BACLOFENE ZENTIVA 10 mg Cpr séc Plq/30

▼This medicine is subject to additional monitoring which will allow rapid identification of new safety information. Healthcare professionals should report any suspected adverse reactions. See section Adverse effects for the reporting procedures for adverse reactions.

White, flat tablet with bevelled edges, with a separation line* on one side.
30 scored tablets under blister.

* The tablet can be divided into equal doses.

For one scored tablet :

Baclofen: 10,00 mg

Excipient with known effect: lactose

Excipients:

Adult

1- Baclofen is indicated as a treatment of spastic contractures

• of multiple sclerosis.
• of spinal cord disorders (of infectious, degenerative, traumatic, or neoplastic aetiology).
• of cerebral origin.

2- Baclofen is indicated to reduce alcohol consumption, after failure of other available drug treatments, in adult patients with alcohol dependence and high-risk alcohol consumption (> 60 g/day for men or > 40 g/day for women).

Paediatric population (6 to 18 years)

Baclofen is indicated as symptomatic treatment of:

• Spastic contractures of cerebral origin (infantile cerebral palsy, cerebrovascular accident, neoplastic or degenerative cerebral disease).
• Muscle spasticity occurring in diseases of the spinal cord of infectious, degenerative, traumatic, or neoplastic origin, or secondary to multiple sclerosis, spastic spinal paralysis, amyotrophic lateral sclerosis, syringomyelia, transverse myelitis.

Dosage

1- Treatment of spastic contractures

Individually adjusted, the dosage is slowly progressive.

The lowest possible dose compatible with an optimal response is recommended.

The optimal dosage must be adjusted individually so as to reduce clonus, flexor/extensor muscle spasms and spasticity, while avoiding as much as possible the occurrence of adverse effects.

To prevent excessive weakness and falls, BACLOFEN ZENTIVA should be used with caution when spasticity is necessary to maintain standing, balance of the locomotor apparatus or other functions. A certain degree of muscle clonus and occasional spasms may be important to support circulatory functions and possibly prevent deep vein thrombosis.

If the therapeutic objective is not achieved after 6 to 8 weeks of treatment at maximum doses, the treatment will be re-evaluated.

Except in emergency situations related to overdose or the occurrence of serious adverse effects, treatment discontinuation should always be gradual (over 1 to 2 weeks, in steps of 10 or 15 mg) (see section Warnings and precautions). If symptoms reappear, treatment must be resumed at the previous dose.

Adults

Start treatment with 15 mg per day, preferably in 2 to 3 divided doses, and increase doses progressively with caution (for example 15 mg every 3-4 days) until the optimal daily dose is reached, which is usually between 30 and 80 mg per day. A bedtime dose may be recommended in cases of painful nocturnal spasticity.

In certain patients particularly sensitive to medicines, it is preferable to start with a lower daily dose (5 or 10 mg) and increase this dose very gradually (see section Warnings and precautions).

In hospital settings, daily dosages of up to 100 to 120 mg may be administered under close clinical supervision.

During rehabilitation of neurological spasticity, a daily dosage of 30 to 40 mg is often sufficient.

Special populations

Paediatric population (6 to 18 years)

Treatment is started with very low doses of the order of 0,3 mg/kg/day divided into 2 to 4 doses (4 doses preferably). Given the recommended doses and the available presentations, BACLOFENE ZENTIVA is not suitable for children weighing less than 33 kg. The daily dosage must be increased cautiously in periods of one to two weeks until the optimal dosage for the child is reached.

As a guide, the usual daily maintenance dosage varies between 0,75 and 2 mg/kg of body weight in three doses. The total daily dose must not exceed 40 mg/day in children under 8 years. In children over 8 years, a maximum dose of 60 mg/day may be administered.

Elderly subjects and patients with spasticity of cerebral or spinal origin:

In order to reduce the frequency of occurrence of adverse effects, administration of a lower initial dose and its gradual increase under supervision are recommended.

Renal insufficiency or dialysis:

Choose an initial daily dosage of approximately 5 mg/day. Signs and symptoms of overdose have been reported with doses above 5 mg per day.

The dosage of baclofen must be adjusted according to its plasma concentration in patients with renal insufficiency. A short haemodialysis is an effective means of removing excess baclofen from the blood circulation.

Hepatic impairment

No studies have been conducted in patients with hepatic insufficiency treated with BACLOFENE ZENTIVA. The liver does not play a primary role in the metabolism of orally administered baclofen (see section Pharmacokinetics). However, BACLOFENE ZENTIVA may cause an increase in liver enzymes. BACLOFENE ZENTIVA must be administered with caution in patients with hepatic insufficiency (see section Warnings and precautions).

2- Reduction of alcohol consumption

BACLOFENE ZENTIVA must be prescribed by a physician preferably experienced in addiction medicine, in addition to psychosocial follow-up focused on therapeutic adherence and the reduction of alcohol consumption.

Treatment may be initiated with or without a prior alcohol withdrawal phase. In the case of withdrawal, treatment with BACLOFENE ZENTIVA will be started within 2 weeks following cessation of alcohol consumption. In the case of acute alcohol withdrawal symptoms, specific treatment will be instituted.

Patients must be closely monitored by their physician during the titration phase.

Treatment with BACLOFENE ZENTIVA will be started at a dosage of 15 to 20 mg per day in 2 to 4 doses for 3 days. The daily dose will be increased in steps of 10 mg every 3 or 4 days. The therapeutic goal is the reduction of alcohol consumption to a low-risk level of consumption (≤ 40 g/day for men and ≤ 20 g/day for women). During the titration phase, the efficacy and tolerability of BACLOFENE ZENTIVA must be regularly assessed in order to determine an optimal dosage (adapted to each patient), namely the lowest dose for an optimal therapeutic response and acceptable tolerability. If this therapeutic goal is not achieved at a dose of 80 mg/day, it is strongly recommended to offer the patient an evaluation and multidisciplinary management specialized in addiction medicine. As no efficacy and safety data are available beyond 300 mg/day, it is strongly recommended not to exceed a dose of 300 mg/day. In case of troublesome and persistent adverse effects (such as drowsiness, asthenia, insomnia, dizziness), the dosage may be reduced to the previously well-tolerated dose. A new attempt to increase the dosage will be made after a period of stability and satisfactory tolerance of 4 days. Several attempts may be made to reach the optimal dosage.

Administration of asymmetric doses according to the intensity of craving (irrepressible urge to drink) depending on the time of day is possible.

Once the therapeutic goal has been achieved and is stable, a dose reduction may be considered. An occasional significant alcohol consumption (> 60 g/day in men or > 40 g/day in women) does not contraindicate continuation of treatment.

If the therapeutic goal is not achieved after 3 months of treatment, BACLOFENE ZENTIVA must be stopped. If treatment must be stopped (for whatever reason), the dosage will be gradually reduced over a period of 2 to 3 weeks. Treatment must never be stopped abruptly because of the risk of onset of withdrawal symptoms, except in an emergency related to overdose or the occurrence of serious adverse effects (see section Adverse effects).

Duration of treatment: there are no study data beyond 12 months.

Special populations

Elderly (≥ 65 years)

No dose adjustment is recommended in these patients in the absence of renal and/or hepatic impairment (see section Pharmacokinetics).

Renal impairment

In case of renal impairment, the dose should be adapted to the state of renal function (see sections Warnings and precautions and Pharmacokinetics). As an indication, the recommended dose adjustment is a reduction of doses of:

• one third in cases of mild renal impairment (creatinine clearance between 50 and 80 mL/min),
• half for moderate renal impairment (creatinine clearance between 30 and 50 mL/min),
• two thirds in cases of severe renal impairment (creatinine clearance less than 30 mL/min in non-dialysed patients).

Due to the risk of accumulation, particular monitoring of tolerance should be implemented.

Hepatic impairment

No dose adjustment is recommended in patients with mild or moderate hepatic impairment (see section Pharmacokinetics).

For patients with severe hepatic impairment (Child-Pugh C), the dose should be increased more gradually during the titration phase in steps of 5 mg every 3 or 4 days. Due to the risk of accumulation, particular monitoring of tolerance should be implemented in patients with moderate to severe hepatic impairment.

