LEFISYO 5 mg /Ml Oral Solution

Зміст інструкції

1. Lefisyo 5 mg/ml oral solution
   1. What is Lefisyo and what is it used for
   2. What you need to know before you take Lefisyo
   3. How to take Lefisyo
   4. Possible side effects
   5. How to store Lefisyo
   6. Package Contents and Other Information

Lefisyo 5 mg/ml oral solution

levomethadone hydrochloride

Read this leaflet carefully before taking this medicine as it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

• 1. What Lefisyo is and what it is used for
• 2. What you need to know before you take Lefisyo
• 3. How to take Lefisyo
• 4. Possible side effects
• 5. How to store Lefisyo
• 6. Contents of the pack and other information

1. What is Lefisyo and what is it used for

Levomethadone hydrochloride, the active ingredient in Lefisyo, is a medicine belonging to the group of
opioids.
Lefisyo is used:
as part of substitution therapy for opioid/opiate dependence in adults, which
includes adequate medical, social and psychological support (integrated treatment program).
as a temporary substitute, for example in case of hospitalisation.

2. What you need to know before you take Lefisyo

Do not take Lefisyo

• If you are allergic to levomethadone or any of the other ingredients of this medicine (listed in section 6).
• If you are taking monoamine oxidase inhibitors (MAO inhibitors, medicines for the treatment of Parkinson's disease or depression) or if you have stopped taking them less than two weeks ago.
• If you are taking medicines that can neutralise or alter the effects of Lefisyo, such as pentazocine and buprenorphine. However, these medicines can be used to treat an overdose of Lefisyo.

Warnings and precautions
Levomethadone can only be used in patients dependent on opioids/opiates by doctors
authorised to provide substitution treatment, as the standard doses used in substitution treatment
can cause severe intoxication or even be fatal in patients not tolerant to opioids.
Talk to your doctor or pharmacist before taking Lefisyo if any of the following applies to you. The doctor will then carry out the treatment only if it is necessary. This is particularly relevant
in cases of:

• Pregnancy and breastfeeding
• Reduced level of consciousness
• Use of this medicine together with other medicines that suppress certain brain functions (e.g. control of breathing) (see sections on "Other medicines and Lefisyo" and "Lefisyo with alcohol")
• Use of Lefisyo at the same time as sedatives or sleeping pills (such as benzodiazepines and related medicines): This can lead to drowsiness, shallow and weak breathing and coma, and may even be fatal (see also "Other medicines and Lefisyo").
• Diseases in which respiratory depression must be avoided, such as
• Asthma
• Lung diseases with chronic constriction of the airways
• Heart failure caused by severe lung disease
• Moderate to severe respiratory depression (slow or shallow breathing, ineffective leading to increased carbon dioxide and decreased oxygen in the body) and dyspnoea (shortness of breath)
• Low levels of oxygen in the blood
• Increased levels of carbon dioxide in the blood In these diseases, breathing may be made difficult or respiratory arrest may occur even at normal doses of Lefisyo. Worsening of pre-existing asthma or skin rashes and blood count abnormalities may occur, especially if you are prone to allergies.
• Increased intracranial pressure: This may increase further.
• Low blood pressure due to dehydration
• Enlarged prostate with incomplete bladder emptying
• Inflammation of the pancreas
• Biliary disorders
• Obstructive and inflammatory bowel diseases
• Pheochromocytoma, a tumour of the adrenal gland that secretes hormone
• Hypothyroidism (a condition in which the thyroid does not produce enough hormones)
• Risk of suicide: Suicide attempts with opioids, especially in combination with some medicines used to treat depression (antidepressants), alcohol and other substances, may be one of the clinical features of substance dependence. Contact your doctor or a specialist support centre if you are unable to stop taking these substances.
• Severe abdominal conditions: Treatment with Lefisyo may also mask severe abdominal disorders. At the first signs of abdominal problems, you should be monitored clinically regularly until the exact cause has been established.
• Cardiac arrhythmias (problems with heart rhythm) or prolonged ventricular activity, known as QT prolongation, or abnormalities in mineral balance, especially in the case of low potassium levels. Some opioids can affect cardiac conduction (QT prolongation on ECG). This can cause a dangerous heart rhythm disorder (too fast, irregular heartbeat, "torsades de pointes"). Immediately inform your doctor if you experience irregular heartbeat or fainting.
• Therapy with antiarrhythmic class I and III drugs
• Slowed heart rate

The dose must be reduced in the elderly and in patients with kidney disease, severe chronic liver
disease or in poor general health.
Talk to your doctor or pharmacist before taking Lefisyo if you suffer from a disorder of the adrenal
glands. Your treatment must be carried out with caution.
Talk to your doctor or pharmacist if you experience any of the following symptoms while taking
Lefisyo: weakness, fatigue, loss of appetite, nausea, vomiting or low blood pressure.
This could be a symptom that the adrenal gland is producing too little cortisol hormone, and a hormonal
supplement may be necessary.
Long-term use of opioids can cause a decrease in sex hormone levels and an
increase in prolactin hormone levels. Contact your doctor if you experience symptoms such as decreased
libido, impotence or absence of menstruation (amenorrhoea).

