Baclofen

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BACLOFEN (BACLOFEN)

Composition:

Active ingredient: baclofen;

1 tablet contains 10 mg or 20 mg of baclofen;

Excipients: microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: round, flat-faced tablets with bevelled edges, white to almost white, with imprint "024" on one side and a score line on the other;

20 mg tablets: round, flat-faced tablets with bevelled edges, white to almost white, with imprint "025" on one side and a score line on the other.

Pharmacotherapeutic group. Centrally-acting muscle relaxants. ATC code M03B X01.

Pharmacological Properties

Pharmacodynamics

Baclofen is a muscle relaxant acting at the spinal cord level; it is a derivative of gamma-aminobutyric acid (GABA). Chemically, baclofen is unrelated to other muscle relaxants.

Baclofen reduces increased muscle tone caused by spinal cord lesions. The drug simultaneously and equally suppresses cutaneous reflexes and muscle tone, while only slightly reducing the amplitude of tendon reflexes.

The mechanism of action likely involves hyperpolarization of ascending nerves and inhibition of both mono- and polysynaptic reflexes at the spinal cord level, mediated by stimulation of GABAB receptors, thereby blocking the release of amino acids—glutamate and aspartate. Baclofen does not affect neuromuscular transmission.

In animal experiments, baclofen increased dopamine metabolism; however, in humans, the drug does not alter the concentration of 5-hydroxyindole acetic acid or dopamine metabolites in cerebrospinal fluid.

Since baclofen may depress central nervous system (CNS) functions at high doses, it may also affect centers located above the spinal cord.

Advantages of baclofen use are associated with its ability to reduce painful flexor spasms and spontaneous muscle contractions, thereby improving patient mobility, reducing dependence on others, and enhancing rehabilitation. Baclofen also reduces pain sensitivity. Improvement in general well-being and sedation occurs less frequently compared to other CNS-acting drugs.

Baclofen stimulates gastric secretion.

Pharmacokinetics

Absorption

Baclofen is rapidly and almost completely absorbed from the gastrointestinal tract.

Significant differences in Tmax, Cmax, and bioavailability following administration of baclofen as a solution versus solid dosage forms are not observed. After single oral doses (10–30 mg), peak plasma concentrations are reached within 0.5–1.5 hours, and the area under the concentration-time curve is dose-proportional.

The extent of absorption decreases with higher doses.

Therapeutic plasma concentration ranges from 80 to 395 ng/mL.

Animal experiments have shown that baclofen distributes into many tissues, but only a small portion crosses the blood-brain barrier.

In patients, maximum concentration (Cmax 500–600 ng/mL) is achieved within 2–3 hours after administration, and concentrations above 200 ng/mL are maintained for up to 8 hours.

Distribution

Baclofen crosses the placental barrier.

A minimal amount of the drug passes into breast milk.

The volume of distribution of baclofen is 0.7 L/kg, and plasma protein binding is approximately 30%. This level remains unchanged across baclofen concentrations ranging from 10 ng/mL to 300 µg/mL. The concentration of the active substance in cerebrospinal fluid is approximately 8.5 times lower than in plasma.

Metabolism

Approximately 15% of the administered dose undergoes hepatic metabolism via deamination. This deamination produces the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, which is pharmacologically inactive.

Elimination

The elimination half-life from plasma averages 3–4 hours. Plasma protein binding rate is approximately 30%.

Baclofen is primarily excreted unchanged. Within 72 hours, approximately 75% of the administered dose is excreted by the kidneys, of which about 5% is eliminated as metabolites.

Special Patient Groups

Elderly patients (≥ 65 years)

Pharmacokinetics in elderly patients is practically the same as in adults under 65 years of age. After a single oral dose, elimination of baclofen is somewhat slower in elderly patients; however, systemic exposure to baclofen is similar to that in adults under 65 years. Extrapolation of these findings to repeated-dose therapy suggests no significant difference in pharmacokinetics between patients under 65 years and elderly patients (≥ 65 years).

Children

In children (aged 2–12 years), following oral administration of 2.5 mg baclofen, Cmax was 62.8±28.7 ng/mL and Tmax ranged from 0.95 to 2 hours. Mean plasma clearance (Cl) was 315.9 mL/h/kg, volume of distribution (Vd) was 2.58 L/kg, and elimination half-life (T1⁄2) was 5.1 hours.