Paediatric population

The safety and efficacy of BACLOFENE ZENTIVA in children and adolescents aged less than 18 years have not been studied in this indication. No data are available (see section ). BACLOFENE ZENTIVA should therefore not be used in children and adolescents for this indication. Pharmacodynamics). BACLOFENE ZENTIVA should therefore not be used in children and adolescents for this indication.

Method of administration

Oral use.

The tablets are to be swallowed during meals with a glass of water.

Due to its pharmaceutical form, BACLOFENE ZENTIVA is not suitable for children under 6 years of age (approximately 33 kg).

This medicine is contraindicated in the following cases:

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Special warnings

BACLOFENE ZENTIVA will be administered only if the benefit outweighs the risk. The occurrence of adverse effects (notably drowsiness and lethargy) should be monitored in patients at risk (multi-disabled, severe stroke, end-stage renal failure).

Psychiatric and nervous system disorders

Cases of suicide and suicide-related events have been reported in patients treated with baclofen. In most cases, patients had risk factors associated with an increased risk of suicide, such as alcohol-related disorders, depression and/or a history of suicide attempts.

In patients presenting with or having previously presented psychiatric disorders, and in particular suicidal ideation and behaviours with a risk of acting on them, a major depressive episode or a history of suicide attempt, the benefits and risks of initiating or continuing treatment with BACLOFENE ZENTIVA must be carefully evaluated. A psychiatric consultation should be planned before initiation of treatment and during treatment.

Careful monitoring of patients, particularly at the start of treatment, should be implemented. Patients (and their relatives) must be informed of the need to immediately report to their physician any behavioural or mood disturbance and any suicidal ideation.

It is recommended to discontinue treatment with BACLOFENE ZENTIVA if psychiatric symptoms, suicidal ideation or suicidal behaviours appear or worsen.

Cases of misuse, abuse and dependence have been observed with baclofen. Particular attention should be paid when treating patients with a history of substance abuse. Patients should be monitored for the occurrence of symptoms of baclofen misuse, abuse or dependence, for example dose escalation, substance-seeking behaviour, and the development of tolerance.

Paediatric population

Clinical experience with the use of baclofen in children under 1 year of age is very limited.

Women of childbearing potential

Given the potential risk in case of exposure during pregnancy, women of childbearing potential must use effective contraception during treatment (see section Fertility, pregnancy and breastfeeding).

Risks related to exposure in utero

Withdrawal symptoms, including postnatal convulsions in the newborn, have been reported following intrauterine exposure to orally administered baclofen. Administration of baclofen to newborns presenting with withdrawal syndrome, with progressive dose reduction, may help control withdrawal reactions (see section Fertility, pregnancy and breastfeeding). This may only be considered exceptionally and in a specialised setting.

Interruption of treatment

Do not stop treatment abruptly because of the risk of withdrawal syndrome. Indeed, abrupt cessation of treatment (by analogy with what has been observed with intrathecal administration) may lead to a withdrawal syndrome, sometimes fatal, with the following symptoms related to a probable increase in serotonergic tone: neuromuscular disorders (spasticity, dyskinesia, rhabdomyolysis, paraesthesia, convulsions or even status epilepticus), pruritus, dysautonomia (hyperthermia, hypotension), disturbances of consciousness and behaviour (confusional state, hallucinations, manic or paranoid psychotic state) and coagulopathy.

Withdrawal symptoms, including postnatal convulsions in the newborn, have been reported following intrauterine exposure to orally administered BACLOFEN ZENTIVA. Administration of BACLOFEN ZENTIVA to newborns presenting with withdrawal syndrome, with progressive dose reduction, may help control withdrawal reactions (see section Fertility, pregnancy and breastfeeding).

Except in emergencies related to overdose or the occurrence of serious adverse effects, treatment must always be discontinued gradually by progressively reducing the dose over a period of approximately 1 to 2 weeks. The following adverse effects have been reported upon abrupt discontinuation of BACLOFEN ZENTIVA, particularly after prolonged drug treatment: anxiety and confusional state, delirium, hallucinations, psychotic, manic or paranoid disorders, convulsions (status epilepticus), dyskinesia, tachycardia, hyperthermia, rhabdomyolysis, temporary worsening of spasticity as a rebound effect, and hypertonia.

