SUBUTEX - PACKAGE LEAFLET - LEAFLETS

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Subutex - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Buprenorphine (buprenorphine hydrochloride)

Subutex 0.4 mg sublingual tablets Subutex 2 mg sublingual tablets Subutex 8 mg sublingual tablets

Indications Why is Subutex used? What is it for?

Subutex contains the active substance buprenorphine and belongs to the category of drugs used in opioid addiction in adults and adolescents over 15 years of age.

Subutex is used to treat opioid (narcotic) addiction such as heroin or morphine in addicts who have agreed to be treated for their addiction, and who also receive medical, social and psychological support.

Contraindications When Subutex should not be used

Do not take Subutex

if you are allergic to buprenorphine or any of the other ingredients of this medicine
if you have severe breathing problems (respiratory failure)
if you have severe liver problems (liver failure)
in case of acute alcoholism
if you suffer from tremor and delirium due to alcohol withdrawal (delirium tremens)
in case of simultaneous treatment with anti MAO drugs
in subjects under the age of 15
if you are breast-feeding

Precautions for use What you need to know before taking Subutex

Talk to your doctor or pharmacist before taking Subutex.

Use Subutex with caution in case of:

asthma or other breathing problems (e.g. chronic obstructive pulmonary disease, cor pulmonale, reduced respiratory reserve, hypoxia (lack of oxygen), hypercapnia (increased concentration of carbon dioxide in the blood), pre-existing respiratory depression or kyphoscoliosis, deviation of the spine which can lead to dyspnoea; cases of respiratory failure have been reported with buprenorphine
reduced normal kidney function
viral hepatitis (an inflammatory process that causes liver cell death) or if you are receiving concomitant therapies and / or have pre-existing liver dysfunction, as you may be at increased risk of liver damage
decreased normal liver function
thyroid gland problems (myxedema (a skin disease characterized by a buildup of mucoid substance), hypothyroidism (reduced thyroid function)) or adrenal gland disorders (e.g. Addison's disease).
low blood pressure (hypotension)
psychosis due to drug intoxication or hallucinogens (toxic psychosis)
urinary tract problems, especially if related to enlarged prostate (prostatic hypertrophy) or narrowing of the urethra (urethral stricture)
head injury, intracranial injury, or other brain disease in which CSF pressure may be increased or if you have a history of seizures
dysfunction of part of the liver (biliary tract)
elderly or debilitated patients

Use Subutex with caution as it can be addictive.

For those who carry out sporting activities: The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

Misuse and abuse

Subutex can be subject to misuse or abuse. Some of the risks of misuse and abuse include overdose, spread of viral infections through the bloodstream, local and bodywide infections, inability to breathe and liver damage (see "Possible Side Effects").

Misuse of Subutex when you are not the patient for whom it was prescribed may be tempting to take this medicine as a drug and could be harmful.

This medicine can be tempting for people who abuse prescription medicines and should be kept in a safe place to protect it from theft.

Respiratory problems

Some deaths have been reported due to inability to breathe (respiratory depression) when buprenorphine was used in combination with certain drugs, for example benzodiazepines, central nervous system depressants such as alcohol and other opioids (see "Other medicines and Subutex) or when buprenorphine has not been used according to the package leaflet.

If buprenorphine is given to some opioid-dependent individuals who cannot tolerate the effects of opioids, life-threatening respiratory depression can occur.

Buprenorphine can cause severe, life-threatening respiratory depression in children who accidentally ingest it. Protect children from accidental exposure.

Dependence

It is advised not to stop treatment abruptly, as it may cause a withdrawal syndrome whose onset may be delayed.

Central nervous system depression: Buprenorphine can cause drowsiness, particularly with concomitant intake of alcohol or other central nervous system depressants (such as benzodiazepines, tranquilizers, sedatives or hypnotics).

Opioid withdrawal syndrome

Buprenorphine can cause withdrawal symptoms in opioid-dependent patients if administration occurs before the effects of recent opioid use or abuse have diminished.

In particular, this can occur if the administration of buprenorphine takes place less than 6 hours after taking the last dose of heroin (or other short-acting opioid), or less than 24 hours after taking. of the last dose of methadone.

In order to avoid withdrawal symptoms, the first dose of buprenorphine should be given when you have objective signs and symptoms of moderate withdrawal (see "How to take Subutex").

In case of abrupt discontinuation of pharmacological treatment with buprenorphine, signs of withdrawal may appear three days after its suspension, reaching a maximum from the third to the fifth day and then gradually decreasing over 8-10 days.

Withdrawal symptoms may also be associated with lower than necessary dosage.

General warnings regarding opioid intake

Use opioids with particular caution:

because they can cause a sharp drop in blood pressure when standing up from a sitting or lying position (orthostatic hypotension).
because they can increase the pressure of the cerebrospinal fluid causing seizures. Therefore, they should be used with caution in case of head trauma, intracranial injury, or in other conditions where cerebrospinal fluid pressure may be increased or if there is a history of seizures.
because they can cause narrowing of the pupil (miosis) which can confuse the diagnosis or hide the evolution of some pathologies in progress
because they can cause changes in the level of consciousness or in the perception of painful symptoms that could confuse the diagnosis or hide the evolution of some pathologies in progress
if you suffer from a skin disease characterized by a buildup of mucoid (myxedema), impaired thyroid function (hypothyroidism) or adrenal gland disorders (e.g. Addison's disease)
if you suffer from psychosis due to drug intoxication or hallucinogens (toxic psychosis)
if you have low blood pressure (hypotension), abnormal enlargement of the prostate (prostatic hypertrophy) or narrowing of the urethra (urethral stricture)
if you suffer from dysfunction of part of the liver (biliary tract)
if you are an elderly or debilitated patient.