Hepatic impairment

Pharmacokinetic data on baclofen use in patients with hepatic impairment are lacking. However, since the liver plays no major role in the metabolism and elimination of baclofen, clinically significant changes in baclofen pharmacokinetics in patients with hepatic impairment are not expected.

Renal impairment

Controlled clinical pharmacokinetic studies of baclofen in patients with renal impairment have not been conducted. The majority of baclofen is excreted unchanged in urine. Limited data on plasma concentrations collected from patients undergoing chronic hemodialysis and those with compensated renal impairment indicate significantly reduced clearance and prolonged elimination half-life of baclofen in these patients. Dose adjustment is recommended in patients with impaired renal function based on systemic baclofen levels. Immediate hemodialysis is an effective method for removing excess baclofen from systemic circulation.

Clinical Characteristics

Indications

Relief of spastic conditions arising from the following diseases:

• multiple sclerosis;
• other spinal cord disorders (e.g., syringomyelia, motor neuron disease, transverse myelitis);
• cerebrovascular accidents;
• cerebral palsy;
• meningitis and encephalitis;
• traumatic brain injury.

At the beginning of baclofen therapy, patient selection is important; the greatest benefit is likely to be observed in patients whose spasticity interferes with physical activity and/or physiotherapy. Treatment should not be initiated until the spastic condition has stabilized.

Children

The medicinal product is used in children under 18 years of age with body weight ≥ 33 kg for symptomatic treatment of cerebral-origin muscle spasticity, particularly caused by cerebral palsy, as well as due to cerebral disorders or in the presence of neoplastic or degenerative brain diseases.

Baclofen is also indicated for symptomatic treatment of muscle spasticity resulting from infectious, degenerative, traumatic, neoplastic diseases of the spinal cord or lesions of unknown origin, such as multiple sclerosis, spastic spinal paralysis, amyotrophic lateral sclerosis, syringomyelia, transverse myelitis, traumatic paraplegia or paraparesis, and spinal cord compression.

Contraindications

Hypersensitivity to baclofen or to any excipient of the medicinal product.

Peptic ulcer disease.

Interaction with other medicinal products and other types of interactions

Levodopa/dopa-decarboxylase inhibitor (DDC) (carbidopa)

In patients with Parkinson's disease receiving treatment with baclofen and levodopa (alone or in combination with the DDC inhibitor carbidopa), confusion, hallucinations, nausea, and agitation have been reported. Worsening of parkinsonian symptoms has also been reported. Therefore, caution should be exercised when baclofen is used concomitantly with levodopa/carbidopa.

Central nervous system (CNS) depressants

Concomitant use of baclofen with other CNS depressants, including other muscle relaxants (e.g., tizanidine), synthetic opioids, or alcohol, may enhance sedative effects (see section "Effect on ability to drive and use machines").

Patients receiving baclofen are at increased risk of developing respiratory depression. In addition, hypotension has been reported with concomitant use of morphine and intrathecal baclofen. Careful monitoring of cardiac and respiratory function is required, especially in patients with cardiovascular or respiratory disorders and with weakness of respiratory muscles.

Baclofen prolongs the analgesic effect induced by fentanyl.

Antidepressants

During concomitant therapy with tricyclic antidepressants, the effect of baclofen may be enhanced, potentially leading to pronounced muscular hypotonia.

Lithium

Concomitant use of oral baclofen and lithium has led to increased hyperkinetic symptoms. Therefore, caution should be exercised when baclofen is used concomitantly with lithium.

Antihypertensive agents and other drugs that lower blood pressure

Since concomitant treatment with baclofen and antihypertensive agents may potentiate blood pressure reduction, dosage adjustment of antihypertensive agents may be necessary.

Agents that impair renal function

Substances or medicinal products that significantly affect renal function may delay the elimination of baclofen, leading to toxic effects (see section "Special precautions for use").

Special precautions for use

Mental disorders and nervous system disorders

During treatment with baclofen, exacerbations of porphyria, psychiatric disorders, chronic alcoholism, hypertension, schizophrenia, depressive or manic disorders, confusion, or Parkinson's disease may occur. Therefore, baclofen should be used with caution in patients suffering from these conditions, and such patients should be closely monitored.

Cases of suicide and suicidal behavior have been reported in patients treated with baclofen. In most cases, patients had additional risk factors associated with an increased risk of suicide, including alcohol abuse disorders, depression, and/or a history of suicide attempts. Patients with additional risk factors for suicide must be under continuous medical supervision during treatment with baclofen. Patients (and caregivers) should be warned to monitor for worsening clinical condition, suicidal behavior or thoughts, unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

Cases of misuse, abuse, and dependence on baclofen have been reported. Therapy should be administered cautiously in patients with a history of substance abuse, and patients should be monitored for signs of misuse, abuse of baclofen, or dependence, such as dose escalation, drug-seeking behavior, or development of addiction.

Epilepsy

Baclofen may enhance epileptic manifestations. Therefore, careful monitoring of patients is required during baclofen administration, and appropriate anticonvulsant therapy should be applied.

Encephalopathy

Cases of encephalopathy have been reported in patients receiving baclofen at therapeutic doses, which were reversible after discontinuation of treatment. Symptoms included somnolence, depressed level of consciousness, confusion, myoclonus, and coma (see sections "Overdose" and "Adverse reactions").

If signs of encephalopathy occur, baclofen administration should be discontinued.

Other

Particular caution should be exercised when administering baclofen to patients receiving antihypertensive therapy (see section "Interaction with other medicinal products and other forms of interaction").

Baclofen should be used with caution in patients with cerebral circulation disorders, respiratory insufficiency, and impaired liver function.

Since the likelihood of adverse effects is higher in elderly patients and in patients with cerebral origin spasticity, dose titration should be performed cautiously (see section "Posology and method of administration").

Renal impairment

Signs of overdose have been observed in patients with renal impairment receiving baclofen at doses exceeding 5 mg per day. Baclofen should be used with caution in patients with renal impairment, and in patients with end-stage renal disease (ESRD – stage 5 CKD, GFR < 15 mL/min), baclofen may be used only if the potential benefit outweighs the potential risk (see section "Posology and method of administration"). Neurological symptoms of overdose, including clinical manifestations of toxic encephalopathy (e.g., confusion, disorientation, somnolence, and depressed consciousness), have been observed in patients with impaired renal function who received oral baclofen at doses exceeding 5 mg per day and at a dose of 5 mg per day in patients with end-stage renal disease undergoing maintenance hemodialysis. Patients with renal impairment should be closely monitored for early detection of signs of toxicity.

Cases of baclofen toxicity have been reported in patients with acute renal failure (see section "Overdose").

Particular caution should be exercised when using baclofen in combination with medicinal products affecting renal function. Renal function should be carefully monitored, and the daily dose of baclofen should be adjusted accordingly to prevent its toxicity.

In addition to discontinuation of treatment, unplanned hemodialysis may be considered as an alternative treatment for patients with severe baclofen toxicity. Hemodialysis effectively removes baclofen from the body, reduces clinical symptoms of overdose, and shortens recovery time.

Urinary disorders

Improvement has been observed in patients with neurogenic disorders affecting bladder emptying when treated with baclofen. Urinary retention may occur in patients with pre-existing increased bladder sphincter tone; therefore, baclofen should be used with caution in such patients.

Abrupt discontinuation

Baclofen treatment should always be discontinued gradually (except in cases of serious adverse reactions), by stepwise dose reduction over approximately 1–2 weeks.

Abrupt discontinuation of baclofen (especially after prolonged use) has been associated with anxiety, confusion, delirium, hallucinations, psychotic, manic, or paranoid disorders, seizures (epileptic status), dyskinesias, tachycardia, hyperthermia, rhabdomyolysis, and transient worsening of spasticity as withdrawal phenomena.

Neonatal seizures have been reported following in utero exposure to oral baclofen (see section "Use during pregnancy or lactation").

Therefore, treatment should be discontinued gradually by stepwise dose reduction over approximately 1–2 weeks, except in cases of serious adverse reactions.

Laboratory tests

Rarely, increased levels of aspartate aminotransferase (AST), alkaline phosphatase, and serum glucose have been observed. Appropriate laboratory tests should be performed in patients with impaired liver function or diabetes mellitus to rule out any changes in these conditions caused by baclofen.

Posture and balance

Baclofen should be used with caution in cases of spasticity necessary for maintaining upright posture and balance during ambulation (see section "Posology and method of administration").

Children

Clinical data on the use of baclofen in children under 1 year of age are very limited. The use of baclofen in children under 1 year of age is not recommended.

Excipients

The medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., practically sodium-free.

Use during pregnancy or lactation

Pregnancy

Oral administration of baclofen increased the incidence of omphalocele (umbilical cyst) in fetuses of rats receiving approximately 13 times the maximum oral dose (on a mg/kg basis) recommended for human use. This anomaly was not observed in mice or rabbits.

There are no adequate and well-controlled studies in pregnant women. Animal data show that baclofen crosses the placental barrier; therefore, it should not be used during pregnancy except when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

Adverse effects in the fetus/newborn

Withdrawal syndrome, including postnatal seizures in newborns, has been reported following in utero exposure to oral baclofen (see section "Special precautions for use").

Lactation

Baclofen passes into breast milk, but in extremely small amounts when administered at therapeutic doses; therefore, no adverse effects of baclofen on the infant are expected.

Fertility

There are no data confirming any specific recommendations for women of reproductive age.

Ability to affect reaction speed when driving or operating machinery

Baclofen may cause dizziness, sedation, somnolence, and visual disturbances (see section "Adverse reactions"), which may impair a patient's reaction ability. Patients experiencing such adverse reactions should refrain from driving vehicles or operating machinery.

Dosage and Administration

The dose should be individually determined by a physician; it is recommended to use the lowest dose that provides an optimal response.

Dosage

Dose titration should be performed carefully to meet individual patient needs while avoiding adverse reactions or interference with organ and system functions related to voluntary muscle activity (e.g., bladder control, central postural support). The lowest effective dose compatible with optimal therapeutic response should be used.

If therapeutic efficacy has not been achieved after 6–8 weeks of treatment with the maximum recommended doses, continuation of baclofen therapy should be reconsidered.

Discontinuation of treatment should always be performed gradually over 1–2 weeks, except in emergency situations related to overdose or the occurrence of serious adverse reactions (see section "Special Warnings and Precautions for Use").

Adults

Treatment should be initiated at a dose of 15 mg (1½ tablets of 10 mg) per day, divided into 2–4 doses. The dose should be cautiously increased by 15 mg (1½ tablets of 10 mg) per day every 3 days until the required daily dose is reached.

For some patients sensitive to baclofen, it may be appropriate to initiate treatment at a lower daily dose (5 mg [½ tablet of 10 mg] or 10 mg) and increase more slowly.

The optimal dose ranges from 30 to 80 mg per day. Adequate symptom control is usually achieved with doses up to 60 mg per day, but careful dose adjustment is often required to meet individual patient needs. If necessary, the dose may be cautiously increased; however, a daily dose exceeding 100 mg is not recommended, except in hospitalized patients under close medical supervision. In such cases, doses of 100–120 mg may occasionally be required.

In some cases, smaller doses administered at more frequent intervals may be more effective than larger doses given less frequently. Some patients benefit from taking baclofen only at night to prevent painful flexor spasms. Similarly, a single dose taken approximately 1 hour before performing specific activities such as washing, dressing, shaving, or physiotherapy often improves mobility.

After reaching the maximum recommended dose, if no therapeutic effect is observed within 6 weeks, a decision regarding continuation of the drug should be made.

Elderly Patients

Elderly patients may be more sensitive to adverse effects, especially at the beginning of baclofen treatment. Therefore, low initial doses should be used, with gradual dose titration based on patient response and under close monitoring.

There are no data indicating that the average maximum dose differs from that in younger patients.

Patients with Renal Impairment

For these patients, as well as for patients on dialysis, an especially low dose of baclofen should be selected—approximately 5 mg per day.

Baclofen may be used in patients with end-stage renal disease only if the expected benefit outweighs the potential risk. Such patients must be closely monitored for early signs and/or symptoms of intoxication (such as somnolence, coma) (see sections "Special Warnings and Precautions for Use" and "Overdose").

Patients with Hepatic Impairment

Studies on the use of baclofen in patients with hepatic insufficiency have not been conducted. The liver does not play a significant role in the metabolism of baclofen after oral administration (see section "Pharmacokinetics"). However, baclofen may increase liver enzyme levels. This medicinal product should be used with caution in patients with hepatic impairment.

Patients with Spastic States of Cerebral Origin

Adverse effects may occur more frequently in these patients. Therefore, dosage regimens should be carefully established, and such patients should be closely monitored.

Children

Treatment should usually begin with a very low dose (approximately 0.3 mg/kg body weight per day), divided into 2–4 doses (preferably 4 equal doses).

The dose should be cautiously increased at weekly intervals until the optimal therapeutic effect is achieved. The usual daily maintenance dose is 0.75–2 mg/kg body weight.

Baclofen tablets should not be prescribed to children with body weight below 33 kg.

Route of Administration

Baclofen should be taken during meals with a small amount of liquid.

Children

Baclofen tablets should not be prescribed to children with body weight below 33 kg.

For information on use in children, see section "Dosage and Administration".

Overdose

Symptoms. Characteristic signs of overdose include symptoms of central nervous system (CNS) depression or encephalopathy: somnolence, loss of consciousness, coma, respiratory depression. Other symptoms may include: confusion, hallucinations, agitation, EEG changes (suppression of bursts and triphasic waves, generalized slowing on EEG), accommodation disturbances, impaired pupillary reflex, generalized muscle hypotonia, myoclonus, hyporeflexia or areflexia, seizures, peripheral vasodilation, arterial hypotension or hypertension, bradycardia, tachycardia or tachyarrhythmia, hypothermia, nausea, vomiting, diarrhea, excessive salivation, elevated liver enzymes (AST and alkaline phosphatase), tinnitus.

Symptoms of overdose may occur even with lower doses of baclofen in patients with renal insufficiency (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

The clinical condition may worsen with concomitant use of other drugs or substances affecting the central nervous system (e.g., alcohol, diazepam, tricyclic antidepressants).

Treatment. There is no specific antidote.

Symptomatic treatment should be applied to manage complications such as arterial hypotension and hypertension, seizures, gastrointestinal disturbances, respiratory depression, and cardiovascular disorders.

Since baclofen is primarily eliminated by the kidneys, fluid intake should be increased, possibly combined with diuretics. Hemodialysis (sometimes unplanned) may be beneficial in patients with renal insufficiency in cases of severe intoxication (see section "Special Warnings and Precautions for Use").

Adverse Reactions

Undesirable effects mainly occur at the beginning of treatment, with too rapid dose escalation or use of high doses, as well as in elderly patients.

They are mostly transient in nature and disappear after dose reduction; they rarely require discontinuation of the drug.

If nausea persists even after dose reduction, it is recommended to take baclofen with food or with milk.

In patients with a history of psychiatric disorders or cerebrovascular disorders (e.g., stroke), as well as in elderly patients, adverse effects may have more serious consequences.

In some patients, increased spasticity has been observed as a paradoxical reaction to baclofen.

The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Organs and systems	Frequency	Adverse reaction
Immune system disorders	Unknown	hypersensitivity
Nervous system disorders	Very common	drowsiness, sedative effect
	Common	dry mouth, respiratory depression, fatigue, confusion, dizziness, headache, insomnia, depression, euphoric mood, myalgia, muscle weakness, ataxia, tremor, nystagmus, hallucinations, nightmares
	Uncommon	paraesthesia, dysarthria, dysgeusia. Decreased seizure threshold and seizures may occur, especially in patients with epilepsy
	Unknown	sleep apnoea syndrome*, encephalopathy
Eye disorders	Common	visual disturbances, accommodation disorders
Cardiovascular system disorders	Common	reduced cardiac output
	Unknown	bradycardia
Vascular disorders	Common	hypotension
Gastrointestinal disorders	Very common	nausea
	Common	gastrointestinal disturbances, urge to vomit, vomiting, constipation, diarrhea
	Uncommon	abdominal pain
Hepatobiliary disorders	Uncommon	liver function abnormalities
Skin and subcutaneous tissue disorders	Common	rash, increased sweating
	Unknown	urticaria, alopecia
Renal and urinary disorders	Common	dysuria, polyuria, enuresis
	Uncommon	urinary retention
Reproductive system and breast disorders	Uncommon	erectile dysfunction
	Unknown	sexual dysfunction
General disorders and administration site conditions	Very rare	hypothermia
	Unknown	withdrawal syndrome, facial swelling, peripheral edema
Investigations	Unknown	increased blood glucose level

*Withdrawal syndrome, including postnatal seizures in newborns, has also been observed after intrauterine exposure to oral baclofen.

* Cases of sleep apnea syndrome have been observed with high-dose baclofen (≥ 100 mg) in patients with alcohol dependence.

Reporting suspected adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life: 3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging

10 tablets per blister, 5 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Rubicon Research Pvt. Ltd.

Manufacturer's address and location of operations

Plot No. K 30/4 and 30/5, Additional M.I.D.C., Ambernath Thane 421506, Maharashtra State, India.