Respiratory disorders

The risk of respiratory depression is increased when co-prescribing CNS depressant medicines. Particular monitoring of respiratory and cardiovascular functions is essential in patients suffering from cardiopulmonary diseases or paresis of the respiratory muscles.

Cases of sleep apnoea have also been reported; patients at risk of sleep apnoea or of worsening sleep apnoea should be monitored.

Porphyria

The use of this medicine is not recommended in patients with porphyria, by extrapolation from animal data.

Encephalopathy

Cases of reversible encephalopathy after treatment discontinuation have been observed in patients receiving baclofen at therapeutic doses. Symptoms included drowsiness, decreased level of consciousness, confusion, myoclonus and coma.

If signs of encephalopathy are observed, baclofen should be discontinued.

Precautions for use

Renal impairment

BACLOFEN ZENTIVA should be used with caution in patients with renal impairment and should be administered to patients with end-stage renal failure only if the expected benefit outweighs the risk incurred (see section Dosage and administration and Pharmacokinetics). Neurological signs and symptoms of overdose, including clinical manifestations of toxic encephalopathy (e.g. confusion, disorientation, drowsiness and impaired level of consciousness), have been observed in patients with renal impairment taking oral baclofen at doses above 5 mg per day, and at doses of 5 mg per day in patients with end-stage renal failure undergoing chronic haemodialysis. Patients with renal dysfunction must be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (see section Overdose).

Special precautions are necessary when BACLOFEN ZENTIVA is combined with medicines or pharmaceutical products that may have a significant impact on renal function. Renal function must be closely monitored and the daily dose of BACLOFEN ZENTIVA must be adjusted to prevent baclofen toxicity.

Severe hepatic impairment

Baclofen should be used with caution in patients with severe hepatic impairment (Child-Pugh C) (see sections Dosage and administration and Pharmacokinetics).

Epilepsy or history of convulsive seizures

In these patients, convulsive seizures may occur at therapeutic doses, in case of overdose or upon discontinuation of baclofen. If antiepileptic treatment is ongoing, it should be continued and monitoring reinforced (see section Adverse effects)

Urinary disorders

In the presence of pre-existing sphincter hypertonia, the possible occurrence of acute urinary retention requires cautious use of baclofen.

Laboratory tests

In cases of hepatic disorders or diabetes, regular checks of transaminases, serum alkaline phosphatases or blood glucose are necessary.

Psychiatric disorders

Cautious use in patients with a history of psychotic disorders, confusional states and depression.

Risk of falls

Due to the sedation and/or muscle-relaxant effect that may occur during treatment with BACLOFEN ZENTIVA, there is a risk of falls with a risk of fractures and/or injuries and/or road traffic accidents. This risk is increased by concomitant intake of alcohol (see section Interactions).

Other situations requiring cautious use in patients who currently have, or have a history of

• cerebrovascular disease,
• respiratory insufficiency,
• gastric or duodenal ulcer,
• Parkinson's disease.

Excipient with known effect

This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

Combinations not recommended

+ Alcohol (beverage or excipient)

Potentiation by alcohol of the sedative effect of baclofen. Impaired alertness may make driving vehicles and using machinery dangerous.

Avoid taking alcoholic beverages and medicines containing alcohol.

Associations requiring precautions for use

+ Antihypertensives

Potentiation of hypotension, especially orthostatic hypotension. Monitoring of blood pressure and dose adjustment of the concomitant treatment, if necessary.

Associations to be taken into account

+ Tricyclic antidepressants

Risk of increased muscle hypotonia.

+ Other sedative medicines

It must be taken into account that many medicines or substances may add together their depressant effects on the central nervous system and contribute to reducing alertness. These include morphine derivatives (analgesics, antitussives and substitution treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedating H1 antihistamines, centrally acting antihypertensives, thalidomide and baclofen.

Potentiation of central depression. Impaired alertness may make driving vehicles and using machinery dangerous.

+ Dapoxetine

Risk of increased adverse effects, notably dizziness or syncope.

+ Levodopa

Risk of worsening of parkinsonian syndrome or central adverse effects (visual hallucinations, confusional state, headaches).

+ Medicinal products causing orthostatic hypotension

Besides antihypertensives, many medicines may cause orthostatic hypotension. This is notably the case for nitrates, phosphodiesterase type 5 inhibitors, alpha-blockers used in urology, imipramine-like antidepressants and phenothiazine neuroleptics, dopamine agonists and levodopa. Their concomitant use therefore risks increasing the frequency and intensity of this undesirable effect. Refer to the interactions specific to each class, with the corresponding levels of constraint.

Women of childbearing potential

Women of childbearing potential must use effective contraception during treatment.

Pregnancy

Studies carried out in animals have demonstrated a teratogenic effect of oral baclofen. When administered orally to animals, baclofen crosses the placenta.

The available clinical data are limited, but cases of malformations have been reported in children exposed in utero to baclofen, with types of malformation consistent with those observed in animals (central nervous system, skeletal abnormalities and omphalocele).

In cases of oral use of baclofen up to delivery, cases of withdrawal syndrome (including postnatal convulsions) have been reported in the newborn (see section Warnings and precautions). This syndrome may be delayed by several days after birth.

Therefore, baclofen must not be used during pregnancy unless absolutely necessary. Women of childbearing potential must use effective contraception during treatment.

In case of exposure during pregnancy, specialised prenatal monitoring focused on the malformations described above must be put in place. In case of exposure at the end of pregnancy, monitoring and appropriate management of the newborn must be implemented.

Breast-feeding

Very little data are available on the use of baclofen during breastfeeding. Consequently, breastfeeding should be avoided.

Fertility

No data are available on the effect of baclofen on human fertility. In rats, baclofen administered at doses non-toxic to the mother had no effect on the fertility of males or females.

BACLOFENE ZENTIVA has a moderate influence on the ability to drive vehicles and use machines. Undesirable effects such as sedation, dizziness and visual disturbances are associated with taking baclofen (see section Adverse effects).

Patients must be advised on the importance of avoiding driving vehicles or using machines if they experience these adverse effects.

Occurring most often at the start of treatment (e.g., sedation) when the dose is increased too quickly or when doses that are too high are used, they are most often transient and can be lessened or eliminated by reducing the dose. They rarely require discontinuation of treatment.

They are sometimes more severe in elderly people, or in those with a psychiatric history or cerebrovascular disorders.

As the epileptogenic threshold may be lowered, seizures may occur, particularly in epileptic patients.

Adverse effects are presented below in decreasing order of frequency using the following categories: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1 000 and < 1/100), rare (≥ 1/10 000 and < 1/1 000), very rare (< 1/10 000), frequency not known (cannot be estimated from the available data).

Immune system disorders
Frequency not known:	hypersensitivity
Nervous system disorders
Very common:	sedation, somnolence especially at the start of treatment
Common:	confusion, dizziness, headache, insomnia, ataxia, tremor
Rare:	paresthesia, dysarthria, dysgeusia, tinnitus
Frequency not known:	Encephalopathy, lowering of the seizure threshold in epileptic patients, paradoxical increase in spasticity in some patients, encephalopathy, sleep apnoea syndrome**
Psychiatric disorders
Common:	euphoric state, depression, hallucinations, confusional state, insomnia
Eye disorders
Common:	accommodation disorders
Musculoskeletal and systemic disorders
Rare :	muscle hypotonia that may be corrected by decreasing the dose administered during the day and by a possible increase in the evening dose.
Disorders of the reproductive organs
Frequency not known:	Sexual dysfunction
Cardiac disorders
Rare:	bradycardia
Respiratory disorders
Common:	respiratory depression
Vascular disorders
Common:	hypotension
Gastrointestinal disorders
Very common:	nausea
Common:	vomiting, constipation, diarrhea, dry mouth
Rare:	abdominal pain, anorexia
Hepatobiliary disorders
Rare:	abnormal liver function (increased alkaline phosphatases and transaminases)
Skin and subcutaneous tissue disorders
Common:	hyperhidrosis, skin rash
Frequency not known:	Urticaria, alopecia
Renal and urinary disorders
Common:	worsening of pre-existing dysuria
General disorders and administration site conditions
Very common:	asthenia
Very rare:	dose-dependent hypothermia
Frequency not known:	withdrawal syndrome* (see section Warnings and precautions), swelling of the face and oedema
Investigations
Common:	decreased cardiac output
Frequency not known:	increased blood glucose (see section Warnings and precautions)

* A withdrawal syndrome, including postnatal convulsions, has also been reported following intrauterine exposure to orally administered BACLOFENE ZENTIVA.

** Cases of sleep apnoea syndrome have been observed with the administration of high doses of baclofen (≥ 100 mg) in patients with alcohol dependence.

Additional adverse effects have been observed with the solution for injection for intrathecal infusion of baclofen: disturbances of consciousness (very common), anxiety, disorientation, hypersalivation, dyspnoea, bradypnoea, pruritus, facial and/or peripheral oedema, pyrexia, pain, chills, urinary incontinence and urinary retention (common), suicide attempt, lethargy, hypertension, venous thrombosis, cutaneous flushing, pallor, muscle hypertonia, dysphagia, nystagmus (uncommon), suicidal ideation, agitation, paranoid reactions, ileus, dehydration, alopecia, erectile disturbances (rare), memory disturbances, pneumonia, aspiration pneumonia (frequency not known).

Withdrawal syndrome

Discontinuation of treatment, particularly if abrupt, may induce a withdrawal syndrome that is sometimes fatal. The withdrawal reactions most frequently reported (by analogy with what has been observed with intrathecal administration) are: neuromuscular disorders (spasticity, dyskinesias, rhabdomyolysis, paraesthesia, convulsions or even status epilepticus), pruritus, dysautonomia (hyperthermia, hypotension), disturbances of consciousness and behaviour (confusional state, anxiety, manic or paranoid psychotic state) and coagulopathy.

Except in emergencies related to overdose or the occurrence of serious adverse effects, treatment must always be discontinued gradually (see sections Dosage and administration and Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

Clinical signs of overdose:

• Symptoms: The predominant features are signs of central nervous system depression or encephalopathy: drowsiness, decreased level of consciousness, respiratory depression, coma and tinnitus.
• Disturbances of consciousness ranging up to coma,
• Muscular hypotonia, sometimes generalised, which may last for 72 hours, possibly reaching the respiratory muscles,
• The following symptoms may also occur: dizziness, confusion, hallucinations, agitation, convulsions, abnormal electroencephalogram (burst suppression and triphasic waves), generalised slowing of the EEG, accommodation disorders, altered pupillary reflexes, myoclonus, hyporeflexia or areflexia, peripheral vasodilation, hypotension or hypertension, bradycardia or tachycardia, or cardiac arrhythmia, hypothermia, nausea, vomiting, diarrhoea, tinnitus, salivary hypersecretion, elevation of liver enzymes (ASAT, alkaline phosphatases), and rhabdomyolysis.

Action to be taken:

• there is no specific antidote
• immediate discontinuation of treatment,
• immediate transfer to a hospital setting,
• rapid elimination of the ingested product.

After ingestion of a potentially toxic quantity, administration of activated charcoal may be considered, especially during the first hours following ingestion. Gastric lavage may be considered on a case-by-case basis, particularly within 60 minutes following ingestion of a potentially lethal overdose.

Comatose patients or patients presenting with convulsive seizures must be intubated before gastric evacuation is initiated. In addition to discontinuation of treatment, unscheduled haemodialysis may be considered as an alternative in patients presenting with severe toxicity due to baclofen. Haemodialysis facilitates the elimination of baclofen, relieves the clinical symptoms of overdose and shortens the time to recovery in these patients.

• symptomatic treatment of visceral failures,
• in case of use of intravenous diazepam for convulsions, administer with caution.

Pharmacotherapeutic class: OTHER CENTRALLY ACTING MEDICINES, ATC code: M03BX01

Mechanism of action

Baclofen is a structural analogue of gamma-aminobutyric acid (GABA). This product has an antispastic action with a spinal site of impact: it slows the transmission of mono- and polysynaptic reflexes by stimulation of GABA Β receptors of the spinal cord.

