Baclofen-kv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BACLOFEN-KV (BACLOFEN-KV)

Composition:

Active substance: baclofen;

1 tablet contains 10 mg or 25 mg of baclofen;

Excipients: microcrystalline cellulose, povidone, wheat starch, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: elongated shape, flat surface, bevelled edges and a score line on one side, white or almost white;

25 mg tablets: flat cylindrical shape with bevelled edges, white or almost white.

Pharmacotherapeutic group. Centrally acting muscle relaxants. ATC code M03BX01.

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 does not belong to other muscle relaxants.

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

The mechanism of this action most likely involves hyperpolarization of ascending neurons and inhibition of both mono- and polysynaptic reflexes at the spinal cord level due to 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 suppress central nervous system (CNS) functions at high doses, there is a possibility of its action on centers located above the spinal cord.

Advantages of baclofen use are related to its ability to reduce painful flexor spasms and spontaneous muscle contractions, thereby improving patient mobility, reducing dependence on assistance from others, and enhancing rehabilitation. Baclofen also reduces pain sensitivity. Thus, improvement in the patient's general well-being and sedation is achieved more easily 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 parameters after administration of baclofen as a solution versus solid dosage forms are not observed. After single oral doses (10–30 mg), peak plasma concentration is reached within 0.5–1.5 hours, with the area under the concentration-time curve being dose-proportional.

The extent of absorption decreases when higher doses are administered.

Therapeutic concentration ranges from 80–395 ng/mL.

It is known 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 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 at baclofen concentrations ranging from 10 ng/mL to 300 µg/mL. The concentration of the active substance in cerebrospinal fluid is 8.5 times lower than in plasma.

Biotransformation

Approximately 15% of the administered dose undergoes biotransformation in the liver via deamination. As a result of deamination, the main metabolite, β-(p-chlorophenyl)-4-hydroxybutyric acid, is formed, which does not exhibit pharmacological activity.

Elimination

The elimination half-life is 3–4 hours.

Baclofen is excreted in urine, with 70–80% eliminated unchanged or as metabolites. The remainder is excreted in feces.

After oral administration, baclofen is almost completely eliminated within 72 hours.

Elderly patients

Pharmacokinetics in elderly patients is practically the same as in adults. Maximum plasma concentration of baclofen is slightly lower than in healthy young volunteers, but the AUC value is similar in both patient groups.

Children

In children (aged 2–12 years), after administration of 2.5 mg baclofen tablets, Cmax levels are 62.8±28.7 ng/mL, and Tmax ranges from 0.95 to 2 hours. The average plasma clearance (Cl) has been reported as 315.9 mL/h/kg, volume of distribution (Vd) as 2.58 L/kg, and elimination half-life (T1⁄2) as 5.1 hours.

Hepatic impairment

There are no pharmacokinetic data on the use of baclofen in patients with hepatic impairment. However, since the liver does not play a significant role in the transformation and elimination of baclofen, clinically significant changes in baclofen pharmacokinetics in patients with hepatic impairment are not expected.

Renal impairment

Controlled clinical studies on the pharmacokinetics of baclofen in patients with renal impairment have not been conducted. The majority of baclofen is excreted unchanged in urine. According to available data, plasma concentrations of the drug in patients undergoing chronic hemodialysis and in patients with compensated renal insufficiency indicate significantly reduced clearance and prolonged elimination half-life in these groups. Dose adjustment in patients with impaired renal function should be based on systemic blood levels of baclofen. Immediate hemodialysis is an effective method for removing excess baclofen from systemic circulation.

Clinical characteristics.

Indications.

Adults

Spastic hypertonia of striated muscles in multiple sclerosis.

Spastic muscle hypertonia due to spinal cord disorders of infectious, degenerative, traumatic, neoplastic or unknown etiology: for example, spastic spinal paralysis, amyotrophic lateral sclerosis, syringomyelia, transverse myelitis, traumatic paraplegia or paraparesis, spinal cord compression. Spastic muscle hypertonia of cerebral origin, particularly in cases of cerebral palsy in children, as well as after cerebrovascular disease or due to neoplastic or degenerative brain disorders.