Elderly patients

The safety and efficacy of buprenorphine in elderly patients over the age of 65 have not been established.

Children and adolescents

No data is available in individuals under 15 years of age; therefore Subutex should not be given to individuals under the age of 15 years.

Interactions Which drugs or foods may change the effect of Subutex

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Subutex should be used with caution together with the following medicines:

Benzodiazepines (used to treat anxiety or sleep disorders): this combination can cause death due to inability to breathe (central respiratory depression). Take into account the extreme danger associated with self-administration of non-prescribed benzodiazepines while taking of this medicine. The concomitant use of benzodiazepines with this medicine should only be done on the prescription of your doctor.
Other central nervous system depressant medicines which may induce somnolence. These drugs reduce alertness by making driving and using machines dangerous. They can also cause central nervous system depression, a very serious condition. Below is a sample list of these drugs:
Other opium derivatives (for example: methadone, pain relievers and cough suppressants)
Some antidepressants or sedatives H1 receptor antagonists (used to treat allergic reactions)
Barbiturates (used to promote sleep or sedation)
Anxiolytics (used for anxiety)
Neuroleptics (drugs used to treat psychosis)
Clonidine (drug used for high blood pressure) and similar substances
Monoamine oxidase inhibitors (MAOIs). Enhancement of the effects of other opiates is "possible". Avoid using Subutex at the same time and for two weeks after stopping treatment with MAOIs.
Opioid pain relievers (analgesics) such as:
methadone
hydromorphone
oxycodone
fentanyl

The pain relieving properties of these drugs may decrease in patients treated with buprenorphine for opioid dependence.

Naltrexone (drug used for opioid addiction): because it can block the effects of Subutex. Furthermore, in opioid-dependent patients being treated with Subutex, it can trigger the sudden onset of intense and prolonged withdrawal symptoms.
Protease inhibitors (used to treat AIDS), antibiotics (macrolides), antifungals (azoles: used to treat fungal infections), gestodene (used as a contraceptive), oral anticoagulants (TAOs, used to prevent or slow the clotting of the blood): because they can enhance the effects of the medicine
Phenobarbital, carbamazepine, phenytoin (medicines to treat epilepsy) and rifampicin (medicines to treat tuberculosis): they can reduce the effect of Subutex.

Subutex and alcohol Subutex should not be taken with alcoholic beverages, and should be used with caution with alcohol-containing medications because alcohol increases the sedative effect of Subutex.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

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

Pregnancy

Towards the end of pregnancy, high doses of buprenorphine can cause respiratory problems in the newborn (respiratory depression) even after a short period of administration. Prolonged administration of buprenorphine during the last three months of pregnancy may cause withdrawal syndrome in the newborn (eg, hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome usually occurs several hours to several days after birth.

Feeding time

Buprenorphine has the potential to inhibit milk secretion or production. Also, as buprenorphine passes into breast milk, breastfeeding is contraindicated.

Fertility

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Driving and using machines

Subutex has moderate influence on the ability to drive and use machines when administered to opioid-dependent patients. The drug may cause somnolence, dizziness or mental confusion, particularly during the initiation of treatment and dose adjustments. When taken together with alcohol or CNS depressant drugs, this effect is likely to be more pronounced.

Exercise extreme caution in driving vehicles and operating hazardous machinery if taking buprenorphine affects your performance.

Subutex contains lactose

This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Subutex: Dosage

Always take this medicine exactly as your doctor or pharmacist has told you.

If in doubt, consult your doctor or pharmacist. Its treatment is prescribed and monitored by doctors who are experienced in the treatment of drug addiction.

Your doctor will work out the optimal dosage for you. During the course of treatment, your doctor may adjust the dose based on your response.

Dosage

The recommended dosage consists of Subutex 0.4 mg, Subutex 2 mg and Subutex 8 mg sublingual tablets which can be placed under the tongue at the same time, or in two separate administrations; the second administration should be placed under the tongue immediately after dissolution of the first.

Start of treatment

It must be gradual, until the optimal therapeutic dosage is reached and the different dosages available (tablets of 0.4 mg, 2 mg and 8 mg) allow this graduality.

Patients who self-administer heroin daily

In case of heroin addiction, the first dose of Subutex should be taken at the onset of the first withdrawal symptoms. Otherwise, buprenorphine can in itself cause a withdrawal syndrome.

Patients on methadone treatment

Subutex (buprenorphine) 8 mg has a similar efficacy to methadone 30 mg. Before replacing methadone with buprenorphine it is recommended to reduce the methadone dosage to below 30 mg / day.

Again, the first administration of buprenorphine should take place in the presence of the first withdrawal symptoms. Otherwise, buprenorphine can in itself cause a withdrawal syndrome.

Dosage adjustment and maintenance

The dosage of Subutex should be progressively increased, and should not exceed the maximum single daily dose of 32 mg. The dose is modified according to the clinical and psychological condition of the patient.

Reduction of dosage and termination of treatment

After a satisfactory stabilization period is reached, the dosage can be gradually reduced and, if judged appropriate by the physician in some patients, treatment can be stopped. The availability in sublingual tablets of 0.4, 2 and 8 mg allows a gradual decrease of the dose.

If buprenorphine treatment is stopped, you will be monitored for the possibility of relapse.

Impaired liver functions

In patients whose liver function is impaired, it is recommended to initiate treatment at lower doses with gradual dosage adjustment. Subutex is contraindicated in patients with severe liver damage (severe hepatic insufficiency), therefore it is recommended that blood tests be performed to check liver function and the presence of viral hepatitis before starting Subutex therapy.