Pharmacodynamic effects

Neuromuscular transmission is not affected by baclofen. Baclofen has an antinociceptive action. In neurological disorders accompanied by skeletal muscle spasms, BACLOFENE ZENTIVA produces a favourable clinical effect on reflex muscle contractions and considerably reduces painful spasms, automatisms and clonus.

It has been shown that baclofen may cause depression of the central nervous system, accompanied by sedation, drowsiness and respiratory and cardiovascular depression.

Absorption

Baclofen is rapidly and completely absorbed from the digestive tract.

Following oral administration of single doses of 10, 20 and 30 mg of baclofen, maximum plasma concentrations were recorded 30 min to 1 hour 30 later, averaging approximately 180, 340 and 650 nanograms/mL respectively. The areas under the plasma concentration curves increase in proportion to the dose administered.

Distribution

The volume of distribution of baclofen is 0,7 L/kg.

The degree of binding to serum proteins is approximately 30% and remains constant over the concentration range from 10 nanograms/mL to 300 nanograms/mL.

In cerebrospinal fluid, the active substance reaches concentrations approximately 8,5 times lower than in plasma.

Crosses the placental barrier and passes into breast milk.

The plasma half-life of baclofen is on average 3 to 4 hours

Biotransformation

Baclofen is metabolised to a small extent, its main metabolite being the acid β-(p-chlorophenyl)-4-hydroxybutyric acid, is pharmacologically inactive (deamination).

Elimination

The plasma elimination half-life is on average between 3 and 4 hours.

Baclofen is eliminated mainly in unchanged form.

Within 72 hours, 75 % of the dose is excreted renally, of which approximately 5 % as metabolites.

The remainder of the dose is eliminated in the faeces.

Special populations

Elderly patients (65 years or older)

In elderly patients, the pharmacokinetics of baclofen are practically the same as those in patients aged under 65 years.

Paediatric population

Following oral administration of a tablet of 2,5 mg of BACLOFENE ZENTIVA in children aged 2 to 12 years, a Cmax between 55 and 100 nanograms/mL and a Tmax between 0,95 and 2 hours have been reported. A mean plasma clearance (Cl) of 315,9 mL/h/kg and a plasma half-life (T1/2) of 5,10 hours have been reported. Tmax and T1/2 are comparable to those of adult pharmacokinetic profiles.

Hepatic impairment

Administration of a single dose of 20 mg of baclofen showed that the pharmacokinetics of baclofen are identical in healthy subjects and in patients with mild hepatic impairment. In patients with moderate or severe hepatic impairment, after a single administration, the mean systemic exposure to baclofen is increased (up to 40 %), without change in maximum plasma concentrations or half-life. A dose reduction is recommended in patients with severe hepatic impairment. (see section Dosage and administration)

Renal impairment

As baclofen is eliminated mainly via the kidneys, its clearance decreases in cases of renal impairment. Baclofen clearance is decreased by approximately 1/3 in patients with mild renal impairment, by half in patients with moderate renal impairment, and by 2/3 in patients with severe renal impairment; an identical dose reduction is recommended for these patients. (see sections Dosage and administration and Warnings and precautions).

Repeated-dose toxicity

In a study of 2 years' duration conducted in rats by oral route, an increased occurrence of ovarian cysts and a slight dose-dependent increase in adrenal gland volume were observed. The clinical relevance of these effects is not known.

Reprotoxicity

Animal studies have shown that orally administered baclofen is teratogenic. Omphaloceles (ventral hernias) were observed in rats but not in mice or rabbits.

Genotoxicity and carcinogenesis

Baclofen has not shown genotoxic potential based on the results of a battery of studies in vitro and in vivo.

A study of 2 years' duration conducted in rats by oral route showed that baclofen was not carcinogenic.

2 years.

Store at a temperature below 25 °C.

No special requirements.

List I

Medicine requiring particular monitoring during treatment.

Marketing authorisation (AMM)

CIP 3400936743199 (Plq/30).

Price:

2,28 euros (Plq/30).