Children (0–18 years)

Baclofen-KV is indicated in children for symptomatic treatment of spastic conditions of cerebral origin arising from cerebral palsy, as well as due to stroke or neoplastic or degenerative brain disorders.

Baclofen-KV is also indicated in children for symptomatic treatment of muscle spasticity resulting from infection and spinal cord disorders of infectious, degenerative, traumatic, neoplastic or 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. Acute phase of peptic ulcer disease of the stomach and duodenum. Porphyria.

Interaction with other medicinal products and other forms of interaction.

For proper medical monitoring, the following interactions should be taken into account:

Medicinal products that depress the central nervous system (CNS)

Concomitant use of baclofen with other agents that depress CNS activity, such as other muscle relaxants (e.g., tizanidine), synthetic opioids, or alcohol, enhances their sedative effects (see section "Special warnings and precautions for use").

In patients receiving baclofen, the risk of respiratory depression is increased. Additionally, 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 concomitant cardiovascular or respiratory disorders and with respiratory muscle weakness.

Lithium

Baclofen may enhance hyperkinesia in patients concurrently receiving lithium salts.

Antidepressants

Tricyclic antidepressants may potentiate the effect of baclofen and significantly reduce muscle tone.

Antihypertensive agents

Baclofen potentiates the effect of antihypertensive agents (dose adjustment may be required).

Drugs impairing renal function

Medicinal products affecting renal function (e.g., ibuprofen) may slow the elimination of baclofen, leading to symptoms of intoxication (see section "Special warnings and precautions for use").

Levodopa/dopa-decarboxylase inhibitor (carbidopa)

In patients with Parkinson's disease receiving levodopa and carbidopa, concomitant administration of baclofen may lead to confusion, hallucinations, headache, nausea, and psychic excitation. Exacerbation of Parkinsonian symptoms has been reported. Therefore, concomitant use of baclofen with levodopa or carbidopa should be undertaken with caution.

Baclofen enhances the analgesia induced by fentanyl.

Special precautions for use.

Psychiatric and nervous system disorders

Treatment with baclofen may exacerbate psychotic syndromes, schizophrenia, depressive or manic disorders, convulsive conditions, dizziness, and symptoms of parkinsonism; therefore, the drug should be used with caution, and patients must remain under continuous medical supervision.

Cases of suicide and suicidal behavior have been reported in patients treated with baclofen. Most patients had additional risk factors associated with increased suicide risk, including alcohol abuse, depression, and/or history of suicide attempts. Patients with such risk factors should be under continuous medical monitoring during baclofen treatment. Patients (and caregivers) should be informed about the need to monitor for clinical worsening, suicidal thoughts or behaviors, or unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.

Misuse, abuse, and dependence have occurred during baclofen treatment. The drug should be prescribed cautiously to patients with a history of substance abuse, and signs of misuse, abuse, or dependence—such as dose escalation, manipulative behavior to obtain the drug, or development of addiction—should be monitored during treatment.

Epilepsy

Patients with epilepsy requiring concomitant therapy with baclofen require continuous clinical monitoring and EEG evaluation, as reduced efficacy of concurrently administered anticonvulsant medications and changes in EEG patterns have been observed.

Other

Caution should be exercised when administering baclofen to patients whose ability to maintain upright posture, balance, or increased range of motion depends on pronounced muscle tone.

The drug should be used cautiously in patients who have had a stroke, respiratory impairment, or hepatic dysfunction.

Renal impairment

Baclofen is primarily excreted unchanged in urine; therefore, the drug should be administered with caution in patients with impaired renal function. The dose should be reduced in these patients. Baclofen may be used in patients with end-stage renal disease (stage 5 chronic kidney disease, GFR [glomerular filtration rate] < 15 mL/min) only if the potential benefit outweighs the risk (see section "Dosage and 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 renal impairment receiving oral baclofen at doses exceeding 5 mg daily, and in patients with end-stage renal disease on hemodialysis receiving 5 mg daily. Patients with renal insufficiency should be closely monitored for early signs of toxicity (see section "Overdose").

