Patient Information Leaflet

Lefisyo 5 mg/ml oral solution

levomethadone hydrochloride
Please read all of 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 give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Lefisyo is and what it is used for

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

2. What you should know before taking Lefisyo

Do not take Lefisyo

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

Warnings and precautions
Levomethadone may only be used in opioid-dependent patients by physicians authorized to provide substitution treatment, as standard doses used in substitution therapy may cause severe intoxication or even be fatal in patients not tolerant to opioids.
Consult your doctor or pharmacist before taking Lefisyo if any of the following apply to you. The doctor will proceed with treatment only if 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 simultaneously with sedatives or sleeping pills (such as benzodiazepines and related medicines): This may lead to drowsiness, shallow and weak breathing, and coma, and may even be fatal (see also "Other medicines and Lefisyo").
Conditions in which respiratory depression must be avoided, such as
- Asthma
- Lung diseases with chronic airway obstruction
- Heart failure caused by severe lung disease
- Moderate to severe respiratory depression (slow or shallow, ineffective breathing leading to increased carbon dioxide and decreased oxygen in the body) and dyspnea (shortness of breath)
- Low blood oxygen levels
- Increased levels of carbon dioxide in the blood
  In these conditions, breathing may become difficult or respiratory arrest may occur even at normal doses of Lefisyo. Worsening of pre-existing asthma or skin rashes and blood count abnormalities, especially if you are prone to allergies, may also occur.
Increased intracranial pressure: This may increase further.
Low blood pressure due to dehydration
Enlarged prostate with incomplete bladder emptying
Pancreatitis
Biliary disorders
Obstructive and inflammatory intestinal diseases
Pheochromocytoma, a tumor of the adrenal gland that secretes hormones
Hypothyroidism (a condition in which the thyroid gland does not produce enough hormones)
Risk of suicide: Suicide attempts with opioids, particularly in combination with certain medicines used to treat depression (antidepressants), alcohol, and other substances such as benzodiazepines, may be one of the clinical features of substance dependence. Consult your doctor or a specialized support center if you are unable to stop using such substances.
Severe abdominal conditions: Treatment with Lefisyo may also mask severe abdominal disorders. At the first signs of abdominal problems, regular clinical monitoring should be performed until the exact cause is established.
Cardiac arrhythmias (heart rhythm problems) or prolonged ventricular activity, known as QT interval prolongation, or mineral imbalances, particularly in cases of low potassium levels. Some opioids may affect cardiac conduction (prolongation of the QT interval on ECG). This may cause a dangerous heart rhythm disorder (too fast, irregular heartbeat, "torsades de pointes"). Inform your doctor immediately if you experience irregular heartbeat or fainting.
Therapy with class I and III antiarrhythmics
Slowed heart rate

Dosage should be reduced in elderly patients and in patients with renal impairment, severe chronic liver disease, or poor general health.
Consult your doctor or pharmacist before taking Lefisyo if you have an adrenal gland disorder. Your treatment should be carried out with caution.
Consult 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 sign that your adrenal gland is producing insufficient cortisol hormone, and you may need to take hormonal supplements.
Long-term use of opioids may cause decreased levels of sex hormones and increased levels of prolactin hormone. Contact your doctor if you experience symptoms such as decreased libido, impotence, or absence of menstruation (amenorrhea).
Additional information
With repeated and long-term use, levomethadone may cause physical and mental dependence and tolerance, resulting in reduced effectiveness. Discontinuation after repeated use or in cases of opioid dependence, or administration of an opioid antagonist (a substance that can block the effects of opioids), may trigger withdrawal syndrome.
Taking Lefisyo by individuals not accustomed to repeated or regular opioid use is dangerous and may cause death due to respiratory arrest.
Lefisyo is for oral use only. Abuse of Lefisyo by intravenous injection causes overdose and potentially fatal adverse effects such as blood poisoning, venous inflammation, and blockage of blood vessels in the lungs.
Abuse of drugs and medicines during substitution therapy may lead to potentially fatal incidents and must be strictly avoided.
Your doctor will perform regular urine tests to detect possible 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 may lead to positive results in anti-doping tests. Moreover, abuse of Lefisyo as a doping agent may pose health risks.
Other medicines and Lefisyo
Inform 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 concomitant use of other medicines.
Inform your doctor if you notice signs of increased effect of Lefisyo or withdrawal symptoms.
The following medicines must not be taken together with Lefisyo:

