Liorasal® Intrathecal (Lioresal® intrathecal)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceBaclofenBaclofen
Dosage form: & nbspSolution for intrathecal administration
Composition:
1 ampoule solution for intrathecal administration contains: active
substance: baclofen 0.05 mg (in an ampoule containing 0.05 mg / ml), 0.5 mg (in an ampoule,
containing 0.5 mg / ml) or 2 mg (in an ampoule containing 2 mg / ml); auxiliary
substance: sodium chloride (9 mg), water for injection (up to 1 ml).
Description:A clear, colorless solution.
Pharmacotherapeutic group:Miorelaxant of central action
ATX: & nbsp

M.03.B.X   Other muscle relaxants of central action

Pharmacodynamics:

Baclofen is an antispastic agent that acts on the spinal cord.

Baclofen is an analogue of gamma-aminobutyric acid (GABA), the main mediator involved in central inhibition processes, stimulating presynaptic GABAβreceptors in the spinal cord baclofen suppresses mono- and polysynaptic reflexes.

In patients with chronic spasticity (eg, tetanus) associated with a lesion of the brain or spinal cord, baclofen reduces the intensity of muscle twitching, painful involuntary muscle spasms,reduces motor automatisms, hyperreflexia, trismus and clonic convulsions. As a result, the motor activity of patients increases, their ability to self-service improves, and rehabilitation therapy is facilitated. Baclofen has antinociceptive effect. The drug does not affect the transfer of impulses in neuromuscular synapses. With the weakening of painful muscle spasms, the volume of active motions increases in patients, which helps to prevent the formation and acceleration of healing of pressure sores, and also to improve the sleep of patients. Also, patients normalize the function of the bladder, which in turn facilitates its catheterization.

Baclofen stimulates gastric secretion. Having a general depressing effect on the central nervous system, baclofen can cause sedation, drowsiness and depress the functions of the respiratory and cardiovascular systems.

Intrathecal administration of baclofen is an effective method of treatment of spasticity, which makes it possible to apply Doses that are at least 100 times smaller than at ingestion Treatment with a drug can be considered as an alternative destructive neurosurgical operations.

After a single intrathecal the introduction of the drug the beginning of its action usually observed after 0.5-1 h.

Maximum antispastic effect develops in about 4 hours, and the duration of action is from 4 to 8 h.

The beginning, maximum severity and the duration of baclofen individual patients can significantly vary depending on the magnitude dose, severity of symptoms, method application and rate of administration of the drug.

With prolonged intrathecal infusion baclofen the beginning of an antispastic action is observed after 6-8 hours.

The maximum effect develops in within 24-48 hours.

Pharmacokinetics:
The following pharmacokinetic parameters of baclofen should be considered taking into account the slow circulation of cerebrospinal fluid (CSF), as well as the concentration gradient between lumbar and cisternal CSF.
Absorptionand I

Yingfusion of the drug directly into the subarachnoid space of dorsal The brain excludes the absorption process as and provides the impact baclofen directly on receptor zones of the posterior horn of the dorsal the brain.

Distribution

After a single intrathecal administration by bolus injection or short-term infusion the volume of distribution calculated for based on the determination of concentrations baclofen in the CSF at the level of the lumbar department, is from 22 to 157 ml.

If a continuous continuous intrathecal infusion of the drug in daily dose of 50 to 1200 μg equilibrium concentrations of baclofen in CSF are between 130 and 1240 ng / ml. FROM taking into account the well-known duration the half-life (T1/2) of baclofen in CSF, its equilibrium concentrations should be achieved within 1-2 days.

During an intrathecal infusion baclofen concentration in the plasma is not exceed 5 ng / ml.

Excretion

After a single intrathecal administration by bolus injection or short-term infusion in dose from 50 to 135 mcg T1/2 baclofen from CSF is from 1 hour to 5 hours. The value of T1 / 2 baclofen when it reaches its equilibrium concentrations in the CSF has not yet been established.

As after a single administration,and after prolonged subarachnoidal infusion at the level of the lumbar spinal cord (performed by means of an implant pump), the clearance of baclofen from CSF is an average of about 30 ml / h.

During the constant infusion of the drug, when the equilibrium state was reached, the ratio of baclofen concentrations in CSF obtained with lumbar puncture and extracted from subarachnoidal tanks was 1.8: 1-8.7: 1 (average 4: 1). This fact is of great clinical importance, since it confirms the possibility of effective treatment of spasticity of predominantly lower extremities with a simultaneous low impact on the muscular tone of the upper limbs and a small number of adverse reactions from the central nervous system (CNS) caused by the effect of the drug on the centers of the brain.