Particular caution is required when baclofen is used in combination with other drugs affecting renal function. Renal function should be carefully monitored, and the daily dose of baclofen should be adjusted to avoid toxicity.

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

Furthermore, after discontinuation of treatment, hemodialysis may serve as an alternative treatment for patients poisoned with baclofen. Hemodialysis effectively removes baclofen from the body, reduces clinical symptoms of overdose, and accelerates patient recovery.

Urinary tract disorders

Caution is advised in patients with increased tone of the urinary sphincter (risk of urinary retention).

Improvement has been observed in patients with neurogenic bladder dysfunction after baclofen administration.

Laboratory tests

Elevated levels of aspartate aminotransferase, alkaline phosphatase, and serum glucose have been observed in some patients receiving baclofen therapy. Laboratory monitoring is recommended, especially in patients with hepatic impairment or diabetes mellitus, to ensure the drug does not induce changes in underlying conditions.

Abrupt discontinuation of treatment

Abrupt discontinuation of the drug (especially after prolonged treatment) may lead to anxiety, confusion, hallucinations, psychotic reactions, manic or paranoid states, convulsions, dyskinesias, tachycardia, hyperthermia, rhabdomyolysis, and worsening of spasticity. Therefore, the dose should be tapered gradually over 1–2 weeks.

Patients aged 65 years and older

Extreme caution is required when treating elderly patients (increased risk of adverse effects).

Withdrawal syndrome has been reported in newborns following in utero exposure to oral baclofen, including postnatal seizures (see section "Use during pregnancy or breastfeeding").

Clinical features of withdrawal syndrome associated with intrathecal baclofen administration may resemble those seen in autonomic dysreflexia, malignant hyperthermia, neuroleptic malignant syndrome, or other conditions associated with hypermetabolic states or diffuse rhabdomyolysis.

Precautions regarding excipients

The drug can be used in patients with celiac disease. Patients with wheat allergy (distinct from celiac disease) should not take this medication.

Use during pregnancy or breastfeeding

Controlled studies on the use of the drug in pregnant women have not been conducted.

Baclofen crosses the placental barrier.

Oral administration of high doses of baclofen increased the incidence of omphalocele (umbilical hernia) in rat fetuses. No teratogenic effects were observed in mice or rabbits.

The drug should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus.

There has been one reported case of withdrawal syndrome (seizures) in a 7-day-old newborn whose mother had taken baclofen at a dose of 80 mg daily during pregnancy. Seizures, which were resistant to standard anticonvulsant therapy, resolved within 30 minutes after administration of baclofen.

Baclofen passes into breast milk, but in extremely small amounts. When administered at therapeutic doses, adverse reactions in the newborn are not expected.

There are no data on the effect of baclofen on human fertility.

In rats receiving non-toxic doses, baclofen did not affect fertility in either males or females.

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 concentration and attention. Patients experiencing these adverse reactions should not drive or operate machinery.

Method of Administration and Dosage

The dose is determined individually, establishing the lowest effective dose that does not cause adverse effects.

Before initiating treatment, the maximum expected efficacy of baclofen therapy should be assessed. The dose should be increased cautiously (particularly in patients aged 65 years and older) until the patient's general condition normalizes. If a sufficiently high initial dose is used or the dose is increased too rapidly, adverse effects may occur.

To prevent excessive weakness and loss of consciousness, Baclofen-KV should be used cautiously if spasticity is necessary to maintain motor function and balance during walking, or if spasticity is required to support daily activities. Maintaining an appropriate level of muscle tone may be essential, and occasional spasms, which may be beneficial for maintaining circulatory function, may be tolerated.

The total daily dose should be divided, preferably into 3 doses for adults and 4 doses for children.