Monoamine oxidase inhibitors: Medicines used to treat depression or Parkinson’s disease. These medicines must be discontinued at least 14 days before starting Lefisyo treatment. Otherwise, potentially fatal suppressive or excitatory effects on respiration and circulation may occur.
Pentazocine, buprenorphine: Medicines for severe pain. If used together with Lefisyo, withdrawal symptoms may occur. Buprenorphine should only be administered at least 20 hours after discontinuation of Lefisyo. In exceptional cases, these medicines may be taken together with this medicine if used to treat Lefisyo overdose.

Inform your doctor if you are taking 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 doxepine)
When used together with Lefisyo, they may cause mutual enhancement of effects on brain functions and may therefore lead, for example, to drowsiness, shallow or weak breathing (see "Warnings and precautions"). Please follow exactly the dosage recommendations provided by your doctor.
- Sedatives and sleeping pills called benzodiazepines (generally ending in "-zepam", such as diazepam, flunitrazepam) and related medicines (such as zolpidem). Concomitant use of Lefisyo and sedatives such as benzodiazepines or related medicines increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be potentially fatal. Therefore, concomitant use should only be considered when no other treatment options are available. However, if your doctor prescribes Lefisyo together with sedatives, the doctor must limit the dose and duration of concomitant treatment. Inform your doctor about all sedatives you are taking, and carefully follow the doctor’s dosage recommendations. It may be helpful to inform friends or family members to be alert for the signs and symptoms listed above. If you experience such symptoms, contact your doctor.
- Some medicines used to treat depression called selective serotonin reuptake inhibitors (SSRIs, such as sertraline, fluvoxamine, fluoxetine, and paroxetine)
- Medicines to treat high blood pressure (such as reserpine, clonidine, urapidil, and prazosine)
- Cimetidine, a medicine used to reduce gastric acid production
- Medicines for treating fungal infections (such as itraconazole, ketoconazole, voriconazole, fluconazole)
- Medicines used to treat heart rhythm disorders (e.g. class I and III antiarrhythmics, such as amiodarone)
- Oral contraceptives
- Carbamazepine and phenytoin, medicines used to treat epilepsy
- Medicines used to treat certain bacterial infections, such as rifampicin, macrolide antibiotics, ciprofloxacin, fusidic acid
- St. John's wort
- Spironolactone (a diuretic)
- Medicines that inhibit HIV replication (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). Inform your doctor if you experience symptoms such as:

Changes in mental state (e.g. agitation, hallucinations, coma)
Fast heartbeat, unstable blood pressure, fever
Exaggerated reflexes, lack of coordination, muscle stiffness
Gastrointestinal symptoms (such as nausea, vomiting, diarrhea)

Lefisyo with alcohol
Do not drink alcohol while taking Lefisyo. Alcohol may unpredictably increase its effect and may 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 may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Levomethadone crosses the placenta and passes into the newborn's blood. Lefisyo may be used during pregnancy after careful risk-benefit assessment by a doctor, preferably under supervision in a specialized medical center.
Due to metabolic changes during pregnancy, dose adjustment may be necessary. Considering fetal well-being, your doctor may also advise you to split the daily dose.
Chronic use during pregnancy may lead to levomethadone dependence and withdrawal symptoms in the newborn, often requiring inpatient treatment. Moreover, if administered before or during delivery, levomethadone may cause respiratory problems in the newborn.
Breastfeeding
Consult your doctor if you are breastfeeding or intend to breastfeed while taking levomethadone, as it may affect the infant. Monitor the infant for unusual signs and symptoms such as increased drowsiness (more than usual), breathing difficulties, or floppiness. Contact your doctor immediately if you notice any of these symptoms.
Fertility
It has been reported that methadone causes sexual dysfunction in male patients receiving maintenance treatment.
Driving and using machines
This medicine, even when used as directed, may alter your reaction ability, thereby impairing your ability to drive or operate machinery. This is particularly relevant when taken together with alcohol and certain other medicines (see also "Other medicines and Lefisyo").
The decision regarding your fitness to drive is made on a case-by-case basis by your treating physician, taking into account your individual response and 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 replacement therapy must be administered by a physician experienced in the treatment of opioid/opiate dependence, preferably at specialized centers for this purpose.
Levometadone is approximately twice as potent as racemic methadone. There is evidence that levometadone metabolism is increased when racemic methadone is co-administered; therefore, this ratio may change. This must be taken into consideration when dosing.
Always take this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor or pharmacist.