Special patient groups

Patients aged> 65 years. Pharmacokinetic data for the use of the preparation Liorasal® Intrathecal remote age group is not present. When single administration of oral forms Lioresal®, there was a slowdown excretion of the drug in comparison with group <65 years, systemic exposure baclofen was the same. Extrapolation of these results to repeated administration of baclofen is not allows us to assume significant differences in pharmacokinetic parameters in different age groups of patients.

Patients aged <18 years. Children have appropriate concentrations Baclofen in plasma is <10 ng / ml.

Patients with impaired hepatic function. Special studies on the use of the drug Liorasal® Intrathecal u patients with impaired liver function not carried out. Since the liver does not play essential role in metabolism baklofen with intrathecal injection, unlikely to change pharmacokinetic parameters at liver damage.

Patients with impaired renal function. Special studies on the use of the drug Liorasal® Intrathecal u patients with impaired renal function was conducted. Because the baclofen is allocated by the kidneys unchanged, it is impossible to exclude the accumulation of the unchanged drug in patients with impaired renal function.

Indications:
Severe chronic spasticity in spinal cord injury (eg, due to trauma,with multiple sclerosis) or the brain with inoperative or intolerant therapy with muscle relaxants for oral administration.
Contraindications:
- Hypersensitivity to baclofen or any other components
preparation.
- Childhood <4 years (efficacy and safety of use in children younger than 4 years are not established).

This drug should not be used intravenously, intramuscularly, subcutaneously
or epidural!
Carefully:
Children aged <18 years. To install an implantable infusion system in children, a sufficient condition is the presence of sufficient body weight (this information is indicated in the instructions for using the implantable infusion system). Clinical data on
The use of the drug in children under 6 years of age is limited.
Patients aged> 65 years. In clinical trials with the use of the preparation Lioresal® Intrathecal in patients aged> 65 years, the tolerability of the drug was similar to that of young patients. Patients aged> 65 years who received baclofen In some cases, there was an increase in the incidence of adverse events (AEs), especially during the dose selection period.When using the drug in this category of patients can not be ruled out the possibility of increasing the risk of AE. However, with individual selection of the dose of the drug, an increase in the incidence of AE in elderly patients is unlikely.
Cautions for certain special conditions of patients. In patients with impaired circulation of cerebrospinal fluid (CSF)
the antispastic activity of the drug may differ from that in patients with normal CSF circulation, due to the uneven distribution of baclofen in the subarachnoid space.
Use of the drug Lioresal® Intrathecal in patients with mental
frustration, schizophrenia, confusion and Parkinson's disease should be carried out with caution and under the condition of careful observation of patients, as there are cases of exacerbation of these diseases (conditions) when baclofen is administered orally.
Particular attention should be given to patients with epilepsy, since there are cases of development of seizures in case of drug overdose, as well as during maintenance therapy and after its termination.
The drug should be used with caution in patients with autonomic dysfunction (dysreflexia) in anamnesis.Occurrence of paroxysm of vegetative dysfunction can be provoked by pain stimulus or sudden discontinuation of the drug administration.
The drug should be used with caution in patients with cerebrovascular or respiratory failure, since baclofen may worsen the course of these conditions.
Deterioration of the course of concomitant diseases not associated with the pathology of the CNS, against the background of drug therapy, is unlikely, since with intrathecal administration the systemic effect of baclofen is much less pronounced compared with ingestion.
However, care should be taken when prescribing the drug to patients with ulcerative lesions of the gastrointestinal tract (including in the anamnesis), hypertonic sphincters, impaired renal function.
The drug should be used with caution in patients with diabetes mellitus.
Pregnancy and lactation:
Pregnancy
There are no special recommendations for women planning a pregnancy. Experience of application of the preparation Lioresal® Intrathecal in pregnant women is limited. After intrathecal administration, a small amount of baclofen is found in the maternal blood plasma.Studies in animals demonstrate the penetration of baclofen through the placental barrier. Drug Liorasal® Intrathecal should be used during pregnancy only if necessary. The drug does not have teratogenic effects in animal studies (mice, rats and rabbits).

Lactation
After oral administration of the drug Liorasal® in therapeutic doses baclofen is excreted in breast milk in quantities that do not lead to the development of undesirable phenomena. Since the drug baclofen is not excreted in breast milk when administered intrathecally, no special recommendations are needed for lactating women.

Fertility
The influence of baclofen on fertility is unlikely from experimental data.
Dosing and Administration:
The drug is intended only for intrathecal administration!

In case of spasticity caused by craniocerebral trauma, it is recommended not to resort to long-term intrathecal administration of the drug until the symptoms of spasticity stabilize (at least 1 year after the trauma).

The preparation Lioresal® Intrathecal is intended for the administration of single test doses (through a catheter located in the spinal canal,or by lumbar puncture) and for long-term use with an implantable pump providing continuous administration of this drug in the subarachnoid space.

Each ampoule of the preparation Liorasal® Intrathecal is intended for single use only. After a single use of the drug, the rest of the contents of the ampoule can not be used.

The drug can not be used when the color changes and the appearance of undissolved visible particles.

The drug can only be mixed with 0.9% sodium chloride solution for injection, provided that the patient's baclofen concentration is not 50 μg / ml, 500 μg / ml or 2000 μg / ml. The drug should not be mixed with any other solution for infusion or injection.

Each drug should be treated in several stages. In order to develop an optimal dosage regimen before switching to maintenance therapy, one-time intrathecal administration of the drug (the initial phase of treatment) is mandatory, followed by a careful dose selection. This is necessary in connection with significant individual variability of the drug effect.Intrathecal administration of the drug with the help of implantable infusion systems should be carried out only by physicians with the necessary knowledge and experience. Specific instructions for programming and / or refilling the reservoir of the implant pump (which must be strictly adhered to) are provided by the manufacturers of these systems.
The clinical efficacy of Lioresal® Intrathecal was established when the drug was administered with the aid of a programmable SynchroMed infusion system implanted under the skin.

Initial phase of treatment

Before the introduction of the drug, you should make sure that the patient does not have infectious diseases, since the presence of an infectious disease can affect the evaluation of the patient's response to a single bolus injection of the preparation Lioresal® Intrathecal.

Before you start a long intrathecal infusion of the drug, you need to make sure that the patient has a response to a single injection (initial phase of treatment). A positive result of intrathecal administration of the drug is a significant decrease in muscle tone and / or frequency or / severity of seizures.The test dose of the drug is usually administered by lumbar puncture or using a catheter placed in the spinal canal.

The initial test dose in children and adults is usually 25 or 50 μg (for children, the dose depends on body weight and age). The test dose should be administered for at least 1 minute by bubbling (mixing with cerebrospinal fluid). To test the dose, a solution with a low concentration of the drug (0.05 mg / ml) is intended. In the absence of a positive result, the test dose can be increased stepwise by 25 μg every 24 hours until an effect lasts about 4-8 hours. In those cases when a positive dose is not observed when a test dose of 100 μg is administered, no further increase in the dose, as well as a continuous intrathecal administration, should be performed.

Before the administration (especially the first) of the preparation, it is necessary to prepare the appropriate resuscitative equipment and medicines needed for relief of life threatening conditions or severe side effects.

Sensitivity to the preparation Liorasal® Intrathecal is very variable.There is one case of coma development in an adult patient after a single injection of a test dose of 25 μg.

The phase of dose selection (adult patients and children over 4 years of age)

After confirmation of the effect in response to the application of single test doses, an intrathecal administration of the drug is made using the implant system.

If the clinical effect of the test dose, established in the initial phase of treatment, lasted up to 12 hours, for administration with the help of an implantable infusion system, a doubled test dose should be applied, which caused a positive effect. It is administered for 24 hours.

If the duration of the effect of the test dose (established in the initial phase of treatment) is more than 12 hours, the daily initial dose for administration within 24 hours with the help of an implantable infusion system is equal to the value of the effective test dose.

In the first 24 hours after the onset of a prolonged intrathecal administration of a dose of baclofen can not be increased.

Spasticity due to damage to the spinal cord. In order to achieve the desired clinical effect, the first 24 hours of treatment should begin a slow daily increase in the dose of the drug.To avoid a possible overdose, do not increase the dose by more than 5-15% for children and 10-30% for adult patients.

Spasticity due to brain damage. In order to achieve the desired clinical effect, the first 24 hours of treatment should begin a slow daily increase in the dose of the drug. To avoid a possible overdose, do not increase the dose for adults and children by more than 5-15%.

When using programmable infusion pumps, the dosage of the drug should be increased only once for 24 hours. When using non-programmable infusion pumps equipped with a 76 cm catheter (through which 1 ml of the drug is delivered within a day), it is recommended that the time intervals necessary for the effect evaluation be 48 hours. In those cases when a significant increase in the daily dose of the drug clinical effect is not achieved, you should check the correct functioning of the infusion pump and the patency of the catheter. The experience of using doses of the drug exceeding 1000 mcg per day is limited. During the initial phase and the phase of drug dose selection,following immediately after the implant installation, the patients should be closely monitored in a properly equipped facility and with trained personnel. In the event of development of life-threatening or serious side effects, equipment for resuscitation should be available. In order to minimize the risk of postoperative complications, the implantation of infusion pumps should be carried out only in those centers where there is relevant experience.