Further information
In cases of long-term and repeated use, levomethadone can cause physical and mental dependence and
tolerance with loss of efficacy, this is known as tolerance. Discontinuation after repeated use or
in case of opioid dependence, or the administration of an opioid antagonist (a substance
that can block the effect of opioids) can trigger withdrawal syndrome.
Taking Lefisyo by people who are not accustomed to taking opioids repeatedly
or regularly is dangerous and can cause death from respiratory arrest.
Lefisyo is for oral use only. Abuse of Lefisyo through intravenous injection causes overdose
and potentially fatal adverse effects such as blood poisoning, vein inflammation and
blockage of blood vessels in the lungs.
Drug and medicine abuse during substitution treatment can lead to potentially fatal accidents
and must be absolutely avoided.
The doctor will perform regular urine tests to detect any concurrent substance use.
When using levomethadone it is important to remember that it is twice as effective as racemic methadone
(see also section 3 "How to take Lefisyo").

Effects of abuse for doping purposes
Taking Lefisyo can lead to positive results in doping tests. Furthermore, the abuse of Lefisyo
as a doping substance can lead to health risks.

Other medicines and Lefisyo
Tell your doctor or pharmacist if you are taking, have recently taken or might
take any other medicines.
The daily dose of Lefisyo required may be affected by taking other medicines.
Tell your doctor if you notice signs of an increase in the effect of Lefisyo or withdrawal symptoms.
The following medicines must not be taken together with Lefisyo:

• Monoamine oxidase inhibitors: Medicines for treating depression or Parkinson's disease. These medicines must be stopped at least 14 days before treatment with Lefisyo. Otherwise, potentially fatal suppressive or excitatory effects on breathing and circulation may occur.
• Pentazocine, buprenorphine: medicines for severe pain. If these are used at the same time as Lefisyo, withdrawal symptoms may occur. Buprenorphine should only be administered 20 hours after stopping Lefisyo. In exceptional cases, these medicines may be taken at the same time as this medicine if they are used in the treatment of Lefisyo overdose. Tell your doctor if you are using any of the following medicines as they may alter the effect of Lefisyo:
• Other medicines that suppress certain brain functions (e.g. control of

breathing), such as

• Strong painkillers (including opioids)
• Some medicines used to treat psychiatric disorders whose active ingredients generally end in "-azine", such as phenothiazines
• Sleeping pills
• Antiepileptic medicines, known as barbiturates, whose active ingredients generally end in "-tal", such as phenobarbital
• Narcotics
• Some medicines for treating depression known as tricyclic antidepressants (e.g. trimipramine and doxepin) When used at the same time as Lefisyo, they can cause mutual amplification of the effect on brain functions and can therefore lead, for example, to drowsiness, or shallow or weak breathing (see "Warnings and precautions"). Please follow the dosage recommendations provided by your doctor exactly.
• Sedatives and sleeping pills called benzodiazepines (generally end in "-zepam", such as diazepam, flunitrazepam) and related medicines (such as zolpidem). The concomitant use of Lefisyo and sedatives such as benzodiazepines or related medicines increases the risk of drowsiness, difficulty breathing (respiratory depression), coma and may be potentially fatal. For this reason, concomitant use should only be considered when other treatment options are not possible. However, if your doctor prescribes Lefisyo together with sedatives, your doctor should limit the dose and duration of concomitant treatment. Tell your doctor about all sedatives you are taking, and carefully follow your doctor's dosage recommendations. It may be helpful to inform friends or family members to be alert for signs and symptoms indicated above. If you experience any of these symptoms, contact your doctor.
• Some medicines used to treat depression called selective serotonin reuptake inhibitors (SSRIs, such as sertraline, fluvoxamine, fluoxetine and paroxetine)
• Medicines for treating high blood pressure (such as reserpine, clonidine, urapidil and prazosin)
• Cimetidine, a medicine used to reduce stomach acid formation
• Medicines for treating fungal infections (such as itraconazole, ketoconazole, voriconazole, fluconazole)
• Medicines used to treat heart rhythm disorders (e.g. antiarrhythmics of class I and III, such as amiodarone)
• Contraceptive pill
• Carbamazepine and phenytoin, medicines used to treat epilepsy
• Medicines used to treat some bacterial infections, such as rifampicin, medicines known as macrolide antibiotics, ciprofloxacin, fusidic acid,
• St John's Wort
• Spironolactone (a diuretic)
• Medicines that inhibit the multiplication of HIV (such as efavirenz, nevirapine, nelfinavir, ritonavir, amprenavir, didanosine, stavudine, zidovudine). The risk of adverse effects increases if you use levomethadone together with antidepressants (such as citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, imipramine, nortriptyline). Tell your doctor if you experience symptoms such as:
• Altered mental status (e.g. agitation, hallucinations, coma)
• Fast heartbeat, unstable blood pressure, fever
• Exaggerated reflexes, lack of coordination, muscle stiffness
• Gastrointestinal symptoms (such as nausea, vomiting, diarrhoea)