Recommended doses
The dose is determined based on the onset of withdrawal symptoms and must be individually adjusted according to your personal situation. As a general rule, once the appropriate dosage has been established, the goal should be the lowest effective maintenance dose.
To prevent overdose, on the first day in the morning you will receive an initial dose of 15–20 mg levometadone hydrochloride (equivalent to 3–4 ml of solution). Depending on subjective and objective effects, an additional evening dose of 10–25 mg levometadone hydrochloride (equivalent to 2–5 ml of solution) may be administered on the same day. In patients with low or unknown tolerance (e.g. following release from correctional facilities), the initial dose must not exceed 15 mg levometadone hydrochloride (3 ml of solution).
After 1–6 days, the initial dose is administered once daily in the morning. The transition to a single daily morning dose is normally made gradually in steps of 5 mg levometadone hydrochloride (1 ml of solution).
If efficacy is insufficient (withdrawal symptoms occur), your doctor may increase the dose by 5–10 mg levometadone hydrochloride (1–2 ml of solution) per day.
The maintenance dose is normally reached within 1–6 days and may reach up to 60 mg levometadone hydrochloride (12 ml of solution). In justified individual cases, considerably higher doses may be used. A dose exceeding 50–60 mg levometadone hydrochloride may only be administered in exceptional cases of proven necessity, after concomitant use of other substances has been ruled out.

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

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

Children and adolescents
There are no data available on the treatment of children and adolescents under 18 years of age. Therefore, the use of Lefisyo is not recommended in children and adolescents.

Method of administration
Lefisyo is for oral use only.
It is ready for use and may 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 the required dose for immediate use from your doctor or from a person authorized by the doctor. The required amount must be measured exclusively by a doctor or a person authorized by the doctor.
A prescription for a certain quantity of medicine that the patient may take independently and take home must be issued by the doctor. In this case, you must take the prescription to a pharmacy, where you will be given the prescribed Lefisyo in daily portions. The doses must be taken as instructed by your doctor.
Lefisyo is for oral use only.
Misuse of Lefisyo by intravenous injection may lead to overdose and potentially fatal adverse effects such as:

Blood poisoning
Phlebitis (vein inflammation)
Pulmonary embolism (blockage of blood vessels in the lungs due to a blood clot)

Duration of treatment
The duration of treatment depends, within the context of the overall therapeutic program, on the progress of substitution therapy and the patient's individual perception. The goal of treatment is drug abstinence. The duration of use may vary from short-term administration (e.g. for substitution in drug-dependent patients requiring inpatient treatment) to long-term medication.

If you take more Lefisyo than you should
If you suspect an overdose, call a doctor immediately! Keep this patient information leaflet available to provide information to the doctor. The doctor will immediately initiate emergency medical measures.
Signs of overdose include:

"Feeling strange"
Poor concentration
Drowsiness
Dizziness upon standing
Cold and clammy skin
Low blood sugar
Reduced breathing, which may also cause blue lips
Slow heart rate and low blood pressure
Pinpoint pupils
Relaxation of skeletal muscles
Extreme drowsiness progressing to loss of consciousness and coma

Severe intoxication may lead to respiratory arrest, circulatory failure, cardiac arrest, and death.
Ingestion of Lefisyo by individuals not accustomed to opioids may result in death due to respiratory arrest. This applies to:

Children under 5 years of age, starting from doses of 0.5 mg levometadone hydrochloride
Older children, starting from doses of 1.5 mg levometadone hydrochloride
Opioid-naïve adults, starting from doses of 10 mg levometadone hydrochloride

Therefore, you must never give Lefisyo to other people!