Supportive therapy

The clinical goal of this drug is to maintain muscle tone at the normal level, and to minimize the severity and frequency of spastic reactions without causing serious side effects. If the drug is used in patients with spasticity in case of brain damage, in addition, it is necessary to select a dose of the drug that would provide the level of muscle tonus desired for optimal functioning of the patient. It should be used the smallest dose of the drug, which causes an adequate effect.To maintain the optimal effect during long-term treatment, the majority of patients require a gradual increase in the dose of the drug over time,
the weakening effect of the drug or the progression of the disease.
For some patients, in order to prevent the occurrence of a "paralysis", it is desirable to maintain a certain degree of spasticity.
Muscle tone and episodic spasmodic reactions are probably
a positive effect on vascular circulation and prevent the formation of deep vein thrombosis.

Adults. Patients with spasticity daily dose can be gradually increased (by 10- 30%) at the spinal cord lesion to maintain adequate effect by changing the infusion pump dosing rate and / or
concentration of the drug in the reservoir. In case of development of side effects
the daily dose can be reduced by 10-20%.

In patients with spasticity in brain damage for
maintain adequate effect daily dose can be gradually increased (5- to 20%, but not more than 20%) by changing the dosing rate
the infusion pump and / or the concentration of the drug in the reservoir. In case of side effects, the daily dose can be reduced by 10-20%.

The sudden need for a significant increase in the dose of the drug indicates problems with the catheter (for example, its torsion or displacement) or the disruption of the infusion pump.

In patients with spasticity in spinal cord injury the maintenance dose of the drug with continuous continuous administration is 12 to 2003 μg per day, in most of them an adequate effect is maintained when 300-800 μg day is used.

In patients with spasticity in brain damage the maintenance dose of the drug with continuous continuous administration is from 22 to 1400 μg per day; the average daily dose to 12 months of therapy is 276 μg, and by 24 months of therapy - 307 μg.

In long-term treatment, approximately 5% of patients develop refractory to increasing doses of the drug due to emerging tolerance or disruption of drug delivery. The resulting tolerance to the drug in this category of patients can be resolved by gradually reducing the dose for 2-4 weeks and switching to another antispastic therapy (for example, morphine sulfate).Sensitivity to the drug Liorasal® Intrathecal can recover after a few days. Treatment with the drug should be resumed using the dose that was administered at the beginning of a prolonged infusion. Care must be taken when transferring the patient from the drug Lioresal® Intrathecal to morphine and back.

The need for regular clinical monitoring of patients to assess the required dose of the drug, the functioning of the infusion system, control of possible side effects or detection of infections persists throughout the treatment period.

Children and adolescents (from 4 to 18 years). In patients with spasticity in the defeat of the brain and spinal cord, the initial maintenance dose of the drug with continuous continuous administration is from 35 to 200 μg per day (an average of 100 μg per day). The maintenance dose depends on the severity of the clinical response with a tendency to gradually increase the total daily dose. Data on the use of the drug in doses exceeding 1000 micrograms per day are limited.

Discontinuation of treatment

The cessation of treatment should always be carried out gradually, by
sequential dose reduction. The exceptions are cases
sudden overdose or serious side effects when an emergency drug withdrawal is required.
With a sharp discontinuation of the drug, regardless of the cause, spasticity increases, itching, paresthesia, lowering blood pressure; complications occur, including hyperactive states with convulsions, fever, and symptoms associated with malignant neuroleptic syndrome (mental disorder
states and muscle rigidity). In rare cases, epileptic seizures / epileptic status, rhabdomyolysis, coagulopathies, multiple organ failure and death occur. All patients receiving Lioresal® Intrathecal are at risk of a sudden discontinuation of the drug. Clinical manifestations similar to dysreflexia, sepsis, malignant hyperthermia, malignant neuroleptic syndrome or other conditions develop,
associated with a hypermetabolic condition or common
rhabdomyolysis.
Patients, as well as caregivers, should be informed of the
the importance of regular visits for the timely filling of the pump, as well as the signs and early symptoms arising from the abrupt withdrawal of the drug.
In most cases, symptoms occur within a few hours
up to several days after the sudden withdrawal of the drug Lioresal® Intrathecal. Frequent causes of sudden withdrawal of drug therapy
Liorasal® Intrathecal is a violation of the function of the catheter and a low volume of the reservoir pump.
Prevention of cases of sudden discontinuation of therapy with Lioresal® Intrathecal requires attention to compliance with the rules for programming and monitoring of the infusion system, for the timely filling of the implant system.
Instructions for implantation, programming and filling of the implant system are supplied by the pump manufacturer and must be strictly followed.
The method of treatment of symptoms caused by discontinuation of the drug,
is the resumption of the drug Lioresal® Intrathecal at the same or approximately the same dose. If the resumption of therapy by
intrathecal administration is postponed, oral or parenteral administration of GABA-receptor agonists such as the liorasal drug with intravenous administration of benzodiazepines may prevent development
fatal complications. Oral or parenteral isolated administration of the drug Liorasal does not provide a delay in the symptoms of discontinuation of baclofen.

Special patient groups

Patients with impaired renal function. Special studies on the use of the drug Lioresal® Intrathecal in patients with impaired renal function were not performed. Because the baclofen is allocated by the kidneys in an unchanged form, care must be taken when prescribing this category of patients.
Patients with impaired hepatic function. Special studies on the use of the drug Liorasal® Intrathecal in patients with impaired liver function were not performed. Since the liver does not play a significant role in the metabolism of baclofen during intrathecal administration, a dose change in liver damage is not required.
Patients aged> 65 years. In clinical trials with the use of the drug Liorasal®Intrathecal in patients aged> 65 years, the tolerance of the drug was similar to that of young patients. With individual selection of dose characteristics associated with the age of the patient is not expected.

Instructions for use of the infusion system.
Intrathecal drug Liorezal® Ampoules containing 10 mg of baclofen in 5 ml and 10 mg baclofen 20 mL, manufactured specifically for use with an infusion pump. The particular concentration of the drug to be applied via an infusion pump depends on the desired total daily dose as well as the infusion rate. For specific recommendations, please refer to the instructions of the manufacturer of the infusion system.
The mode of infusion. Immediately after the installation of the infusion system, the drug is most often used in the regime of permanent infusion. Once stabilization is achieved and the patient is picked up the daily dose can be started more complex mode of administration Intrathecal Liorezal®, allowing to provide optimal control of spasticity in individual intervals of day (if it allows
existing model of the infusion pump). For example, those patients who have
spasticity increases at night, may increase hourly
infusion rate by 20%. Changes in the rate of infusion of the drug should be
are programmed so that it occurs 2 hours before the desired clinical effect begins.
Stability of the drug. It has been established that the stability of the preparation Lioresal® Intrathecal in the implantable SynchroMed infusion system is maintained for 11 weeks.
Side effects:
Some of the undesirable phenomena listed below (AE) have been established in spasticity patients with spinal cord injury, but may also occur in spastic patients with brain damage. Below are those AEs that occurred most often regardless of the nature of the disease. Frequency of development of undesirable reactions
is estimated as follows: very often (> 1/10); often (> 1/100, <1/10);
infrequently (> 1 / 1,000, <1/100); rarely (> 1 / 10,000, <1 / 1,000); very rarely (<1 / 10,000), including individual messages.
From the nervous system: very often - drowsiness (24.8%), headache
(19.9%), seizures (10.4%); often confused, sedative, dizziness, dysarthria, lethargy, insomnia, disorientation; paresthesia,
infrequently - ataxia, memory impairment, nystagmus.
Convulsions and headache are more common in patients with spasticity of cerebral genesis than in patients with spasticity of cerebrospinal
origin.
Mental disorders: often - depression, anxiety, agitation; infrequently - suicidal thoughts and attempts, hallucinations, paranoia, euphoria.
From the side of the organ of vision: often - a violation of accommodation, blurred vision, diplopia.
From the heart: infrequently bradycardia.
From the side of the vessels: often - lowering blood pressure (37.4%); infrequently - increased blood pressure, deep vein thrombosis, redness or blanching of the skin (different localization).
From the respiratory system, chest and mediastinum: often - respiratory depression, pneumonia, dyspnea.
From the gastrointestinal tract: often - nausea / vomiting, constipation, dry mouth, diarrhea, decreased appetite, increased salivation; infrequent intestinal obstruction, dysphagia, decreased taste perception. Nausea and vomiting are more common in patients with spasticity of cerebral origin than in patients with spasticity of spinal cord origin.
From the skin and subcutaneous tissues: often, urticaria / pruritus, swelling of the face and / or
peripheral edema; infrequently - alopecia, increased sweating.
From the side of the kidneys and urinary system: very often - urinary retention
(11.4%); often - incontinence, violation of sexual function. Urinary retention is more common in patients with spasticity of cerebral
genesis than in patients with spasticity of cerebrospinal origin.
From the genitals and the breast: often - various violations
sexual function.
From the musculoskeletal system: very often - muscle hypotension; often - increased muscle tone.
From the side of metabolism and nutrition: infrequently - dehydration.
General disorders and disorders at the site of administration: often - asthenia, pyrexia,
painful sensations, chills; infrequently - hypothermia; rare - life-threatening
symptoms associated with a sudden discontinuation of the drug.
According to spontaneous reports from post-marketing research and
Literary sources revealed the following AEs (frequency unknown):
From the nervous system: dysphoria.
From the respiratory system, chest and mediastinum: bradypnoe.
There were AEs associated with the infusion system (eg, catheter granuloma, catheter bias with possible complications, infection of the site
implantation, meningitis, overdose due to improper handling of
device), in a number of cases, however, the possibility of occurrence of AE due to the use of baclofen is not ruled out.
Overdose:
Signs and symptoms of an overdose should be given special attention constantly, especially during the initial phase and the phase of drug dose selection, as well as during the resumption of the drug after a break in treatment. Manifestations of an overdose can develop suddenly or gradually.
Symptoms of overdose: excessive muscle hypotension, drowsiness, staggering, dizziness, convulsions, blurred consciousness, hypothermia, excessive salivation, nausea and vomiting.
Significant overdose leads to respiratory depression, apnea and coma. Serious overdose can occur, for example, if the contents of the catheter are accidentally released during the test of its patency or clarification of its position, other possible causes of overdose may be errors inthe programming of an infusion pump, an excessive rapid dose increase and the simultaneous use of baclofen inward. Possible violations of the function of the infusion pump should also be analyzed.
Treatment of overdose. There is no specific antidote for the treatment of an overdose of the drug that has occurred during its intrathecal administration. In general, the following measures should be taken:
1. The balance of the baclofen solution must be removed as soon as possible from the infusion pump.
2. In patients with respiratory depression, intubation should be performed if necessary (in this condition, the patient should be kept until the drug is completely removed).
Separate reports indicate that the reverse development of side effects from the central nervous system, especially drowsiness and respiratory depression, can cause physostigmine, used intravenously.
With intravenous injection of physostigmine, care should be taken, as this may be accompanied by the onset of seizures, bradycardia, and impaired intracardiac conduction.
In adults, intravenous administration of physostigmine can be undertaken in a total dose of 1-2 mg for 5-10 minutes. In this period of time, careful monitoring of patients is necessary.If a positive effect is noted, in order to maintain adequate breathing and patient consciousness, physostigmine can be used repeatedly at a dose of 1 mg at 30-60 minute intervals.
In children, an attempt of intravenous injection of physostigmine at a dose of 0.02 mg / kg at a speed of no more than 0.5 mg per minute is possible. Physostigmine in this dose can be applied repeatedly until a positive effect is achieved or until a maximum dose of 2 mg is reached.
With a significant overdose of physostigmine may be ineffective. In these cases, artificial ventilation may be required as maintenance therapy.
At an early stage of an overdose, if a lumbar puncture is not contraindicated, consider removing 30-40 ml of cerebrospinal fluid (to reduce the concentration of baclofen).
It is necessary to carry out therapy in order to maintain the functions of the cardiovascular system.
If seizures develop, caution should be administered intravenously diazepam.
Interaction:
Experience of using the drug Liorasal® Intrathecal when combined with the use of systemic drugs is limited.It can be assumed that low systemic exposure of baclofen after intrathecal administration of the preparation Lioresal® Intrathecal reduces the pharmacokinetic interaction.

Not recommended drug interactions.

Levodopa / DOPA-decarboxylase inhibitors. Joint use of the oral form of the drug Liorasal and levodopa / DOPA decarboxylase inhibitor leads to an increased risk of such undesirable phenomena as visual hallucinations, confusion, headache and nausea. It is also possible to increase the symptoms of Parkinsonism. Care should be taken when prescribing Lioresal® Intrathecal to patients receiving levodopa / DOPA-decarboxylase inhibitors.

Possible drug interactions.