Lefisyo with alcohol
Do not drink alcohol while taking Lefisyo. Alcohol can unpredictably increase its effect and can
cause severe intoxication with signs and symptoms such as drowsiness, shallow and weak breathing and
coma, and in some cases may even be fatal.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant, are planning to become pregnant, or are breastfeeding
with breast milk, ask your doctor or pharmacist for advice before taking this medicine.
Pregnancy
Levomethadone crosses the placenta and enters the bloodstream of the newborn. Lefisyo can be used
during
pregnancy after a careful benefit-risk assessment by a doctor, preferably
under supervision in a specialised medical centre.
Due to changes in metabolism during pregnancy, a dose increase may be necessary.
Considering the well-being of the foetus, the doctor may also advise you to divide the daily dose.
Chronic use during pregnancy can lead to habituation and dependence on levomethadone in the
foetus, as well as withdrawal symptoms after birth, which often require treatment in hospital. Furthermore, if administered before or during delivery, levomethadone can cause respiratory problems in the newborn.
Breastfeeding
Ask your doctor if you are breastfeeding or intend to breastfeed while taking
levomethadone, as it may affect the baby. Check the baby for abnormal signs and symptoms
such as increased drowsiness (more than usual), difficulty breathing or flaccidity. Contact
your doctor immediately if you notice any of these symptoms.
Fertility
Methadone has been reported to cause sexual dysfunction in male patients receiving
maintenance treatment.

Driving and operating machinery
This medicine, even when used as directed, can change your ability to react in such a way as to impair your ability to drive vehicles and use machinery. This is particularly relevant when taken in combination with alcohol and certain other medicines (see also "Other medicines and Lefisyo").
The decision regarding your suitability to drive is made on a case-by-case basis by your doctor, taking into account individual response and the respective dosage.

Lefisyo contains sodium benzoate
This medicine contains 0.3 mg of sodium benzoate per ml.

Lefisyo contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per ml, i.e. essentially ‘sodium-free’.

3. How to take Lefisyo

Levometadone hydrochloride substitution therapy must be administered by a physician with
experience in the treatment of opioid/opiate dependence, preferably at specialized centers
for this purpose.
Levometadone is approximately twice as effective as racemic methadone. There is evidence that the metabolism
of levometadone is increased when racemic methadone is administered, therefore this
ratio may change. This must be taken into consideration when determining dosage.
Take this medicine following the instructions of your doctor exactly. If you have any doubts, consult
your doctor or pharmacist.

Recommended doses
The dose is established based on the onset of withdrawal symptoms and must be adjusted for you in
relation to your individual situation. As a general rule, once the dosage is defined, the
goal should be the minimum maintenance dose.
In order to prevent an overdose, on the first day, in the morning you will receive 15-20 mg of the
initial dose of levometadone hydrochloride (corresponding to 3-4 ml of solution). Depending on the subjective
and objective effect, in the evening of the first day an additional dose of 10-25 mg of
levometadone hydrochloride is administered (corresponding to 2-5 ml of solution). In patients with a
low or unknown tolerance threshold (for example, following release from correctional facilities), the initial
dose should not exceed 15 mg of levometadone hydrochloride (3 ml of solution).
After 1-6 days, the initial dose is administered once a day, in the morning. The transition to the
single daily dose in the morning is usually carried out gradually with 5 mg of levometadone
hydrochloride (1 ml of solution).
In case of insufficient efficacy (onset of withdrawal symptoms), the doctor may increase the
dose of 5-10 mg of levometadone hydrochloride (1-2 ml of solution), per day.
The maintenance dose is normally reached within 1-6 days and can reach up to 60 mg of
levometadone hydrochloride (12 ml of solution). In individually justified cases, a considerably higher dose may be reached. A dose greater than 50-60 mg of levometadone hydrochloride can be
administered only in exceptional cases of proven necessity after excluding the concomitant use
of other substances.

Note
The daily dose of levometadone required may be increased by interactions with other medicines
or if some medicines increase the metabolism of Lefisyo (see also paragraph 2 "Other
medicines and Lefisyo"). For this reason, any withdrawal symptoms must be carefully monitored even in patients undergoing stable treatment and, if necessary, the dose must be adjusted.

Elderly and patients with impaired renal and hepatic function
The dose must be reduced in the elderly and in patients with kidney disease, chronic severe liver disease
or in poor general health.

Children and adolescents
No data are available on the treatment of children and adolescents under 18 years of age. The use of
Lefisyo is therefore not recommended in children and adolescents.

Method of administration
Lefisyo is for oral use only.
It is ready for use and can be taken mixed with drinking water or beverages, such as orange juice or
raspberry syrup.
When taken for immediate use, Lefisyo must be swallowed and taken under medical supervision. You will receive from the doctor, or from a person authorized by the doctor, the dose required for immediate
use. The required amount is measured exclusively by a doctor or by a person authorized
by the doctor.
The prescription of a certain amount of medicine that the patient can take independently, to
take home, must be written by the doctor. In this case, you must take the prescription to the pharmacy and you
will be given Lefisyo prescribed in daily portions. The doses must be taken as instructed
by the doctor.
Lefisyo is for oral use only.
Incorrect use of Lefisyo by injecting it intravenously leads to overdose and potentially fatal adverse effects, such as

• Blood poisoning
• Venous inflammation
• Blockage of blood vessels in the lungs caused by a blood clot

Duration of treatment
The duration of treatment is based, within the context of the overall therapeutic program, on the
progression of substitution treatment and on the individual perceptions of the patient. The goal of
treatment is drug abstinence. The duration of use can vary from short-term administration (e.g. for substitution in drug addicts requiring treatment in an inpatient setting) to long-term medication.

If you take more Lefisyo than you should
provision for doctor information. The doctor will immediately initiate emergency medical measures.
Signs of overdose are:

• "Feeling strange"
• Poor concentration
• Drowsiness
• Dizziness when getting up
• Cold and clammy skin
• Low blood sugar
• Reduced breathing, which also causes blue lips
• Slowed heartbeat and low blood pressure
• Pinpoint pupils
• Relaxation of skeletal muscles
• Feeling of great drowsiness with loss of consciousness up to coma. Severe poisoning can lead to respiratory arrest, circulatory failure, cardiac arrest and death. Taking Lefisyo by people who are not used to it can lead to death due to respiratory arrest. This concerns:
• Children under 5 years of age starting from doses of 0.5 mg of levometadone hydrochloride
• Older children starting from doses of 1.5 mg of levometadone hydrochloride
• Adults not accustomed to opioids starting from doses of 10 mg of levometadone hydrochloride

Therefore, you should never give Lefisyo to other people!
If you forget to take Lefisyo
Take the forgotten dose on the same day only if you have taken less Lefisyo than prescribed and are
experiencing withdrawal symptoms. Under no circumstances increase the dose prescribed for that
day.Inform the doctor if you have not experienced any withdrawal symptoms after taking a
smaller amount so that he can adjust the daily dose.

Levometadone withdrawal
If the prescribed dose of levometadone is too low, withdrawal symptoms (blood stasis
(congestion) in the nasal area, abdominal pain, diarrhea, muscle pain, anxiety) may occur within 24
hours of the dosage interval. Treating physicians must be aware that it may be
necessary to change the dose if the patient reports withdrawal symptoms.

If you stop taking Lefisyo
You should not stop suddenly or interrupt the treatment ifyou have been taking it for a long time.
Suddenly stopping taking Lefisyo can lead to serious, even potentially fatal withdrawal symptoms. Long-term treatment must end slowly and gradually.
Talk to your doctor about any changes you want to make to your treatment.
If you have any doubts about the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following withdrawal symptomsare commonat the beginning of therapy (may affect up to 1 in 10 people):

• Anxiety
• Loss of appetite
• Involuntary muscle contractions
• Depression
• Intestinal cramps, abdominal cramps
• Nausea, vomiting
• Diarrhea
• Fever, chills alternating with hot flashes
• Yawning
• Goosebumps
• Weight loss
• Fast heartbeat
• Runny nose, sneezing
• Dilated pupils
• Irritability
• Drowsiness
• Physical pain
• Fainting
• Heavy sweating
• Increased tearing
• Restlessness and tremor

Other possible side effects
From common(may affect 1 in 10 people) to uncommon(may affect up to 1 in 100):

• Shallow and weak breathing
• Nausea, vomiting, constipation, biliary spasms
• Palpitations, slow heartbeat
• Confusion, disorientation
• Dizziness, sedation
• Hives and other types of rash, itching
• Reduced sexual desire and/or impotence
• Reduced urine volume, urinary disorders
• Fluid retention in the tissues
• Insomnia, agitation
• Loss of appetite, fatigue (tiredness), weakness
• Feeling “up” or feeling “down”
• Sweating, dry mouth
• Blurred vision
• Headache

From rare(may affect 1 in 1,000) to very rare(may affect up to 1 in

• 10,000):
• Skin redness and feeling of warmth
• Respiratory arrest
• Cardiac arrest
• Decreased blood pressure when getting up
• Circulatory dysfunction
• Brief periods of fainting due to irregular heartbeat
• Shock
• Bleeding

Frequency not known(frequency cannot be estimated from available data):

• Low blood sugar

Note
Once the regular daily dose is reached, side effects may decrease within a few
weeks. Constipation and increased sweating often persist and can be relieved with
appropriate measures. Ask your doctor about it.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your
doctor, pharmacist or nurse. You can also report side effects directly
through the national system:
Website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Lefisyo

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package and label after
Exp. The expiry date refers to the last day of the month.
This medicine does not require any particular storage temperature.
Store in the original package to protect the medicine from light.
After first opening, this medicine must be used within 90 days, when stored at
a temperature below 25°C in the original package to protect the medicine from light.
Solutions diluted with fruit juice (such as orange juice or raspberry syrup) or with drinking water
for immediate use must be used within 7 days if stored at a temperature below
25°C.
Solutions diluted with drinking water, or with preserved and viscous diluents to take home, must
be used within 3 months, if stored at a temperature below 25°C. Keep the preparation to
take home out of the reach of children.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Lefisyo contains

• The active ingredient is levomethadone hydrochloride.
• The other ingredients are: glycerol, sodium benzoate (E 211), citric acid monohydrate and purified water.

Description of Lefisyo and package contents
Lefisyo is a clear and colourless oral solution.
Pack with an amber glass bottle (type III), closed with a child-resistant cap (PP) with
PE insert and evident tamper-proof ring.
Package sizes:
100 ml, 500 ml and 1000 ml oral solution
Not all pack sizes may be marketed.

Marketing Authorisation Holder
ALKALOID-INT d.o.o.
Šlandrova ulica 4
Ljubljana-Črnuče, 1231, Slovenia
email: [email protected]

Manufacturer
ALKALOID-INT d.o.o.
Šlandrova ulica 4
Ljubljana-Črnuče, 1231, Slovenia
email: [email protected]

The following information is intended exclusively for doctors and healthcare professionals:
Note for the pharmacist:
The prescription preparation intended for home use can be prepared by diluting Lefisyo 1:2 with
drinking water (one part of Lefisyo and two parts of water) or in preserved and viscous diluents with a
ratio of 1:1.

For the prescription of the medicine to take home, Lefisyo is prepared in portions based on the daily
dose and labelled. These daily portions are given to the patient.
Advice to doctors regarding the treatment of an overdose:
Immediate emergency medical intervention or, if necessary, intensive care (e.g.
intubation and ventilation) is mandatory. Specific opioid antagonists (e.g.
naloxone) can be used to treat the symptoms of intoxication. The various opioid antagonists
differ from each other in terms of dosage (consult the manufacturer's information!). In
particular, it is important to consider that levomethadone can have a prolonged depressive
effect on breathing (up to 75 hours), while opioid antagonists have a much shorter
duration of action (1 to 3 hours). Therefore, once the antagonistic effects subside,
further injections may be necessary. Measures to prevent a decrease in body temperature and to support
blood volume may also be necessary.
In case of oral levomethadone intoxication, gastric lavage can only be performed after
administration of an antagonist. Protection of the airways by intubation is
particularly important in case of gastric lavage and before administration of the
antagonists (vomiting may occur). Alcohol, barbiturates, bemegride, phenothiazines and scopolamine
should not be used in the treatment of intoxications.
Levomethadone is not dialyzable.