If therapeutic effect is not achieved after 6–8 weeks of treatment with the maximum recommended doses, the necessity of continuing or discontinuing treatment should be evaluated.

Treatment should always be discontinued gradually by reducing the dose over a period of 1–2 weeks, except in emergency situations related to overdose or the occurrence of serious adverse reactions (see section "Special Instructions").

The following dosage regimen is recommended.

Adults

Treatment should be initiated at a daily dose of 15 mg, divided into several equal doses. The following stepwise dose escalation schedule is proposed, although individual patient characteristics should always be considered:

Days 1–3: 5 mg (½ of a 10 mg tablet) three times daily,

Days 4–6: 10 mg (1 tablet) three times daily,

Days 7–9: 1½ tablets of 10 mg three times daily,

Days 10–12: 2 tablets of 10 mg three times daily.

Some patients, particularly those sensitive to medications, may require initiation at a lower daily dose (5 or 10 mg) and a more gradual dose escalation (see section "Special Instructions").

Therapeutic effect is achieved in most patients at doses ranging from 30 mg to 80 mg per day.

This dosing regimen ensures good tolerability of the drug.

If necessary, the dose may be cautiously increased.

Patients requiring higher doses of the drug (75–100 mg per day) may be administered baclofen in 25 mg tablets.

The daily dose should not exceed 100 mg.

Duration of treatment depends on the patient's clinical condition.

Baclofen treatment should not be discontinued abruptly due to the risk of hallucinations and exacerbation of spastic states.

Elderly Patients

The drug dose should be increased with particular caution in elderly patients due to an increased risk of adverse effects.

Children

Treatment should be initiated at a very low dose (approximately equivalent to 0.3 mg/kg body weight per day), administered in 2–4 divided doses (preferably 4 equal doses).

The dose should be cautiously increased in children at weekly intervals until the optimal therapeutic effect is achieved.

The usual daily maintenance dose is generally 0.75–2 mg/kg body weight.

The maximum daily dose should not exceed 40 mg for children under 8 years of age. For children aged 8 years and older, the maximum daily dose is 60 mg.

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

Patients with Renal Impairment

For such patients, as well as for patients on dialysis, recommended doses should be reduced to 5 mg per day.

Baclofen may be used in patients with end-stage renal disease when potential benefit outweighs the risk. In these patients, symptoms of early toxicity (such as somnolence, lethargy) should be monitored (see sections "Special Instructions" and "Overdose").

Hepatic Impairment

Studies have not been conducted in patients with hepatic impairment receiving Baclofen-KV. The liver does not play a significant role in the metabolism of baclofen following oral administration (see section "Pharmacokinetics"). However, Baclofen-KV may cause elevated liver enzyme levels. Baclofen-KV should be administered with caution to patients with hepatic impairment (see section "Special Instructions").

Patients with Spastic States of Cerebral Origin

Adverse effects are most frequently observed in this patient group; therefore, an appropriate dosing regimen should be established, and these patients should remain under close medical supervision.

Method of Administration

Baclofen-KV 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 recommendations on pediatric use, see section "Method of Administration and Dosage".

Overdose.

Symptoms. In case of overdose, the following central nervous system (CNS)-related adverse effects may develop: somnolence, loss of consciousness, coma, respiratory depression.

Other symptoms may include: confusion, hallucinations, mental agitation, accommodation disturbances, absence of pupillary reflexes, tinnitus, muscle hypotonia, myoclonus, clonic seizures, depressed or absent reflexes, seizures, EEG changes (burst-suppression pattern and triphasic waves), peripheral vasodilation, arterial hypotension or hypertension, bradycardia, tachycardia or tachyarrhythmia, hypothermia, nausea, vomiting, diarrhea, excessive salivation, elevated liver enzymes, rhabdomyolysis.

Symptoms of overdose may occur at lower baclofen doses in patients with renal insufficiency (see sections "Method of Administration and Dosage" and "Special Instructions").

The patient's condition may worsen when other drugs or substances affecting the central nervous system (e.g., alcohol, diazepam, tricyclic antidepressants) are used concomitantly.

Treatment. There is no specific antidote.

Symptomatic treatment should be applied to manage complications associated with arterial hypotension, arterial hypertension, seizures, gastrointestinal disturbances, respiratory depression, nervous system depression, or circulatory system depression.

Induce vomiting or perform gastric lavage as soon as possible, and administer activated charcoal.

Patients in a comatose state should be intubated prior to gastric lavage.

If necessary, administer saline laxatives.

For patients with respiratory arrest, perform artificial ventilation and ensure cardiovascular support.

According to some data, physostigmine administered intravenously (1–2 mg over 5–10 minutes) may reverse CNS-related adverse effects, particularly somnolence and respiratory depression, in mild poisoning cases. If no improvement occurs after the first dose of physostigmine, a subsequent dose may be administered after 30–60 minutes.

Administration of the drug together with diuretics may be indicated to enhance urinary excretion of baclofen.

In cases of severe poisoning, hemodialysis may be considered for patients with renal insufficiency (see section "Special Instructions").

If seizures occur, diazepam should be administered intravenously with extreme caution.

Adverse reactions

Undesirable effects most commonly occur at the beginning of treatment (e.g., drowsiness and lethargy), during rapid dose escalation or administration of high doses of baclofen, as well as in elderly patients.

They are mainly transient in nature and resolve after dose reduction. In the case of severe adverse reactions, the drug should be discontinued.

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 diseases (e.g., stroke), as well as in elderly patients, adverse effects may have more serious consequences.

A lowered seizure threshold and seizures are possible, particularly in patients with epilepsy.

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

Unfavorable muscle hypotonia may occur, impairing the patient's ability to walk or perform self-care activities; this can usually be alleviated by reassessing the dosing regimen (i.e., reducing daytime doses and increasing the evening dose).

Many of the reported adverse reactions may be related to the underlying disease being treated.

Adverse reactions (Table 1) are listed according to MedDRA frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 1

From the nervous system
Very common	Lethargy, somnolence
Common	Dizziness, ataxia, tremor, headache, nystagmus
Rare	Paresthesia, dysarthria, dysgeusia
Frequency unknown	Sleep apnea syndrome*
From the eye organs
Common	Blurred vision, accommodation disturbances
From the cardiovascular system
Common	Reduced cardiac output
Frequency unknown	Bradycardia
From the vascular system
Common	Hypotension
Gastrointestinal disorders
Very common	Nausea
Common	Gastrointestinal discomfort, constipation, diarrhea, vomiting, dry mouth
Rare	Abdominal pain
From the liver and biliary system
Rare	Liver function abnormalities
From the skin and subcutaneous tissue
Common	Skin rash, hyperhidrosis
Frequency unknown	Urticaria
From the kidneys and urinary system
Common	Polyuria, enuresis, dysuria
Rare	Urinary retention
From the reproductive system and breast
Rare	Erectile dysfunction
From the respiratory system, thoracic organs and mediastinum
Common	Respiratory depression
From the psyche
Common	Confusion, hallucinations, depression, insomnia, euphoria, nightmares
From the musculoskeletal system and connective tissue
Common	Muscle weakness, myalgia
General disorders
Very rare	Hypothermia
Frequency unknown	Withdrawal syndrome** (see section 4.4)
Diagnostic investigations
Frequency unknown	Increased blood glucose level

* Cases of sleep apnea syndrome have been observed in patients with alcohol dependence when baclofen was used at high doses (≥ 100 mg).

** Withdrawal reactions, including postnatal seizures, have also been reported after intrauterine exposure to oral baclofen.

Increased spasticity (paradoxical reaction to the drug) has been observed in some patients.

Unwanted muscle stiffness may occur, causing difficulties for patients in walking or performing self-care activities. This stiffness usually resolves after dose adjustment (e.g., reducing the total daily dose while increasing the evening dose).

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister; 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's address. 38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua