heart disease.
It is recommended that heart rate and blood pressure be measured and recorded before starting treatment and during treatment, after each dose adjustment and at least every 6 months thereafter to identify possible clinically important increases. The use of a percentile graph is recommended for pediatric patients. Current guidelines for hypertension should be followed for adults.
Atomoxetine must not be used in patients with severe cardiovascular or cerebrovascular disease (see section 4.3 Contraindications - Severe cardiovascular and cerebrovascular diseases). Atomoxetine should be used with caution in patients whose underlying medical conditions may be aggravated by an increase in blood pressure and heart rate, such as patients with hypertension, tachycardia, or with cardiovascular or cerebrovascular disease.
Patients who develop symptoms such as palpitations, chest pain from exertion, unexplained syncope, dyspnoea or other symptoms suggesting heart disease during treatment with atomoxetine should undergo prompt specialist cardiology evaluation.
Furthermore, atomoxetine should be used with caution in patients with congenital or acquired long QT syndrome or family history of QT interval prolongation (see sections 4.5 and 4.8).
Since orthostatic hypotension has also been reported, atomoxetine should be used with caution in any situation that may predispose the patient to hypotension or in situations associated with sudden changes in heart rate or blood pressure.
Cerebrovascular effects
Patients with additional risk factors for cerebrovascular disorders (such as a history of cardiovascular disease, concomitant use of medicinal products that raise blood pressure) should be evaluated at each visit for neurological signs and symptoms after starting atomoxetine treatment.
Hepatic effects
Spontaneous cases of liver injury, characterized by elevated liver enzymes and bilirubin associated with jaundice, have been reported very rarely. In addition, severe hepatic injury, including acute liver failure, has been reported very rarely. Strattera must be discontinued in patients with jaundice or with laboratory tests indicating liver damage and must not be re-administered.
Psychotic or manic symptoms
Manic or psychotic symptoms that occur during treatment with atomoxetine, for example hallucinations, delusional ideas, mania or agitation in patients without a previous history of psychotic disorder or mania, may be caused by atomoxetine at the usual doses. If such symptoms occur, the possibility that they are caused by atomoxetine and discontinuation of treatment should be considered. The possibility that Strattera causes worsening of pre-existing psychotic or manic symptoms cannot be ruled out.
Aggressive behavior, hostility or emotional lability
In clinical trials, hostility (mainly aggression, oppositional behavior and anger) was observed more frequently in children, adolescents and adults treated with Strattera than in those treated with placebo. In clinical trials, emotional lability was observed more frequently in children treated with Strattera than in those treated with placebo. Patients should be closely monitored for the appearance or worsening of aggressive behavior, hostility or emotional lability.
Possible allergic events
Although uncommon, allergic reactions, including anaphylactic reactions, rash, angioneurotic edema and urticaria, have been reported in patients receiving atomoxetine.
Convulsions
Seizures are a potential risk associated with atomoxetine. Treatment with atomoxetine should be initiated with caution in patients with a history of seizures. Discontinuation of atomoxetine treatment should be considered in any patient who develops seizures or in the event of an increase in seizure frequency when no other cause is identified.
Growth and development
Growth and development in children and adolescents should be monitored during treatment with atomoxetine. Patients requiring long-term treatment should be monitored periodically and consideration should be given to reducing the dose or discontinuing therapy in those children and adolescents with unsatisfactory growth or weight gain.
Clinical data do not suggest a negative effect of atomoxetine on cognitive function or sexual maturation, however the amount of long-term data available is limited. Therefore, patients requiring long-term therapy should be carefully monitored.
Onset or worsening of comorbid depression, anxiety and tics
In a controlled study conducted in pediatric patients with ADHD and the simultaneous presence of chronic motor tics or Tourette's syndrome, patients treated with atomoxetine did not experience worsening of tics compared to those treated with placebo. In a controlled study conducted in adolescent patients with ADHD and the simultaneous presence of major depressive disorder, patients treated with atomoxetine did not experience worsening of depression compared to those treated with placebo. In two controlled studies conducted in patients with ADHD (one in pediatric patients and one in adult patients) and the simultaneous presence of anxiety disorders, patients treated with atomoxetine did not experience worsening of anxiety compared to those treated with placebo.
Rare cases of anxiety and depression or depressed mood and very rare cases of tics have been reported in the postmarketing period in patients taking atomoxetine (see section 4.8).
Patients who are being treated for ADHD with atomoxetine should be carefully monitored for the appearance or worsening of symptoms of anxiety, depressed mood, and depression or tics.
Children under 6 years of age
Strattera should not be used in patients less than 6 years old as efficacy and safety have not been established in this age group.
Other therapeutic use
Strattera is not indicated for the treatment of episodes of major depression and / or anxiety, as the results of clinical trials in adults in these conditions in the absence of ADHD have shown no effect compared to placebo (see section 5.1).
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other medicinal products on atomoxetine:
MAOIs: atomoxetine should not be used in combination with MAOIs (see section 4.3).
CYP2D6 inhibitors (SSRIs (such as fluoxetine and paroxetine), quinidine, terbinafine): In patients receiving these drugs, exposure to atomoxetine can be increased 6 to 8-fold and Css max be 3-4 times higher because l " atomoxetine is metabolised by CYP2D6. In patients already taking CYP2D6 inhibitor medicinal products, slower titration and a lower final dose of atomoxetine may be required. If a CYP2D6 inhibitor is prescribed or discontinued after titration of atomoxetine to the appropriate dose has been performed, the clinical response and tolerability in this patient should be reassessed to determine if a dosage adjustment is necessary.
Caution is advised when administering atomoxetine concomitantly with potent inhibitors of cytochrome P450 enzymes other than CYP2D6 to patients who are CYP2D6 poor metabolisers as the risk of a clinically relevant increase in atomoxetine exposure in vivo is unknown.
Salbutamol (or other beta 2 agonists):
Atomoxetine should be administered with caution to patients being treated with high doses of salbutamol (or other beta 2-agonists) taken by nebulisation or systemically as cardiovascular effects may be potentiated.
Contradictory results have been reported regarding this interaction. Systemic administration of salbutamol (600 mcg i.v. in 2 hours) in combination with atomoxetine (60 mg twice daily for 5 days) caused increases in heart rate and blood pressure. This effect was most marked after an initial concomitant administration of salbutamol and atomoxetine, but returned to baseline at the end of 8 hours. However, in a separate study conducted in healthy Asian adults, rapid metabolisers of atomoxetine, the effects on blood pressure and heart rate of a standard dose of salbutamol administered by inhalation (200 micrograms) were not enhanced by concomitant short-term administration of atomoxetine (80 mg once daily for 5 days). Similarly, heart rate after multiple inhalations of salbutamol (800 mcg) was similar in the presence or absence of atomoxetine.
Care should be taken in monitoring heart rate and blood pressure and dose adjustments of either atomoxetine or salbutamol (or other beta 2 agonists) may be warranted in the event of significant increases in heart rate and blood pressure during concomitant administration of these medicines.
There is a potential for an increased risk of QT interval prolongation when atomoxetine is administered with other QT interval prolonging drugs (such as neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium or cisapride), medicines that cause electrolyte imbalance (such as thiazide diuretics) and medicines that inhibit CYP2D6.
Seizures represent a potential risk associated with atomoxetine. Caution is advised in the simultaneous use of medicines known for their ability to induce a lowering of the seizure threshold (such as tricyclic antidepressants or SSRIs, neuroleptics, phenothiazines or butyrophenone, mefloquine, chloroquine, bupropion or tramadol ) (see section 4.4). In addition, caution is advised when concomitant benzodiazepine treatment is discontinued due to the possible occurrence of seizures associated with treatment discontinuation.
Antihypertensive drugs
Atomoxetine should be used with caution together with antihypertensive medicinal products. Due to the possible increase in blood pressure, atomoxetine may reduce the efficacy of antihypertensive medicines / medicines used to treat hypertension. Care should be taken in monitoring blood pressure and a re-evaluation of treatment with atomoxetine or antihypertensive medicines may be justified in the case of significant changes in blood pressure.
Pressor agents or medicines that increase blood pressure
Due to the possible increased effects on blood pressure, atomoxetine should be used with caution together with pressor agents or medicines that can increase blood pressure (such as salbutamol). Care should be taken in monitoring blood pressure and a re-evaluation of treatment with either atomoxetine or with blood pressure-increasing agents may be warranted in the event of a significant change in blood pressure.
Medicines that interfere with norepinephrine:
Medicinal products that interfere with noradrenaline should be used with caution concomitantly with atomoxetine due to possible additive or synergistic pharmacological effects. Examples of such medicines include antidepressants such as imipramine, venlafaxine and mirtazapine, or decongestants such as pseudoephedrine or phenylephrine.
Medicines that affect gastric pH:
Medicinal products that increase gastric pH (magnesium hydroxide / aluminum hydroxide, omeprazole) have no effect on the bioavailability of atomoxetine.
Medicinal products with high plasma protein binding:
In vitro drug displacement studies have been performed using therapeutic concentrations of atomoxetine and other highly plasma protein binding drugs. Warfarin, acetylsalicylic acid, phenytoin or diazepam do not affect the binding of atomoxetine to human albumin. Similarly, atomoxetine does not affect the binding of these compounds to human albumin.
04.6 Pregnancy and breastfeeding
Pregnancy
Animal studies in general do not indicate direct harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3). Clinical data on atomoxetine exposure in pregnancy are limited. Such data are insufficient to indicate whether or not there is an "association between atomoxetine and adverse effects during pregnancy and lactation. Atomoxetine should not be used during pregnancy unless that the potential benefit does not justify the potential risk to the fetus.
Feeding time
In rats, atomoxetine and / or its metabolites are excreted in human milk.It is not known whether atomoxetine is excreted in human milk. Due to lack of data, atomoxetine should be avoided during breastfeeding.
04.7 Effects on ability to drive and use machines
Data on effects on the ability to drive and use machines are limited. Atomoxetine has been associated with an "increased frequency of fatigue, somnolence and dizziness compared to placebo in pediatric and adult patients. Patients should be advised to use caution when driving vehicles or operating hazardous machinery, until they are reasonably sure that their abilities are not affected by atomoxetine.
04.8 Undesirable effects
Children and adolescents:
In the placebo-controlled studies in pediatric patients, the most commonly associated adverse events with atomoxetine were headache, abdominal pain1 and decreased appetite, reported by approximately 19%, 18% and 16% of patients, respectively, but these rarely cause discontinuation of treatment (discontinuation rates are 0.1% for headache, 0.2% for abdominal pain and 0.0% for decreased appetite). Abdominal pain and decreased appetite are usually transient.
In association with decreased appetite, some patients experienced growth retardation in terms of both weight gain and height at the start of treatment. On average, after an "initial decrease in" weight and height gain, patients treated with atomoxetine recovered to mean weight and height predicted from baseline patient group data on long-term treatment.
Nausea, vomiting and somnolence2 may occur in approximately 10% - 11% of patients, especially in the first month of therapy. However, these episodes were generally mild to moderate and transient and did not lead to a significant number of treatment interruptions (the rate of discontinuation ≤ 0.5%).
In both pediatric and placebo-controlled adult studies, patients treated with atomoxetine experienced an increase in heart rate and systolic and diastolic blood pressure (see section 4.4).
Due to the effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope (0.8%) have been reported in patients taking atomoxetine. Atomoxetine should be used with caution in any condition that predisposes the patient to hypotension.
The table of undesirable effects below is based on adverse event reports and laboratory tests performed during clinical trials and spontaneous reports reported in children and adolescents in the post-marketing period.
Table: Adverse reactions
Estimated frequency: Very common (≥1 / 10), common (≥1 / 100,
1 Also includes upper abdominal pain, epigastric, abdominal and stomach discomfort.
2 Also includes sedation.
3 Includes initial, central and terminal insomnia (early morning awakening).
4Heart rate and blood pressure are based on measuring vital signs.
* See section 4.4.
** See sections 4.4 and 4.5.
Poor metabolisers CYP2D6 (PM)
The following adverse events occurred at a rate of at least 2% in CYP2D6 poor metaboliser patients and were statistically significantly more frequent in CYP2D6 poor metabolisers (PM) patients than in CYP2D6 extensive (EM) metabolisers patients: appetite (24.1% in PM patients, 17.0% in EM patients); combined insomnia (including insomnia, central insomnia and initial insomnia, 14.9% in PM patients, 9.7% in EM patients); combined depression (including depression, major depression, depressive symptoms, depressed mood and dysphoria, 6.5% in PM patients and 4.1% in EM patients), weight reduction (7.3% in PM patients, 4.4% in EM patients EM), constipation (6.8% in PM patients, 4.3% in EM patients); tremor (4.5% in PM patients, 0.9% in EM patients); sedation (3.9% in PM patients , 2.1% in EM patients); excoriation (3.9% in PM patients, 1.7% in EM patients); enuresis (3.0% in PM patients, 1.2% in EM patients); conjunctivitis (2.5% in PM patients, 1.2% in EM patients); syncope (2.5% in PM patients, 0.7% in EM patients); early morning awakening (2.3% in PM patients, 0.8% in EM patients); mydriasis (2.0% in PM patients, 0.6% in EM patients). The following event, while not meeting the above criteria, is noteworthy: generalized anxiety disorder (0.8% in PM patients, 0.1% in EM patients). Furthermore, in studies lasting up to 10 weeks, weight loss was more pronounced in PM patients (mean 0.6 kg in EM patients and 1.1 kg in PM patients).
Adults:
In adult ADHD clinical trials during treatment with atomoxetine, the most frequent adverse events by system organ class were gastrointestinal disorders, nervous system disorders and psychiatric disorders. The most common adverse events reported ( ≥5%) were decreased appetite (14.9%), insomnia (11.3%), headache (16.3%), dry mouth (18.4%) and nausea (26.7%) ). Most of these events were mild to moderate in severity and the most frequently reported serious events were nausea, insomnia, fatigue and headache.
The occurrence of urinary retention or hesitation in adult patients should be considered potentially related to atomoxetine.
The table of undesirable effects below is based on adverse event reports and laboratory tests performed during clinical trials and spontaneous reports in adults in the post-marketing period.
Table: Adverse reactions
Estimated frequency: Very common (≥1 / 10), common (≥1 / 100,
1 Also includes upper abdominal pain, epigastric, abdominal and stomach discomfort.
2 Also includes initial, central and terminal insomnia (early morning awakening).
3 Heart rate and blood pressure are based on measuring vital signs.
4 Includes anaphylactic reactions and angioneurotic edema.
* See section 4.4.
** See sections 4.4 and 4.5.
Poor metabolisers CYP2D6 (PM)
The following adverse events occurred at a rate of at least 2% in CYP2D6 poor metaboliser patients and were statistically significantly more frequent in CYP2D6 poor metabolisers (PM) patients than in CYP2D6 extensive (EM) metabolisers patients: blurred vision ( 3.9% in PM patients, 1.3% in EM patients), dry mouth (34.5% in PM patients, 17.4% in EM patients), constipation (11.3% in PM patients, 6, 7% in EM patients), nervousness (4.9% in PM patients, 1.9% in EM patients), decreased appetite (23.2% in PM patients, 14.7% in EM patients), uterine leiomyoma (2.3% in PM patients, 0.1% in EM patients), tremor (5.4% in PM patients, 1.2% in EM patients), insomnia (19.2% in PM patients, 11.3 % in EM patients), sleep disturbance (6.9% in PM patients, 3.4% in EM patients), central insomnia (5.4% in PM patients, 2.7% in EM patients), terminal insomnia ( 3% in PM patients, 0.9% in EM patients), urinary retention (5.9% in PM patients, 1.2% in EM patients), erectile dysfunction (20.9% in PM patients, 8.9% in EM patients), ejaculation disorder (6.1% in PM patients , 2.2% in EM patients), hyperhidrosis (14.8% in PM patients, 6.8% in EM patients), peripheral coldness (3% in PM patients, 0.5% in EM patients).
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , Website: (http://www.agenziafarmaco.gov.it/it/responsabili).
04.9 Overdose
Signs and symptoms:
Non-fatal cases of acute and chronic overdose of atomoxetine used alone have been reported in the post-marketing period. The most commonly reported acute and chronic overdose symptoms were gastrointestinal symptoms, somnolence, dizziness, tremor and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate activation of the sympathetic nervous system (eg tachycardia, increased blood pressure, mydriasis, dry mouth) have also been observed, and cases of pruritus and rash have been reported. events were mild to moderate. In some cases of overdose with atomoxetine, seizures and very rarely QT interval prolongation have been reported. There have also been reports of fatal cases of acute overdose associated with taking atomoxetine with at least one other medicine.
Experience with atomoxetine overdose in clinical trials is limited. No fatal cases of overdose occurred in clinical trials.
Treatment of overdose:
The patient should be given artificial ventilation. To limit absorption, activated charcoal may be useful if the patient presents within 1 hour of ingestion. Monitoring of vital and cardiac parameters is recommended, together with appropriate symptomatic and supportive measures. The patient should be observed for a minimum of 6 hours. Given the high binding of atomoxetine to plasma proteins, it is unlikely that dialysis is useful in the treatment of overdose.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: centrally acting sympathomimetics.
ATC code: N06BA09.
Mechanism of action and pharmacodynamic effects
Atomoxetine is a potent and highly selective inhibitor of the presynaptic norepinephrine transporter, this constitutes its alleged mechanism of action, without presenting a direct action on the serotonin or dopamine transporters. Atomoxetine has minimal affinity for others. noradrenergic receptors or for transporters or other neurotransmitter receptors The two major oxidative metabolites of atomoxetine are 4-hydroxyatomoxetine and N-desmethylatomoxetine.
4-hydroxyatomoxetine has the same potency as atomoxetine as an inhibitor of the norepinephrine transporter but, unlike atomoxetine, this metabolite also exerts an inhibitory action on the serotonin transporter. However, any effect on this transporter is probably minimal, since since most of 4-hydroxyatomoxetine is further metabolised, therefore it is found in plasma at very low concentrations (1% of the concentration of atomoxetine in patients who are rapid metabolisers and 0.1% of the concentration of atomoxetine in those poor metabolisers) N-desmethylatomoxetine has substantially lower pharmacological activity than atomoxetine. At steady-state it is present in plasma at concentrations below those of atomoxetine in extensive metabolisers and at concentrations comparable to those of atomoxetine in poor metabolisers.
Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In a randomized, double-blind, placebo-controlled study in adults to assess the potential for abuse by comparing the effects of atomoxetine with those of placebo, atomoxetine did not it has been associated with a response pattern that suggests stimulating or euphoric properties.
Clinical efficacy and safety
Pediatric population
Clinical trials with Strattera involved over 5,000 children and adolescents with ADHD. The acute efficacy of Strattera in the treatment of ADHD was initially established in six randomized, double-blind, placebo-controlled studies lasting between six and nine weeks.
The signs and symptoms of ADHD were evaluated by comparing the mean changes from baseline to endpoint of patients treated with Strattera and those treated with placebo. In each of the six studies, atomoxetine was statistically significantly superior to placebo in reducing the signs and symptoms of ADHD.
Furthermore, the efficacy of atomoxetine in maintaining symptom response was demonstrated in a one-year, placebo-controlled study conducted mainly in Europe in more than 400 children and adolescents (acute open label treatment for approximately 3 months followed by 9 months of double-blind maintenance treatment versus placebo). The percentage of patients who relapsed after 1 year was 18.7% with atomoxetine and 31.4% with placebo, respectively. After one year of treatment with atomoxetine, patients who continued treatment with atomoxetine for an additional 6 months were less likely to relapse or partially return symptoms than patients who stopped active treatment and switched to placebo. (2% vs. 12% respectively). During long-term treatment, periodic evaluation of the response to ongoing treatment should be performed for children and adolescents.
Strattera was effective in a single daily dose and in two separate administrations, one in the morning and one in the late afternoon / early evening. Strattera given as a single daily dose showed a statistically significantly greater reduction in the severity of ADHD symptoms compared to placebo, according to the judgment of teachers and parents.
The European Medicines Agency has deferred the obligation to submit the results of studies with Strattera in a subset of the pediatric population aged 4 to 6 years for the treatment of ADHD (see section 4.2 for information on pediatric use).
Studies with active comparator
In a 6-week, randomized, double-blind, parallel-group pediatric study to evaluate the non-inferiority of atomoxetine to a standard comparator such as prolonged-release methylphenidate, the comparator was shown to be associated with a higher response rate than to atomoxetine. The percentage of patients classified as responders was 23.5% (placebo), 44.6% (atomoxetine) and 56.4% (methylphenidate). Both atomoxetine and comparator were statistically superior to placebo and methylphenidate was statistically superior to atomoxetine (p = 0.016). However, this study excluded patients who were non-responders to stimulants.
Adult population
Strattera has been studied in over 4800 adults who met the DSM-IV diagnostic criteria for "ADHD. The acute efficacy of Strattera in the treatment of adults was established in six randomized, double-blind, placebo-controlled trials of duration. between ten and sixteen weeks. The signs and symptoms of ADHD were evaluated by comparing the mean changes from baseline to the endpoint of patients treated with atomoxetine and those treated with placebo. In each of the six studies, atomoxetine was statistically significantly superior to placebo in reducing signs and symptoms of ADHD (Table X). Patients treated with atomoxetine had statistically significantly greater improvements in terms of Overall Clinical Impression of severity (CGI-S scale) at the endpoint compared to placebo-treated patients in all 6 acute studies and had statistically significantly greater improvements in ADHD-related functioning in all 3 acute studies in which this was evaluated (Table X). Long-term efficacy was confirmed in 2 6-month, placebo-controlled studies, but was not demonstrated in a third study (Table X).
Table X Mean changes in efficacy measures in placebo-controlled studies
Abbreviations: AAQoL = Total score of the quality of life scale for adults with ADHD; AISRS = Investigator's symptom rating scale total score for adults with ADHD; ATX = atomoxetine; CAARS-Inv: SV = Conners scale for adults with ADHD (investigator): screening version (Conners Adult ADHD Rating Scale, Investigator Rated, screening version Total ADHD Symptom Score); CGI-S = Overall Clinical Impression of Severity; LOCF = Last observation completed; PBO = placebo.
a: ADHD symptom scales; results shown for the LYBY Study are according to the AISRS scale; results for all other studies are according to the CAARS-Inv: SV scale.
In sensitivity analyzes that used a "completed baseline observation (baseline-observation-carried-forward method) for patients with no post-baseline measurement (i.e. all patients treated). The results were consistent with the results shown in Table X.
In clinically significant response analyzes in all 6 acute studies and in both successful long-term studies, using a variety of a priori and post hoc definitions, patients treated with atomoxetine consistently had higher response rates in statistically significantly compared to patients treated with placebo (Table Y).
Table Y Number (n) and percentage of patients meeting response criteria in pooled placebo-controlled studies
a Includes all studies in Table X except: CGI-S acute response analysis excludes 2 studies in patients with comorbid disorders (LYBY, LYDQ); CAARS acute response analysis excludes 1 study in which the CAARS scale was not performed (LYBY).
In two of the acute studies, patients with comorbid alcoholism or social anxiety disorders were studied and in both studies ADHD symptoms improved. In the comorbid alcohol abuse study, there were no differences between atomoxetine and placebo in relation to alcohol use behaviors. In the comorbid anxiety study, the comorbid anxiety condition did not worsen with treatment with atomoxetine.
The efficacy of atomoxetine in maintaining symptom response was demonstrated in a study where, after an initial 24-week active treatment period, patients who met the criteria for a clinically significant response (defined by an improvement in score of both CAARS-Inv: SV and CGI-S) were randomized to receive atomoxetine or placebo for an additional 6 months of double-blind treatment. At the end of 6 months, they met the criteria for maintaining a clinically significant response. higher percentages of patients treated with atomoxetine than placebo (64.3% vs. 50.0%; p = .001). Patients treated with atomoxetine demonstrated statistically significantly better maintenance of functioning than patients treated with placebo, as demonstrated by a smaller mean change in the total score on the quality of life scale for adults with ADHD ( YYQoL) in the third month (p = .003) and in the sixth month (p = .002).
QT / QTc study
A thorough QT / QTc study, conducted in healthy adult CYP2D6 poor metabolisers (PM) patients treated with doses up to 60 mg of atomoxetine twice daily, demonstrated that, at maximum expected concentrations, the effect of atomoxetine on The QTc interval was not significantly different from that of placebo. There was a slight increase in the QTc interval with increasing concentration of atomoxetine.
05.2 Pharmacokinetic properties
The pharmacokinetics of atomoxetine in children and adolescents are similar to that in adults. The pharmacokinetics of atomoxetine have not been evaluated in children less than six years of age.
Absorption: Atomoxetine is rapidly and almost completely absorbed after oral administration, reaching the mean maximum observed plasma concentration (Cmax) approximately 1-2 hours after administration. The absolute bioavailability of atomoxetine after oral intake varies from 63% to 94%, in relation to interindividual differences in the modest first pass metabolism. Atomoxetine can be taken with or without food.
Distribution: Atomoxetine is widely distributed and is highly bound (98%) to plasma proteins, mainly albumin.
Biotransformation: Atomoxetine is primarily metabolised by the cytochrome P450 2D6 (CYP2D6) enzyme system. Individuals with reduced activity of this metabolic pathway (poor metabolisers) represent approximately 7% of the Caucasian population and have higher plasma concentrations of atomoxetine than individuals with normal activity (extensive metabolisers).
In poor metaboliser patients, the AUC of atomoxetine is about 10 times higher and Css max is about 5 times higher than in fast metaboliser patients. The major oxidative metabolite that is formed is 4-hydroxyatomoxetine which is rapidly glucuronidated. hydroxyatomoxetine is equipotent to atomoxetine, but is present in the blood at much lower concentrations. Although 4-hydroxyatomoxetine is formed mainly by CYP2D6, in individuals lacking CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. Atomoxetine at therapeutic doses does not inhibit it. nor does it induce CYP2D6.
Cytochrome P450 enzymes: Atomoxetine did not result in clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6 and CYP2C9.
Elimination: The mean elimination half-life of atomoxetine following oral administration is 3.6 hours in extensive metabolisers and 21 hours in poor metabolisers. Atomoxetine is eliminated mostly as 4-hydroxyatomoxetine-OR-glucuronide, mainly in the urine.
Linearity / non-linearity: the pharmacokinetic profiles of atomoxetine are linear over the dose range studied in both extensive and slow metabolisers.
Special populations
Hepatic injury leads to reduced clearance of atomoxetine, "increased exposure to" atomoxetine (2-fold increased AUC in moderate hepatic injury and 4-fold increased in severe hepatic injury), a "prolonged half-life of the drug compared to healthy control subjects. with the same genotype as the CYP2D6 rapidly metaboliser. In patients with moderate to severe hepatic impairment (Child-Pugh Classes B and C), initial and maintenance doses should be adjusted (see section 4.2).
Mean plasma concentrations of atomoxetine in subjects with end stage renal disease (ESRD) were generally higher than the mean plasma concentrations in healthy control subjects as evidenced by an increase in Cmax (7% difference) and AUC0- ? (difference of approximately 65%). After adjustment for body weight, differences between the two groups are minimized. The pharmacokinetic profiles of atomoxetine and its metabolites in individuals with ESRD suggest that no dosage adjustment would be necessary ( see section 4.2).
05.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity or reproductive and developmental toxicity. Due to dose limitations imposed by clinical response ( or excessive drug response) to the medicinal product in animals, together with the observed metabolic differences between species, the maximum tolerated doses in animals, used in non-clinical studies, produced atomoxetine exposures similar or slightly higher than those obtained in the CYP2D6 poor metaboliser patients with the maximum recommended daily dose.
A study was conducted in juvenile rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Mild delays in maturation of vaginal patency (all doses) and separation of the foreskin (≥ 10 mg / kg) were observed. / day), slight decrease in epididymal weight and sperm count (≥ 10 mg / kg / day); however there were no effects on fertility or reproductive capacity. The significance of these findings for humans is not known.
Pregnant rabbits were treated with atomoxetine doses up to 100 mg / kg / day administered via gavage during the period of organogenesis. At this dose, in 1 of the 3 studies, a reduction in the birth of live fetuses, an increase in early resorption, a slight increase in the incidence of atypical origin of the carotid artery and in the absence of the subclavian artery were observed. These effects were seen at dosages that caused mild maternal toxicity. The incidence of these effects is within the historical control values. The no-effect dose for these findings was 30 mg / kg / day. Atomoxetine unbound plasma exposure (AUC) in rabbits at doses of 100 mg / kg / day was approximately 3.3-fold (in CYP2D6 extensive metabolisers) and 0.4-fold (CYP2D6 poor metabolisers). ) compared to that in men at a maximum daily dose of 1.4 mg / kg / day. The results of one of the three rabbit studies were equivocal and relevance to humans is unknown.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Pregelatinised starch (maize)
Dimethicone
Capsule shell:
Sodium lauryl sulfate
Jelly
Capsule head shell dyes
10 mg: Titanium dioxide E171
18 mg: Yellow iron oxide E172
25 mg, 40 mg, 60 mg: FD&C Blue 2 (Indigo carmine) E132 and Titanium dioxide E171
80 mg and 100 mg: Yellow iron oxide E172, red iron oxide E172 and titanium dioxide E171
Capsule body shell dyes
10 mg, 18 mg and 25 mg and 80 mg: Titanium dioxide E171
40 mg: FD&C Blue 2 (Indigo carmine) E132 and Titanium dioxide E171
60 mg: Yellow iron oxide E172
100 mg: Yellow iron oxide E172, red iron oxide E172 and titanium dioxide E171
Edible Black Ink SW-9008 (containing Shellac and Black Iron Oxide E172) or Edible Black Ink SW-9010 (containing Shellac and Black Iron Oxide E172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Polyvinyl chloride (PVC) / polyethylene (PE) / Polychlorotrifluoroethylene (PCTFE) blisters sealed with aluminum foil.
Available in packs of 7, 14, 28 and 56 capsules. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
The capsules must not be opened. Atomoxetine is an eye irritant. If the contents of the capsules come into contact with the eyes, the affected eye should be washed immediately with water and medical attention should be sought. Hands and any potentially contaminated surfaces should be washed as soon as possible.
07.0 MARKETING AUTHORIZATION HOLDER
Eli Lilly Italia S.p.A.
Via Gramsci 731/733
Sesto Fiorentino (FI)
08.0 MARKETING AUTHORIZATION NUMBER
STRATTERA 10 mg hard capsules, 7 hard capsules: AIC N. 037063056
STRATTERA 10 mg hard capsules, 14 hard capsules: AIC N. 037063068
STRATTERA 10 mg hard capsules, 28 hard capsules: AIC N. 037063070
STRATTERA 10 mg hard capsules, 56 hard capsules: AIC N. 037063082
STRATTERA 18 mg hard capsules, 7 hard capsules: AIC N. 037063094
STRATTERA 18 mg hard capsules, 14 hard capsules: AIC N. 037063106
STRATTERA 18 mg hard capsules, 28 hard capsules: AIC N. 037063118
STRATTERA 18 mg hard capsules, 56 hard capsules: AIC N. 037063120
STRATTERA 25 mg hard capsules, 7 hard capsules: AIC N. 037063132
STRATTERA 25 mg hard capsules, 14 hard capsules: AIC N. 037063144
STRATTERA 25 mg hard capsules, 28 hard capsules: AIC N. 037063157
STRATTERA 25 mg hard capsules, 56 hard capsules: AIC N. 037063169
STRATTERA 40 mg hard capsules, 7 hard capsules: AIC N. 037063171
STRATTERA 40 mg hard capsules, 14 hard capsules: AIC N. 037063183
STRATTERA 40 mg hard capsules, 28 hard capsules: AIC N. 037063195
STRATTERA 40 mg hard capsules, 56 hard capsules: AIC N. 037063207
STRATTERA 60 mg hard capsules, 7 hard capsules: AIC N. 037063219
STRATTERA 60 mg hard capsules, 14 hard capsules: AIC N. 037063221
STRATTERA 60 mg hard capsules, 28 hard capsules: AIC N. 037063233
STRATTERA 60 mg hard capsules, 56 hard capsules: AIC N. 037063245
STRATTERA 80 mg hard capsules, 7 hard capsules: AIC N. 037063258
STRATTERA 80 mg hard capsules, 14 hard capsules: AIC N. 037063260
STRATTERA 80 mg hard capsules, 28 hard capsules: AIC N. 037063272
STRATTERA 80 mg hard capsules, 56 hard capsules: AIC N. 037063284
STRATTERA 100 mg hard capsules, 7 hard capsules: AIC N. 037063296
STRATTERA 100 mg hard capsules, 14 hard capsules: AIC N. 037063308
STRATTERA 100 mg hard capsules, 28 hard capsules: AIC N. 037063310
STRATTERA 100 mg hard capsules, 56 hard capsules: AIC N. 037063322
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
April 19, 2007
10.0 DATE OF REVISION OF THE TEXT
AIFA Resolution of 3 November 2014
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