Patients with viral hepatitis (an inflammatory process that causes the death of liver cells), and / or with liver disease who receive concomitant drug therapies, have an increased risk of liver damage; the doctor will recommend regular monitoring of the condition of the liver. liver.

Impaired kidney functions

It is generally not necessary to adjust the dose of Subutex in patients with impaired normal kidney function, however your doctor may adjust the dose according to your needs.

Administration

Sublingual administration is the only effective and safe way to take this drug. The tablet should be kept under the tongue until it dissolves completely. This typically occurs in 5-10 minutes. Do not swallow or consume any food or drink until the tablet is completely dissolved.

Use in children and adolescents

The safety and efficacy of buprenorphine in subjects below the age of 15 have not been established. Subutex is contraindicated in children below the age of 15 (see section 2).

Subutex sublingual tablets should be used in adults and children over the age of 15 who have given their consent to treat their drug addiction situation.

Since there are no data available in adolescents (aged 15-18), patients in this age group should be monitored more closely during treatment.

Instructions for Use

How to remove the tablet from the blister

Remove a single section from the blister by tearing along the perforated line.
Starting from the raised edge, pull the film to remove the tablet

Overdose What to do if you have taken too much Subutex

If you take more Subutex than you should

If you accidentally swallow or take an overdose of Subutex, notify your doctor immediately or go to the nearest hospital emergency department.

Symptoms

If you have taken too much Subutex, the following may occur:

severe respiratory problem (respiratory depression) which can progress to "interruption of" respiratory activity (respiratory arrest) with the risk of death
vomiting, another symptom that can be dangerous
narrowing of the pupil (miosis)
sedation
nausea
sudden drop in blood pressure (cardiovascular collapse)

Treatment

In the event of an overdose, if necessary, your doctor may give you Naloxone (a substance used to counter the effects of opioid overdose).

If you stop taking Subutex

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

In case of abrupt discontinuation of a maintenance treatment, signs of withdrawal may appear three days after the suspension itself, reaching a maximum from the third to the fifth day and then gradually decreasing over 8-10 days.

Side Effects What are the side effects of Subutex

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most frequent side effects are pain and those related to withdrawal symptoms: insomnia (i.e. difficulty in sleeping), headache, nausea and excessive sweating.

Below is a summary of other side effects considered serious or otherwise significant:

in case of abuse or intravenous misuse of the drug: local reactions, sometimes infected (abscess, cellulitis), potentially serious acute hepatitis, pneumonia, endocarditis and other serious infections.
inability to breathe (respiratory depression)
deaths caused by respiratory depression, in combination with benzodiazepines and other central system depressant drugs, alcohol or other opioids (see "Other medicines and Subutex") or when buprenorphine is not used according to the package leaflet
allergic (hypersensitivity) reactions such as: rash (hives), itching, constriction of the bronchi (bronchospasm), inability to breathe (respiratory depression), sudden swelling of the face, lips, tongue and / or throat which may cause difficulty to breathe and swallow which may be severe enough to require immediate medical attention (angioedema) and severe allergic reaction that appears rapidly and requires immediate medical attention (anaphylactic shock)
abnormal liver function (increased liver transaminases)
severe liver infection (acute hepatitis, cytolytic hepatitis)
yellowing of the skin and eyes (jaundice), rapid deterioration of kidney function (hepatorenal syndrome), mental confusion due to severe liver problem (hepatic encephalopathy) and death of liver cells (liver necrosis)
neonatal drug withdrawal syndrome (in infants of women who took buprenorphine during pregnancy) (see "Pregnancy, Breastfeeding and Fertility")
hallucination, sudden drop in blood pressure when standing up from a sitting or lying position (orthostatic hypotension), inability of the bladder to empty (urinary retention) and dizziness.

Other side effects

Very common side effects (may affect more than 1 in 10 people):

Difficulty falling asleep (Insomnia)
Headache (Headache)
Nausea
Excessive sweating (Hyperhidrosis)
Withdrawal syndrome
Ache

Common side effects (may affect up to 1 in 10 people):

Inflammation of the mucous membrane of the bronchi (bronchitis), infection, flu, inflammation of the pharynx (pharyngitis), rhinitis
Enlarged lymph nodes (lymphadenopathy)
Loss of appetite
Restlessness, anxiety, depression, hostility, nervousness, paranoia, confusion, abnormal thinking
Sedation, dizziness / vertigo, abnormal increase in muscle tone (hypertonia), headache (migraine), impaired sensation in the limbs (paraesthesia), sleepiness, transient loss of consciousness (syncope), tremors
Disorders of lacrimation, dilation of the pupil of the eye (mydriasis)
Palpitations
Increased caliber of blood vessels (vasodilation)
Respiratory depression, cough, yawning, difficulty in breathing (dyspnoea)
Abdominal pain, constipation, diarrhea, dry mouth, stomach upset (dyspepsia), gastrointestinal upset, gas buildup in the intestine (flatulence), dental upset, vomiting
Rash
Joint pain (arthralgia), back pain, bone pain, muscle spasms, muscle pain (myalgia), neck pain
Painful menstrual cycle (dysmenorrhea)
Weakness (asthenia), chest pain, chills, malaise, fluid accumulation (peripheral edema), fever (pyrexia)

Uncommon side effects (may affect up to 1 in 100 people):

Psychosis, euphoria
Incoherent speeches
Double vision (diplopia), visual abnormalities, inflammation of the conjunctiva (conjunctivitis)
Bluish discoloration of the skin due to insufficient oxygenation of the blood (cyanosis)
Inability of the bladder to empty (urinary retention)
Ringing in the ears (tinnitus)
Weakness, fatigue

Rare side effects (may affect up to 1 in 1,000 people):

Allergy (hypersensitivity)
Feeling detached from your body (depersonalization), hallucinations
Lack of muscle coordination, fainting
Pallor
Stopping of breathing (apnea)

Undesirable effects with frequency not known (frequency cannot be estimated from the available data):

Drug addiction
Convulsions
Narrowing of the pupil (miosis)
Faster heart beat (tachycardia), decreased heart rate (bradycardia)
High blood pressure (hypertension), low blood pressure (hypotension)
Neonatal withdrawal syndrome

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at 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.

Expiry and Retention

Do not store above 30 ° C.

Store in the original package to protect the medicine from moisture

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. The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Subutex contains

Subutex 0.4 mg sublingual tablets

The active ingredient is: 0.432 mg buprenorphine hydrochloride equivalent to 0.4 mg buprenorphine base;
The other ingredients are: lactose monohydrate, mannitol, maize starch, povidone K30, citric acid, sodium citrate, magnesium stearate.

Subutex 2 mg sublingual tablets

The active ingredient is: 2.16 mg buprenorphine hydrochloride equivalent to 2 mg buprenorphine base;
The other ingredients are: lactose monohydrate, mannitol, maize starch, povidone K30, citric acid, sodium citrate, magnesium stearate.

Subutex 8 mg sublingual tablets

The active ingredient is: 8.64 mg buprenorphine hydrochloride equivalent to 8 mg buprenorphine base.
The other ingredients are: lactose monohydrate, mannitol, maize starch, povidone K30, citric acid, sodium citrate, magnesium stearate.

What Subutex looks like and contents of the pack

Subutex 0.4 mg sublingual tablets: 7 sublingual tablets

Subutex 2 mg sublingual tablets: 7 sublingual tablets

Subutex 8 mg sublingual tablets: 7 sublingual tablets

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.

Further information on Subutex can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

SUBUTEX SUBLINGUAL TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

SUBUTEX 0.4 mg sublingual tablets

One sublingual tablet contains:

active ingredient: buprenorphine hydrochloride 0.432 mg equivalent to buprenorphine base 0.4 mg.

Excipients with known effects: lactose monohydrate 29.626 mg.

SUBUTEX 2 mg sublingual tablets

One sublingual tablet contains:

active ingredient: 2.16 mg buprenorphine hydrochloride equivalent to 2 mg buprenorphine base.

Excipients with known effects: lactose monohydrate 47.94 mg.

SUBUTEX 8 mg sublingual tablets

One sublingual tablet contains:

active ingredient: buprenorphine hydrochloride 8.64 mg equivalent to buprenorphine base 8 mg.

Excipients with known effects: lactose monohydrate 191.76 mg.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Sublingual tablet.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Replacement therapy in opiate addiction, within a medical, social and psychological treatment.

04.2 Posology and method of administration

SUBUTEX sublingual tablets are for use in adults and children over 15 years of age who have given their consent to treat their drug addiction situation.

Dosage

Precautions to be taken before administration

Before initiating therapy with SUBUTEX, the physician should be aware of the partial agonist profile of the buprenorphine molecule. Buprenorphine binds to the µ and κ opioid receptors and can precipitate withdrawal symptoms in opioid-dependent patients. The type of opioid dependence (ie short-acting or long-acting opioids), the length of time since the last opioid intake, and the degree of opioid dependence should be considered. In order to avoid precipitation of withdrawal symptoms, induction with buprenorphine should be undertaken in the presence of objective and clear withdrawal symptoms, demonstrated for example by a score indicating mild to moderate withdrawal according to the validated Clinical Scale for opioid withdrawal (COWS - Clinical Opioid Withdrawal Scale) (see section 4.4).

It is recommended that liver function tests be performed at baseline and the presence of viral hepatitis before starting therapy.

Regular monitoring of liver function is recommended (see section 4.4).

Induction phase

It must be gradual, until the optimal replacement dose is reached and the different dosages available (tablets from 0.4 mg to 8 mg) allow this graduality.

- Subjects who self-administer heroin daily: buprenorphine is an agonist / antagonist that acts as an antagonist when administered under the effect of a pure agonist, so it must be administered when the first vegetative withdrawal symptoms appear; otherwise buprenorphine can by itself induce a withdrawal syndrome proportionate to the subject's state of tolerance and therefore, to the last dose of heroin taken.

- Subjects receiving methadone: 8 mg of buprenorphine has a similar substitution efficacy to 30 mg of methadone. Before substituting methadone with buprenorphine it is recommended to reduce the methadone dosage to below 30 mg / day. Also in this case, the first administration of buprenorphine must take place in the presence of the first vegetative symptoms of methadone withdrawal. Otherwise, buprenorphine can in itself induce a withdrawal syndrome proportionate to the state of tolerance of the subject and therefore, to the last dose of methadone taken.

Adjustment of dosage and maintenance: The SUBUTEX dose should be progressively increased according to the individual patient's clinical response and should not exceed the maximum single daily dose of 32 mg.

The dose is adjusted based on the reassessment of the patient's clinical and psychological status.

Dose reduction and termination of treatment: after reaching a satisfactory stabilization period, the dose can be gradually reduced to a lower maintenance dose; if judged appropriate, treatment may be discontinued in some patients. The availability in sublingual tablets of 0.4, 2 and 8 mg allows a dose decrease.

Patients should be monitored after termination of buprenorphine treatment due to the possibility of relapse.

Special populations

Elderly patients: The safety and efficacy of buprenorphine in elderly patients over 65 years of age have not been established.

Hepatic impairment:

Baseline liver function tests and verification for viral hepatitis are recommended prior to initiation of therapy (see section 4.4).

Elevated plasma levels of buprenorphine have been found in patients with moderate and severe hepatic impairment. Patients should therefore be monitored for signs and symptoms of toxicity or overdose caused by increased buprenorphine levels. SUBUTEX sublingual tablets should be used with caution in patients with moderate hepatic impairment (see sections 4.4 and 5.2). In patients with severe hepatic impairment the use of buprenorphine is contraindicated (see section 4.3).

Renal impairment: It is generally not necessary to adjust the buprenorphine dose for patients with renal impairment. Caution is advised when administering to patients with renal impairment as dose adjustment may be required (see sections 4.4 and 5.2).

Pediatric population: The safety and efficacy of buprenorphine in children below 15 years of age have not been established. SUBUTEX is contraindicated in children below 15 years of age (see sections 4.3 and 4.4).

Since there are no data available in adolescents (aged 15-18), patients in this age group should be monitored more closely during treatment.

Method of administration

Administration is sublingual. Physicians should advise patients that the sublingual route is the only effective and safe route for administering this drug. The tablet should be held under the tongue until it dissolves completely, which usually takes 5-10 minutes. Patients should not swallow or consume any food or drink until the tablet is completely dissolved. The dose consists of SUBUTEX 0.4 mg, SUBUTEX 2 mg and SUBUTEX 8 mg tablets, which can be placed under the tongue at the same time or in two separate portions; the second portion should be placed under the tongue immediately after dissolving the first.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1; severe respiratory failure, severe hepatic failure (see sections 4.2, 4.4 and 5.2), acute alcoholism or delirium tremens (see sections 4.2 and 4.4); concomitant treatment with anti MAO (see section 4.5); subjects less than 15 years of age (see sections 4.2 and 4.4); breastfeeding (see section 4.6).

04.4 Special warnings and appropriate precautions for use

SUBUTEX sublingual tablets are only recommended for the treatment of opioid dependence.

The physician should pay attention to the risk of abuse and misuse (eg intravenous administration) especially at the start of treatment.

Misuse, abuse and diversion: As with other opioids, legal or illicit, SUBUTEX can be subject to misuse or abuse. Some of the risks of misuse and abuse include overdose, spread of hematogenous viral infections or localized and systemic infections, respiratory depression and liver damage (see section 4.8).

The misuse of SUBUTEX by anyone other than the predestined patient exposes new drug addicts to take buprenorphine as the primary drug of abuse and thus constitutes an additional risk; this could occur if the medicine is distributed for illicit use directly by the intended patient or if the medicine is not safeguarded from theft.

Suboptimal treatment with SUBUTEX may result in patient misuse, leading to overdose or discontinuation of treatment. A patient underdosed with SUBUTEX may continue to respond to uncontrolled withdrawal symptoms by self-medication with opioids, alcohol or other hypnotic sedatives such as benzodiazepines.

To minimize the risk of misuse, abuse and diversion, physicians should take appropriate precautions when prescribing and dispensing SUBUTEX, such as avoiding prescribing multiple renewals at an early stage of treatment, and conducting patient follow-up visits. with clinical monitoring appropriate to the patient's needs.

Respiratory depression: A few cases of death from respiratory depression have been reported when buprenorphine was used in combination with benzodiazepines (see section 4.5) or when buprenorphine was not used in accordance with the summary of product characteristics.

Deaths have also been reported in association with concomitant administration of buprenorphine and other central nervous system depressant drugs such as alcohol and other opioids (see section 4.5).

If buprenorphine is given to some opioid-dependent individuals who cannot tolerate the effects of opioids, life-threatening respiratory depression can occur.

Buprenorphine can cause severe, potentially fatal respiratory depression in children who accidentally ingest it. Protect children from accidental exposure.

This product should be used with caution in patients with asthma or respiratory insufficiency (e.g., chronic obstructive pulmonary disease, cor pulmonale, reduced respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis, spinal deviation which may lead to dyspnea). Patients presenting with the physical and / or pharmacological risk factors described above should be monitored and a dose reduction may be considered.

Central nervous system depression: Buprenorphine may cause drowsiness, particularly with the concomitant intake of alcohol or other central nervous system depressants (such as benzodiazepines, tranquilizers, sedatives or hypnotics) (see sections 4.5 and 4.7).

Dependence: Buprenorphine is a partial agonist which binds to µ (mu) -opioid receptors and chronic administration produces opioid-type addiction. Animal studies as well as clinical experience have shown that buprenorphine can be addictive, but at a lower level than a full agonist (eg morphine).

In general, the withdrawal syndrome is milder than that of a complete agonist, and may have a "delayed onset".

Abrupt discontinuation of treatment is not recommended, as it may cause a withdrawal syndrome whose onset may be delayed.

Hepatitis, hepatic eventsCases of acute liver injury have been reported in opioid-dependent subjects, both in clinical trials and in post-marketing adverse reaction reports (see section 4.8). The spectrum of abnormalities ranges from transient asymptomatic elevations of liver transaminases to case reports of cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing mitochondrial damage (genetic disease, abnormalities of the liver enzymes, hepatitis B or hepatitis C virus infections, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic drugs) and injecting drug abuse may have a causal or additional role. These important factors should be taken into account before prescribing SUBUTEX and during treatment.

When a hepatic event is suspected, further biological and etiological evaluations should be made. Based on the results, the drug can be cautiously suspended to prevent withdrawal symptoms and a return to illicit drug use. If treatment is continued, liver function should be closely monitored. Viral hepatitis positive patients, who receiving concomitant therapies (see section 4.5) and / or who have pre-existing liver dysfunction are at an increased risk of liver injury and these underlying factors should be considered before prescribing SUBUTEX and during treatment (see section 4.2).