If you forget to take Lefisyo
Take the missed dose on the same day only if you have taken less Lefisyo than prescribed and are experiencing withdrawal symptoms. Under no circumstances should you increase the prescribed dose for that day. Inform your doctor if you did not experience any withdrawal symptoms after taking a reduced amount, so that the daily dose can be adjusted.

Levometadone withdrawal
If the prescribed dose of levometadone is too low, withdrawal symptoms (nasal congestion, abdominal pain, diarrhea, muscle pain, anxiety) may occur within 24 hours of the dosing interval. Treating physicians should be aware that dose adjustment may be necessary if the patient reports withdrawal symptoms.

If you stop taking Lefisyo
Do not stop suddenly or discontinue treatment if you have been taking it for a long time. Stopping Lefisyo abruptly may lead to severe, potentially life-threatening withdrawal symptoms. Long-term treatment should be discontinued slowly and gradually.
Talk to your doctor about any changes you wish to make to your treatment.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The following withdrawal symptoms are common at the beginning of treatment (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 flushes
Yawning
Goosebumps
Weight loss
Rapid heartbeat
Runny nose, sneezing
Dilated pupils
Irritability
Drowsiness
Physical pain
Fainting
Excessive sweating
Increased lacrimation
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, slowed 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 tissues
Insomnia, agitation
Loss of appetite, fatigue (tiredness), weakness
Feeling “high” or feeling “low”
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 flushing and sensation of warmth
Respiratory arrest
Cardiac arrest
Drop in blood pressure upon standing
Circulatory dysfunction
Brief episodes of fainting due to irregular heartbeat
Shock
Bleeding

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

Low blood sugar levels

Note
Once the regular daily dose has been reached, side effects may decrease within a few weeks. Constipation and increased sweating often persist and can be relieved with appropriate measures. Please consult your doctor about this.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting 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 stated on the carton and label after Exp. The expiry date refers to the last day of the month.
This medicine does not require any special storage temperature.
Store in the original container to protect the medicine from light.
After first opening, this medicine must be used within 90 days when stored below 25°C in the original container to protect the medicine from light.
Diluted solutions 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 below 25°C.
Diluted solutions with drinking water, or with stored viscous diluents taken home, must be used within 3 months if stored below 25°C. Keep the preparation taken home out of the reach of children.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Lefisyo contains

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

Description of the appearance of Lefisyo and package contents
Lefisyo is a clear, colourless oral solution.
Pack: amber glass bottle (type III), closed with a child-resistant cap (PP) with PE insert and tamper-evident ring.
Pack 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 physicians and healthcare professionals:

Note for the pharmacist:
The prescribed preparation indicated for home use may be prepared by diluting Lefisyo 1:2 with drinking water (one part Lefisyo and two parts water), or in preserved, viscous diluents at a ratio of 1:1.

For the prescription of the medicinal product to be taken home, Lefisyo is prepared in portions according to the daily dose and labelled. These daily portions are given to the patient.

Warning to physicians regarding overdose management:
Immediate emergency medical intervention or, if necessary, intensive care treatment (e.g. intubation and ventilation) is mandatory. Specific opioid antagonists (e.g. naloxone) may be used to treat intoxication symptoms. Different opioid antagonists vary in dosage (refer to the manufacturer's instructions!). It is particularly important to note that levomethadone may cause prolonged respiratory depression (up to 75 hours), whereas opioid antagonists have a much shorter duration of action (1 to 3 hours). Therefore, once the antagonist effects wear off, repeated injections may be required. Measures to prevent hypothermia and to support intravascular volume may also be necessary.

In cases of oral levomethadone intoxication, gastric lavage should be performed only after administration of an antagonist. Airway protection via intubation is particularly important when performing gastric lavage and prior to administering antagonists (vomiting may occur). Alcohol, barbiturates, bemegride, phenothiazines, and scopolamine must not be used in the treatment of intoxications.

Levomethadone is not dialysable.