Anesthetics. The combined use of intrathecal baclofen and preparations for general anesthesia (including fentanyl, propofol) can lead to an increased risk of cardiac and seizure disorders. Care should be taken when using these drugs together.
Morphine. The combined use of morphine and the drug Lioresal® Intrathecal led to a reduction in blood pressure in one patient.The possibility of dyspnea and other symptoms of CNS depression is not ruled out. Since the joint use of the drug Liorasal® Intrathecal and other drugs used intrathecally,
not investigated, the safety of the combination is also not established.
Alcohol and other substances that affect the central nervous system. The oppressive effects on the central nervous system of alcohol and other drugs (including analgesics, neuroleptics, benzodiazepines, anxiolytics) can be enhanced with Lioresal® Intrathecal.
Tricyclic antidepressants. Joint use of oral
Baclofen with tricyclic antidepressants may enhance it
the main action, which leads to pronounced muscular hypotension. When
Use of the preparation Liorasal® Intrathecal in this combination is recommended to be careful.
Hypotensive drugs. Since the use of oral baclofen, together with antihypertensive agents, may lead to a more significant decrease in blood pressure, when administering Lioresal® Intrathecal together with antihypertensive agents, the blood pressure should be regularly monitored and, if necessary, the doses of the antihypertensive drug should be adjusted.
Special instructions:Necessary medical support. Implantation of the infusion system should be carried out only after a thorough evaluation of the patient's response to a single injection of the preparation Liorasal® Intrathecal and / or the selection of a dose of the drug. Since there is a risk of complications associated with the initial administration and selection of a dose of the drug Lioresal® Intrathecal (general oppressive effects on CNS function, vascular collapse and / or respiratory depression), these stages of drug use should be performed under medical supervision, with the proper equipment and in accordance with the instructions in the section "Method of administration and dose". In the event of a marked, life-threatening drug overdose, it is necessary to prepare appropriate resuscitation equipment and medicines in advance. Appropriate training of physicians in the conduct of continuous intrathecal infusion therapy is required.

Monitoring of the patient's condition. After surgical implantation of the pump
The patient's condition should be carefully monitored until
it becomes clear that his reaction to the administration of the drug is acceptable and sufficient
is stable.This is especially necessary during the initial phase of use
the infusion system and every time the dosing rate and / or the concentration of baclofen in the pump reservoir changes. The patient and doctors, as well as all persons involved in the care of the patient, must be sure to receive full information about the possible dangers of this method of therapy. Everyone who participates in the treatment and care of the patient should be instructed about the signs and symptoms of drug overdose, the activities to be performed if it occurs, and the necessary care at home for the infusion system and the site of implantation.
Cases of granuloma on the end of an implanted catheter, leading to various serious neurological diseases, including paralysis, are described. Although the occurrence of catheter granulomas is associated with the appointment of the drug Lioresal® Intrathecal,
assisted MRI with contrasting and histopathological methods. With the appointment of baclofen as monotherapy, there were no cases of catheter-induced granulomas.The most frequent symptoms of catheter granulomas were: a decrease in therapeutic efficacy (increased spasticity, spasticity resumption with previously achieved positive result of therapy, development of withdrawal syndrome, decreased effectiveness of the drug with frequent or significant increase in dose), pain, neurological disorders / dysfunctions. Special attention should be paid to patients when any new neurological symptoms appear, as well as to detect prodromal symptoms of catheter granulomas, especially in the case of joint use of narcotic analgesics. When any new neurologic symptoms appear that resemble the symptoms and signs of a catheter granuloma, the consultation of a neurosurgeon is advised, since the symptoms of a catheter granuloma are similar to those of severe spasticity. In some cases, diagnostic imaging is required to confirm or exclude a catheter granuloma.

The phase of dose selection. During the application of the first test dose of the drug Lioresal® Intrathecal (initial phase of treatment), especially in patients with heart, lung, respiratory muscle weakness,
simultaneous use of benzodiazepine drugs or narcotic analgesics (that is, if there is an increased risk of respiratory depression), the functions of the respiratory and cardiovascular systems must be carefully monitored.

Implantation of the infusion pump. Before the implantation of the infusion pump
It should be ensured that the patient has no infectious diseases, since they can increase the risk of surgical complications. In addition, the availability of
systemic infectious process can make it difficult to select a dose of the drug.
Infection of the catheter insertion site or catheter misalignment can lead to disruption of the drug and the appearance of withdrawal symptoms.

Re-fill the infusion pump reservoir. Re-filling of the infusion pump reservoir should be performed by personnel with appropriate experience and qualifications, and in accordance with the instructions provided by the manufacturer of the pump. In order to
prevention of complete emptying of the infusion pump reservoir (which can lead to a recurrence of severe spasticity or potential
life-threatening symptoms associated with the sudden discontinuation of the preparation of Lioresal® intrathecal), care should be taken to carefully calculate the intervals between repeated filling. Filling the tank should
occur in strictly aseptic conditions in order to avoid microbial contamination and serious infectious diseases of the central nervous system. Extreme caution is required when filling an implant pump equipped with an injection port that provides direct access to the intrathecal catheter. Direct injection into the catheter through the access port can cause an overdose with life-threatening symptoms.

Additional caveats for dose selection. To avoid the development of excessive muscle weakness and the resulting falls of the patient, the drug should be used with caution in those cases where maintaining a certain degree of spasticity is necessary to maintain a vertical position and balance of balance during walking, as well as in other situations where spasticity of muscles is necessary to ensure the optimal activity of the patient and his ability to care for himself.
Preservation of muscle tone at a certain level and the assumption of periodic spasticity enhancement may be important for
maintenance of peripheral blood circulation and, possibly, help prevent deep vein thrombosis. To avoid possible overdose with Liorasal® Intra-Tracheal or the development of adverse drug interactions, it is advisable, under careful monitoring of the physician, to attempt to stop the intake of simultaneously used muscle relaxants (preferably before the intrathecal administration of the drug). In the period of continuous intrathecal infusion therapy of the preparation Liorasal® Intrathecal, rapid dose reduction or sudden withdrawal of simultaneously used muscle relaxants should be avoided.

Use in specific patient categories.
Special studies on the use of the drug Lioresal® Intrathecal in patients with impaired renal function not carried out. Because the baclofen is allocated by the kidneys in an unchanged form, care must be taken when prescribing this category of patients.
Patients with impaired circulation of cerebrospinal fluid (CSF) the antispastic activity of the drug may differ from that in patients with normal CSF circulation, due to the uneven distribution of baclofen in the subarachnoid space. Use of the drug Lioresal® Intrathecal in patients with mental disorders, schizophrenia, confusion and Parkinson's disease should be performed with caution and under the condition of careful monitoring of patients, since there are cases of exacerbation of these diseases (conditions) with the application of baclofen inward. Particular attention should be given to patients with epilepsy, because there are cases of development of seizures in case of drug overdose, as well as during maintenance therapy and after its termination.
The drug should be used with caution in patients with autonomic dysfunction (dysreflexia) in anamnesis. Occurrence of paroxysm of vegetative dysfunction can be provoked by pain stimulus or sudden discontinuation of the drug administration. The drug should be used with caution in patients with cerebrovascular or respiratory insufficiency, as baclofen may worsen the course of these conditions. Deterioration of the course of concomitant diseases not related to the pathology of the central nervous system, against the background of drug therapy, is unlikely, since with intrathecal administration the systemic effect of baclofen is much less pronounced compared with ingestion. However, care should be taken when prescribing the drug to patients with ulcerative lesions of the gastrointestinal tract (including in the anamnesis), hypertonic sphincters, impaired renal function.The drug should be used with caution in patients with diabetes mellitus.

Termination of treatment. The cessation of treatment should always be carried out gradually, by successively reducing the dose of the drug. An exception is the case of a sudden overdose or serious side effects when an emergency drug withdrawal is required.
With a sharp discontinuation of the drug, regardless of the cause, spasticity increases, itching, paresthesia, lowering blood pressure; complications occur, including hyperactive states with seizures, fever, as well as symptoms,corresponding to a malignant neuroleptic syndrome (mental disorder and muscle rigidity). In rare cases, epileptic seizures / epileptic status, rhabdomyolysis, coagulopathies, multiple organ failure and death occur. All patients receiving Lioresal® Intrathecal are at risk of a sudden discontinuation of the drug. Clinical manifestations similar to dysreflexia, sepsis, malignant hyperthermia, malignant neuroleptic syndrome, or other conditions associated with hypermetabolic state or widespread rhabdomyolysis develop.
Patients, as well as caregivers, should be informed of the importance of regular visits for the timely filling of the pump, as well as the signs and early symptoms arising from the abrupt withdrawal of the drug.

In most cases, the symptoms occur within a few hours to several days after the sudden withdrawal of the drug Lioresal® Intrathecal. Frequent causes of sudden withdrawal of Lioresal® Intrathecal therapy are violations of catheter function and a low volume of the pump reservoir.Prevention of cases of sudden discontinuation of therapy with Lioresal® Intrathecal requires attention to compliance with the rules for programming and monitoring of the infusion system, for the timely filling of the implant system.
Instructions for implantation, programming and filling of the implant system are attached by the pump manufacturer and must be strictly followed.
The treatment of symptoms caused by discontinuation of the drug is the resumption of the drug Liorasal® