METASEDIN 5 mg TABLETS

2. What you need to know before you take Metasedin

Do not take Metasedin

• If you are allergic to metadone or any of the other components of this medicine (listed in section 6).
• If you have respiratory or pulmonary problems such as severe obstructive respiratory disease, emphysema, or bronchial asthma. Do not take this medicine during an acute asthma attack.
• If you have heart symptoms as a result of chronic pulmonary processes (Cor pulmonale).
• If you have high pressure inside the skull or have had a recent head injury.
• If you are taking monoamine oxidase inhibitors (MAOIs) to treat depression or if you have taken an MAOI in the last two weeks.
• If you are addicted to other drugs.
• During childbirth.
• If you have a pheochromocytoma, a tumor of the adrenal glands.
• If you have a known intestinal problem called paralytic ileus.

Warnings and precautions

Consult your doctor or pharmacist if you present any of the following symptoms before starting or while taking Metasedin:

• If you have low blood pressure (hypotension).
• If you have liver or kidney problems.
• If you have low thyroid function (hypothyroidism).
• If you have weakness, fatigue, loss of appetite, nausea, vomiting, or low blood pressure. This may be a symptom that your adrenal glands are producing a very low amount of the cortisol hormone, so you may need to take a hormonal supplement.
• If you have disorders of the bile ducts (gallbladder and bile duct).
• If you have prostate enlargement (prostatic hyperplasia).
• If you suffer from a disease characterized by muscle weakness, called myasthenia gravis.
• If you have inflammatory or obstructive intestinal disorders.
• If you are addicted to alcohol.
• If you have epilepsy.
• If you are pregnant or breastfeeding.
• If you are in shock.
• If you are an elderly person or are extremely ill. In these cases, you may be more sensitive to the medicine.
• If you are prone to allergic reactions, you may suffer from, for example: an exacerbation of asthma, skin redness, etc.
• If you have acute pain in the abdominal area, since the administration of this medicine or other similar medicines may make it more difficult to diagnose and monitor the clinical evolution.
• If you have any risk factors for prolongation of the QT interval (cardiac conduction disorder) such as:

• History of irregular heartbeats,
• history of heart disease,
• family history of sudden death without apparent cause,
• low levels of potassium, sodium, or magnesium,
• liver disease.

• Long-term consumption can cause a decrease in sex hormone levels and an increase in prolactin hormone. Consult your doctor if you present symptoms such as decreased libido, impotence, or absence of menstruation (amenorrhea).

• During the induction phase of maintenance treatment with metadone, patients must stop consuming heroin and may present typical withdrawal symptoms (tearfulness, nasal congestion, sneezing, yawning, etc.), which must be differentiated from metadone side effects.
• The administration of usual doses of an opioid antagonist to a patient with physical dependence on metadone or other opioids precipitates an acute withdrawal syndrome. The intensity of the symptoms will depend on the degree of dependence of the subject and the dose of antagonist administered.

• Metadone may alter the results of some blood tests (blood values of hormones such as prolactin and other hormones related to the thyroid (such as thyroxine, thyroxine-binding globulin [TBG], and triiodothyronine)).

Tolerance, dependence, and addiction

This medicine contains an opioid medicine called metadone. Repeated use of opioids can decrease the effectiveness of the medicine (your body gets used to the medicine, this is known as tolerance). Repeated use of Metasedin can also cause dependence, abuse, and addiction, which can lead to a potentially fatal overdose.

The risk of side effects may increase with a higher dose and longer duration of use.

Dependence or addiction can make you feel that you no longer have control over the amount of medicine you need to take or how often you need to take it. When used to treat pain, you may feel that you need to continue taking the medicine, even when it no longer helps to relieve your pain.

The risk of becoming dependent or addicted varies from person to person. You may have a higher risk of becoming dependent or addicted to Metasedin if:

• You or a family member have a history of abuse or dependence on alcohol, prescription drugs, or illicit substances ("addiction").
• You are a smoker.
• You have ever had problems with your mood (depression, anxiety, or a personality disorder) or have received psychiatric treatment for other mental illnesses.

If you notice any of the following signs while taking Metasedin, it could be a sign that you have become dependent or addicted.

• You need to take the medicine for a longer period than recommended by your doctor.
• You need to take more doses than recommended.
• You are using the medicine for reasons other than those prescribed, for example, "to calm down" or "to help you sleep".
• You have made repeated and unsuccessful attempts to stop or control the use of the medicine.
• You do not feel well when you stop taking the medicine and feel better when you take it again ("withdrawal symptoms").

If you notice any of these signs, talk to your doctor to address the most appropriate therapeutic strategy in your case, including when it is appropriate to stop taking it and how to do it safely (see section 3 "If you stop treatment with Metasedin").

Respiratory disorders related to sleep

Metasedin can cause sleep-related respiratory disorders such as sleep apnea (pauses in breathing during sleep) and sleep-related hypoxemia (low oxygen levels in the blood). Symptoms may include pauses in breathing during sleep, nighttime awakenings due to lack of breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else observes these symptoms, contact your doctor. Your doctor may consider reducing the dose.

Use in athletes

This medicine contains a component that can produce a positive result in doping tests.

Children and adolescents

Metasedin is not recommended for use in children and adolescents under 18 years of age, due to the lack of safety and efficacy data in this population. Additionally, children are more sensitive to the effects of metadone than adults.

Other medicines and Metasedin

There are some medicines that can affect the proper functioning of Metasedin or Metasedin itself can reduce the effectiveness of other medicines that are being taken at the same time. These drug interactions can increase or decrease the effect of one of the two medicines and may increase the risk or severity of side effects.

Do not take Metasedin if you are taking monoamine oxidase inhibitors (MAOIs) or if you have taken an MAOI in the last two weeks.

Tell your doctor or pharmacist if you are taking, have recently taken, or may need to take any other medicine, such as:

• The simultaneous use of Metasedin and sedative medicines such as benzodiazepines or related drugs (e.g., opioid analgesics such as codeine, pentazocine, buprenorphine) increases the risk of drowsiness, difficulty breathing (respiratory depression), coma, and is potentially fatal, particularly in elderly patients. Due to this, simultaneous use should only be considered when no other therapeutic options are possible. However, if your doctor prescribes Metasedin along with sedative medicines, they will restrict the dose and duration of simultaneous treatment.
• Gabapentin and pregabalin (medicines used to treat epilepsy, nerve pain, or anxiety). These can increase the risk of opioid overdose, respiratory depression, and can be potentially fatal.
• Tell your doctor about all sedative medicines you are taking, and strictly follow the dosage recommendation indicated by your doctor. It may be helpful to inform your friends or family that they should be alert to the signs and symptoms described above. If you experience these symptoms, contact your doctor.
• Additionally, buprenorphine or pentazocine may precipitate withdrawal symptoms in a patient addicted to metadone.
• Drugs used to reverse the effects of opioid drugs (naloxone).

• Central nervous system depressant medicines, including general anesthetics, drugs used to treat schizophrenia and psychoses (phenothiazines), treatment of insomnia, or other central nervous system sedatives, since metadone can increase the risk of respiratory depression, decreased blood pressure, and deep sedation or coma.
• However, if your doctor prescribes Metasedin along with sedative medicines, they will restrict the dose and duration of simultaneous treatment.
• Tell your doctor about all sedative medicines you are taking, and strictly follow the dosage recommendation indicated by your doctor. It may be helpful to inform your friends or family that they should be alert to the signs and symptoms described above. If you experience these symptoms, contact your doctor.

• The risk of side effects increases if metadone is consumed simultaneously with antidepressants (such as citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, imipramine, nortriptyline). Consult your doctor if you present symptoms such as:

• changes in mental status (such as restlessness, hallucinations, coma)
• rapid heartbeat, unstable blood pressure, fever
• exaggerated reflexes, discoordination, muscle rigidity
• gastrointestinal symptoms (such as nausea, vomiting, diarrhea)

• Serotoninergic medicines used to treat migraines, such as sumatriptan.
• Medicines to treat heart disorders, such as verapamil, bepridil, or enalapril.
• Medicines that produce electrolyte disturbances and affect cardiac conduction (such as antiarrhythmics, diuretics, or lithium).
• Medicines used to treat epilepsy, such as phenytoin, carbamazepine, phenobarbital, and primidone.
• Cannabidiol (a medicine used to treat seizures).
• Antibiotics such as ciprofloxacin or macrolide antibiotics such as erythromycin or clarithromycin.
• Medicines used to treat fungal infections, such as ketoconazole, itraconazole, miconazole, and fluconazole.

• Rifampicin or phenytoin, which can trigger a withdrawal syndrome.
• Cimetidine, which potentiates the effects of metadone.

• Drugs that acidify or alkalize the urine and can alter the elimination of metadone, increasing or decreasing its effects (e.g., ascorbic acid [vitamin C] and ammonium chloride).
• Antiretroviral medicines to treat HIV, such as ritonavir, nevirapine, efavirenz, abacavir, and nelfinavir. Your doctor may need to change the dose of metadone you take while taking these medicines.
• St. John's Wort, a herbal preparation used for depression.

Taking Metasedin with food, drinks, and alcohol

Alcohol can increase the side effects of metadone, so it should not be taken during treatment with this medicine.

Grapefruit juice may modify the effect of metadone, so it should not be taken with Metasedin.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

If Metasedin is used during pregnancy, your baby may suffer from withdrawal syndrome. Be careful if you are taking a pregnancy test, as metadone may interfere with the results.

Metasedin should not be used if you are in labor.

Breastfeeding

Metadone is excreted in breast milk. It will only be administered to breastfeeding mothers when the benefits to the baby outweigh the possible risks. Breastfeeding in these conditions could prevent the appearance of a withdrawal syndrome in the newborn.

Talk to your doctor if you are breastfeeding or thinking of doing so while taking metadone, as it could affect your baby. Monitor your baby for any abnormal signs and symptoms, such as increased sleepiness (more than usual), difficulty breathing, or floppiness. Contact your doctor immediately if you observe any of these symptoms.

Driving and using machines

Metasedin can cause drowsiness, dizziness, or other symptoms that can affect your ability to drive or operate machinery. If you notice any of these side effects, avoid driving vehicles or using machines.

Metasedin contains lactose

This medicine contains lactose. If your doctor has told you that you have an intolerance to some sugars, consult them before taking this medicine.

3. How to take Metasedin

Follow the instructions for administration of this medicine exactly as indicated by your doctor or pharmacist. If you are in doubt, consult your doctor or pharmacist again.

Before starting treatment and periodically during treatment, your doctor will talk to you about what you can expect from the use of Metasedin, when and for how long you should take it, when to contact your doctor, and when to stop taking it (see also "If you stop treatment with Metasedin").

The dosage must be individualized, so your doctor will establish the appropriate dose for you and make any necessary adjustments.

If you think the effect of this medicine is too strong or too weak, tell your doctor or pharmacist.

Use in adults:

1 to 2 tablets per dose, depending on the intensity of the pain. This dose may be repeated according to medical criteria.

The tablets should be swallowed without chewing, with a little water.

Remember to take your medicine.

Your doctor will indicate the duration of treatment with Metasedin.

If you take more Metasedin than you should

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone 91 562 04 20, indicating the medicine and the amount ingested.

If you take too much metadone, you may present:

• respiratory problems;
• extreme drowsiness, which can evolve into a decrease in level of consciousness and coma;
• very small pupils;
• muscle weakness;
• cold skin;

• sometimes, a drop in blood pressure and slow pulse;

• a low blood sugar level may occur;
• a brain disorder (known as toxic leukoencephalopathy) may occur.

In case of extreme intoxication, respiratory arrest, circulatory collapse, heart failure, and death may occur.

If you forget to take Metasedin

Do not take a double dose to make up for forgotten doses.

If you stop treatment with Metasedin

Sudden interruption of treatment, in patients with physical dependence, can precipitate a withdrawal syndrome. Your doctor will indicate how to gradually reduce the dose.

If you have any other doubts about the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

In general, methadone causes adverse effects similar to those of morphine.

The most serious adverse effects of methadone, as with other opioids, are respiratory depression (difficulty breathing) and, to a lesser extent, a decrease in blood pressure, with cases of respiratory arrest, shock, and cardiac arrest having occurred. The most frequent adverse effects are dizziness, sedation, nausea, vomiting, and excessive sweating. These effects seem to be more intense in outpatient patients and in those who do not have intense chronic pain. In such patients, the use of lower doses is recommended. Some adverse effects can be alleviated if the patient lies down.

Tell your doctor immediately if you experience:

• An allergic reaction, such as swelling of the face, lips, tongue, or throat, difficulty breathing, swelling, and severe itching of the skin with bumps.
• Cardiac disorders, such as alterations in heart rhythm (both rapid and missed beats), difficulty breathing, and dizziness.
• If your breathing becomes slow and shallow.
• Worsening of pressure inside the head or headache, if you already suffer from this condition after a head injury or brain disease.
• If you have asthma and it worsens.

Other possible adverse effects may be the following:

Very Common (may affect more than 1 in 10 patients)

nausea, vomiting.

Common (may affect up to 1 in 10 patients)

excessive sweating

fatigue, somnolence, sedation

weight gain

fluid retention

constipation

rash, which may appear and disappear

blurred vision, small pupils, dry eyes

dizziness, vertigo

changes in mood, feeling overly excited (euphoria) or seeing or hearing things that are not real (hallucinations)

Uncommon (may affect up to 1 in 100 patients)

difficulty breathing (respiratory depression), especially with high doses

worsening of asthma

low blood pressure

headache, syncope, or sudden loss of consciousness

feeling discouraged (dysphoria), agitation, confusion, disorientation, difficulty sleeping

you may become dependent on Metasedin, for more information, see section 2 "Warnings and Precautions"

itching, skin rashes, hives

dry mouth or nose, tongue inflammation, facial redness

difficulty urinating (urinary retention), pain in the lower back and abdomen caused by muscle spasms

alteration of bile duct movement (may manifest as nausea, vomiting, or both, biliary pain in the upper right abdomen or radiating to the right shoulder area)

low body temperature (hypothermia)

feeling of weakness, fatigue

decreased sexual desire or difficulty achieving or maintaining an erection

painful menstrual period, absence of menstruation

milky secretion from the nipple (galactorrhea)

increased fluid in the lung (pulmonary edema)

Rare (may affect up to 1 in 1000 patients)

alterations in heart rhythm (both rapid and missed beats)

abnormality in the electrocardiogram (ECG), known as QT interval prolongation, which can lead to a heart rhythm disorder called "torsade de pointes" (especially with high doses of methadone)

cardiac arrest

shock

respiratory arrest

Other adverse effects reported, with unknown frequency, are

loss of appetite

bloating, swollen legs (this may be a sign that your body is retaining more water than normal)

increased intracranial pressure (especially with high doses)

involuntary, rapid, and repetitive eye movements, strabismus

reduced visual acuity

sleep apnea (pauses in breathing during sleep)

reduced platelet count, which increases the risk of bleeding or bruising in patients with chronic hepatitis

low levels of potassium and magnesium

decreased production of adrenal and sex hormones

low blood sugar levels

high levels of prolactin in the blood

If you observe any other reaction not described in this prospectus, consult your doctor or pharmacist.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report it directly through the Spanish Pharmacovigilance System for Human Use Medicines, Website: www.notificaRAM.es.

By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Metasedin

Keep this medicine out of sight and reach of children. Store this medicine in a safe and protected place, where others cannot access it. It can cause serious harm and be fatal to people who have not been prescribed it.

Do not store at a temperature above 25°C.

Do not use this medicine after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Medicines should not be thrown away through drains or into the trash. Deposit the packaging and medicines you no longer need at the SIGRE point in the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition of Metasedin

• The active ingredient is methadone hydrochloride. Each tablet contains 5 mg of methadone hydrochloride.
• The other components are lactose, cornstarch, povidone, and magnesium stearate.

Appearance of the Product and Package Contents

Metasedin 5 mg tablets are presented in the form of white, circular, biconvex tablets, in packages with 20 tablets and 800 tablets (Clinical Package).

Some package sizes may not be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Esteve Pharmaceuticals, S.A.

Passeig de la Zona Franca, 109

08038 Barcelona

Spain

Manufacturer

Towa Pharmaceutical Europe, S.L.

c/ de Sant Martí, 75-97

08107 Martorelles (Barcelona)

Spain

Date of the Last Revision of this Prospectus: March 2023

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/.