Precipitation of opioid withdrawal syndrome: When initiating treatment with SUBUTEX, it is important to be aware of the partial agonist profile of buprenorphine. Sublingually administered buprenorphine may precipitate withdrawal symptoms in opioid-dependent patients if administration occurs before the resulting agonist effects from the recent use of opioids or abuse have decreased, particularly if the administration takes place less than 6 hours after taking the last dose of heroin or other short-acting opioid, or in the case of in which administration takes place less than 24 hours after taking the last dose of methadone. In order to avoid precipitation of withdrawal symptoms, upon induction of short- or long-acting opioids, the patient should show objective signs and withdrawal symptoms prior to the induction dose (see section 4.2).

In case of abrupt discontinuation of the maintenance drug treatment, signs of withdrawal may appear three days after the suspension itself, reaching a maximum from the third to the fifth day and then gradually decreasing over 8-10 days.

Withdrawal symptoms may also be associated with suboptimal dosing.

Hepatic impairment:

Elevated plasma levels of buprenorphine have been reported in patients with moderate and severe hepatic impairment (see section 5.2). Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased buprenorphine levels (see section 4.2). SUBUTEX sublingual tablets should be used with caution in patients with moderate hepatic impairment. In patients with severe hepatic impairment the use of buprenorphine is contraindicated (see section 4.3).

Renal impairment: Renal elimination may be prolonged since 30% of the administered dose is eliminated by the renal route. The metabolites of buprenorphine accumulate in patients with renal insufficiency. Caution is recommended in dosing in patients with renal impairment ( see section 4.2).

Allergic reactions: Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include skin rash, urticaria and pruritus. Bronchospasm, angioedema and anaphylactic shock have been reported A history of hypersensitivity to buprenorphine is a contraindication to its use.

Although respiratory depression may become evident at doses above the recommended therapeutic range, doses within the recommended therapeutic range can cause clinically significant respiratory depression in some circumstances.

General warnings regarding the administration of opioids:

• Opioids can cause orthostatic hypotension (see section 4.8).

• Opioids can increase cerebrospinal fluid pressure causing seizures, therefore they should be used with caution in patients with head trauma, intracranial injury, or in other conditions where cerebrospinal pressure may be increased or if there is a history of seizures.

• Opioid-induced myosis, changes in the level of consciousness or pain perception as a symptom of the disease may interfere with patient assessment, confuse the diagnosis, or hide the clinical course of concomitant diseases.

• Opioids should be used with caution in patients suffering from myxedema, hypothyroidism, or adrenocortical insufficiency (eg, Addison's disease).

• Opioids should be used with caution in patients with toxic psychosis.

• Opioids should be used with caution in patients suffering from hypotension, prostatic hypertrophy or urethral stricture.

• Opioids have been found to increase intracoledocal pressure; therefore they should be used with caution in patients suffering from biliary tract dysfunction.

• Opioids should be administered with caution to elderly or debilitated patients.

Pediatric use: No data is available in children under 15 years of age; therefore SUBUTEX should not be administered to individuals under the age of 15 (see sections 4.2 and 4.3).

Doping warning

For those who play sports: the use of the drug without therapeutic need constitutes doping and can in any case determine positive anti-doping tests

Important information about some of the ingredients

SUBUTEX contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

SUBUTEX should be used with caution when administered with:

• Alcohol: Alcohol increases the sedative effect of buprenorphine, SUBUTEX should not be taken with alcoholic beverages and should be used with caution with alcohol-containing drugs (see sections 4.4, 4.7 and 4.8).

SUBUTEX should be used with caution together with:

• Benzodiazepines: this combination can cause death due to respiratory depression of central origin; therefore patients should be closely monitored when this combination is prescribed and this combination should be avoided where there is a risk of abuse. Patients should be advised of the extreme danger of self-administering non-prescribed benzodiazepines while taking this medicinal product and advised that concomitant use of benzodiazepines with this medicinal product should only be on a prescription basis (see sections 4.4 and 4.8);

• Other central nervous system depressant drugs: Combining central nervous system depressant drugs with buprenorphine increases central nervous system depression (see sections 4.4 and 4.8). The reduced level of alertness can make driving and using machines dangerous (see section 4.7). Examples of central nervous system depressants are: other opium derivatives (eg methadone, analgesics and cough suppressants), some antidepressants, H1 receptor antagonist sedatives, barbiturates, anxiolytics, neuroleptics, clonidine and related substances;

• Monoamine oxidase inhibitors (MAOIs): depending on what happens with morphine, an enhancement of the effects of other opioids is possible. Avoid concomitant administration and within two weeks of stopping MAO treatment (see section 4.3);

• Opioid analgesics: The analgesic properties of other opioids such as methadone and other level III analgesics (hydromorphone, oxycodone or fentanyl) may be reduced in patients treated with buprenorphine for opioid dependence. Adequate analgesia may be difficult to achieve when a complete opioid agonist is administered to patients treated with buprenorphine. Conversely, the possibility of overdose with higher than usual doses of complete agonists, such as methadone or level III analgesics, should be considered. , especially when trying to counter the effects of the partial agonist buprenorphine or when plasma levels of buprenorphine are decreasing. Patients in need of analgesia and undergoing treatment for opioid dependence can best be managed by multidisciplinary teams that include both the pain management specialist and the opioid addiction specialist (see section 4.4, "Precipitation of withdrawal syndrome. opioids ");

• Naltrexone: Naltrexone is an opioid antagonist capable of blocking the pharmacological effects of buprenorphine. For opioid-dependent patients being treated with buprenorphine, the antagonist naltrexone may trigger the sudden onset of intense and prolonged opioid withdrawal symptoms. For patients receiving naltrexone, the expected therapeutic effects of buprenorphine administration may be blocked by the antagonist naltrexone.

• CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent CYP3A4 inhibitor) showed an increase in the Cmax and AUC (area under the curve) of buprenorphine (approximately 50% and 70%, respectively) and, to a lesser extent, norbuprenorphine. Patients treated with buprenorphine should be closely monitored. Slow dose reduction may be necessary if CYP3A4 inhibitors (e.g. HIV protease inhibitors, macrolide and azole antifungal antibiotics, gestodene, TAO ) are administered concurrently.

• CYP3A4 inducers: Concomitant use of CYP3A4 inducers and buprenorphine may reduce plasma concentrations of buprenorphine, potentially resulting in suboptimal treatment of opioid dependence with buprenorphine. Careful monitoring of patients receiving SUBUTEX is advised if such enzyme inducers (eg phenobarbital, carbamazepine, phenytoin, rifampicin) are administered concurrently. The dose of buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.

04.6 Pregnancy and lactation

Pregnancy

There are insufficient human data to evaluate the safety of buprenorphine when administered during pregnancy. Buprenorphine should only be used during pregnancy if the possible therapeutic benefit justifies the possible risk to the fetus. Towards the end of pregnancy, high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Prolonged administration of buprenorphine by the mother during the last three months of pregnancy may result in withdrawal syndrome in the neonate (eg, hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions) The syndrome usually occurs within hours to several days after birth (see section 4.8).

Due to the long half-life of buprenorphine, neonatal monitoring for several days at the end of pregnancy should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

Feeding time

As shown in rat studies, buprenorphine has the potential to inhibit milk secretion or production. Furthermore, as buprenorphine is excreted in breast milk, breastfeeding is contraindicated (see section 4.3).

Fertility

Animal studies have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown.

04.7 Effects on ability to drive and use machines

SUBUTEX has a moderate influence on the ability to drive and use machines when administered to opioid-dependent patients.

The medicine may cause somnolence, dizziness or mental confusion, particularly during the induction of treatment and dose adjustment phases. When taken together with alcohol or drugs that exert a depressive action on the central nervous system this effect is likely to be more marked (see sections 4.4 and 4.5). Patients should be reminded to exercise extreme caution when driving vehicles and operating hazardous machinery in the event that buprenorphine affects the performance of such activities.

04.8 Undesirable effects

The most common adverse drug reactions are those related to withdrawal symptoms (i.e. insomnia, headache, nausea and hyperhidrosis) and pain.

Summary table of adverse reactions

Table 1 summarizes:

• Adverse reactions observed during major clinical trials.

The frequency of side effects listed below is defined using the following convention: Very common (≥1 / 10); Common (≥1 / 100,

• The most commonly reported adverse reactions during post-marketing surveillance.

The frequency of events not reported in the main clinical studies cannot be estimated and is defined as not known.

Adverse drug reactions are presented by MedDRA system organ class, in internationally agreed order based on preferred term and frequency of reporting.

Table 1- Undesirable effects observed in major clinical trials and / or during post-marketing surveillance listed by system / organ class SYSTEM / ORGAN CLASS Very common (≥1 / 10) Common (≥1 / 100, Uncommon (≥1 / 1,000 to Rare (≥1 / 10,000, Frequency not known Infections and infestations Bronchitis, Infection, Flu, Pharyngitis, Rhinitis Disorders of the blood and lymphatic system Lymphadenopathy Disorders of the immune system Hypersensitivity Metabolism and nutrition disorders Loss of appetite Psychiatric disorders Insomnia Restlessness, Anxiety, Depression, Hostility, Nervousness, Paranoia, Confusion, Abnormal thinking Psychosis, Euphoria Depersonalization, Hallucinations Drug addiction Nervous system disorders Headache Sedation, Dizziness / Vertigo, Hypertonia, Migraine, Paraesthesia, Somnolence, Syncope, Tremors Incoherent speeches Lack of muscle coordination, Fainting Convulsions Eye disorders Disorders of lacrimation, Mydriasis Diplopia, Visual anomalies, Conjunctivitis Miosis Cardiac pathologies Palpitations Cyanosis Tachycardia, Bradycardia Vascular pathologies Vasodilation Pallor Hypertension, Hypotension Respiratory, thoracic and mediastinal disorders Respiratory depression, cough, yawning, dyspnea Apnea Renal and urinary disorders Urinary retention Ear and labyrinth disorders Tinnitus Gastrointestinal disorders Nausea Abdominal pain, Constipation, Diarrhea, Dry mouth, Dyspepsia, Gastrointestinal complaints, Flatulence, Dental disorders, Vomiting Skin and subcutaneous tissue disorders Hyperhidrosis Rash Musculoskeletal and connective tissue disorders Arthralgia, Back pain, Bone pain, Muscle spasms, Myalgia, Neck pain Pathology of the reproductive system and breast Dysmenorrhea General disorders and administration site conditions Withdrawal syndrome, Pain Asthenia, Chest pain, Chills, Malaise, Peripheral edema, Pyrexia Weakness, fatigue Neonatal withdrawal syndrome

Description of selected adverse reactions

Below is a summary of other post-marketing adverse events considered serious or otherwise significant:

In case of abuse or intravenous misuse of the drug: local reactions, sometimes septic (abscess, cellulitis), potentially serious acute hepatitis, pneumonia, endocarditis and other serious infections (see section 4.4).

Respiratory depression occurred. Deaths due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines (see section 4.5) or when buprenorphine was not used according to the summary of product characteristics.

Deaths have been reported in association with concomitant administration of buprenorphine and other central nervous system depressant drugs such as alcohol or other opioids (see sections 4.4 and 4.5).

The most common signs and symptoms of hypersensitivity include skin rash, hives, itching.Cases of bronchospasm, respiratory depression, angioedema and anaphylactic shock have been reported.

There have been cases of elevated hepatic transaminases, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy and hepatic necrosis (see section 4.4).

A neonatal drug withdrawal syndrome has been reported among infants of women who took buprenorphine during pregnancy. The syndrome may be milder and more prolonged than that caused by short-acting complete opioid µ-receptor agonists. The nature of the syndrome may vary with the mother's drug addict background (see section 4.6).

Cases of hallucination, orthostatic hypotension, urinary retention and vertigo have been reported (see section 4.4).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.

04.9 Overdose

Symptoms

In principle, symptoms similar to those of other centrally acting opioids should be expected in the event of an overdose of buprenorphine. Acute manifestations include: miosis, sedation, nausea, vomiting, cardiovascular collapse, respiratory depression.

The main symptom requiring intervention is respiratory depression which can progress to respiratory arrest with the risk of death.

The other symptom that can be dangerous is vomiting, of which aspiration must be prevented.

Treatment

In the event of an overdose, general supportive measures should be put in place, including close monitoring of the patient's respiratory and cardiac status. In particular, symptomatic treatment of respiratory depression should be undertaken, by implementing general resuscitation measures. A patent airway and assisted or controlled ventilation must be ensured. The patient should be transferred to an environment with a full resuscitation facility.

If the patient vomits, care should be taken to prevent aspiration of the vomitus.

The use of an opioid antagonist (eg naloxone) is recommended, bearing in mind that buprenorphine's counteracting respiratory symptoms may be less effective than that of other complete opioid agonists.

The long duration of action of buprenorphine must be taken into account when determining the duration of treatment needed to counteract the effect of overdose. Naloxone can be cleared more rapidly than buprenorphine, allowing previously controlled symptoms of buprenorphine overdose to return. Naloxone may not be effective in resolving respiratory depression caused by buprenorphine; therefore the primary goal of managing overdose should be to re-establish adequate ventilation, mechanically assisted if necessary.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: other nervous system drugs; drugs used in addiction disorders; drugs used in opioid addiction

ATC code: N07BC01.

Buprenorphine is a partial opioid agonist / antagonist that binds to the µ and κ receptors in the brain. Its activity in maintenance therapy is attributable to its slow reversible binding to the µ receptor which, over a prolonged period, minimizes the need for the drug for drug addicted patients.

Buprenorphine has a large safety margin due to its partial agonist / antagonist activity, which limits its depressive effects, especially on cardiac and respiratory functions.

During clinical trials in opioid-dependent subjects, buprenorphine has shown a ceiling effect for some parameters, such as mood, feeling of well-being and respiratory depression.

05.2 "Pharmacokinetic properties

Absorption

When administered orally, buprenorphine undergoes a hepatic "first-pass" metabolic process with N-dealkylation and glucuronide conjugation in the small intestine. Therefore, oral use of this drug is inappropriate.

Peak plasma concentrations are reached 90 minutes after sublingual administration and the maximal dose-concentration relationship is linear between 2 and 16 mg.

Distribution

Absorption of buprenorphine is followed by a rapid distribution phase and a half-life of between 2 and 5 hours.

Metabolism

Buprenorphine is metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (known as norbuprenorphine) via cytochrome P450 CYP3A4 and glucuronoconjugation of the parent molecule and the dealkylated metabolite. N-dealkylbuprenorphine is an agonist with weak intrinsic activity (see section 4.2).

Elimination

The elimination of buprenorphine is bi- or tri-exponential, with a long terminal elimination phase of 20-25 hours, due in part to the reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.

Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuronide conjugated metabolites (70%), the remainder is eliminated in the urine (see section 4.2).

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetic parameters of buprenorphine was observed in a post-marketing clinical study following administration of a single dose of buprenorphine / naloxone 2.0 / 0.5 mg sublingual tablets in healthy subjects and in subjects with different grades. of hepatic impairment.

With reference to the pharmacokinetic parameters of buprenorphine it was observed that, compared to healthy subjects, Cmax increased 1.2-fold, 1.1-fold and 1.7-fold, respectively, in subjects with mild hepatic impairment (Child-Pugh Class A). , moderate (Child-Pugh Class B) and severe (Child-Pugh Class C). AUC values in subjects with mild hepatic impairment were similar to healthy subjects, while in subjects with moderate and severe hepatic impairment they were increased by 4.6 and 2.8-fold, respectively.

05.3 Preclinical safety data

The acute toxicity of buprenorphine was determined in mice and rats following oral and parenteral administration.

The mean lethal dose (LD50) in mice was 26, 94 and 261 mg / kg by intravenous, intraperitoneal and oral administration, respectively.

The LD50 values in the rat were 35, 243 and 600 mg / kg for intravenous, intraperitoneal and oral administration, respectively.

When administered continuously subcutaneously to beagle dogs for one month, rhesus monkeys orally for one month, and rats and baboons intramuscularly for six months, buprenorphine exhibited low tissue and biochemical toxicity.

Studies in rats and rabbits have shown foetotoxicity including post-implantation loss. Furthermore, oral administration of high doses during pregnancy and lactation resulted in a slight delay in the development of some neurological functions in newborn rats (righting reflex and alarm response).

There is no undesirable effect on fertility or general reproductive function in rats, although at the highest intramuscular dose (5 mg / kg / day) the mothers experienced difficulty in delivery and a high neonatal mortality occurred (see section 4.6).

After 52 weeks of oral treatment at a dose of 75 mg / kg / day there was minimal to moderate "bile duct hyperplasia with associated peribial fibrosis in treated dogs.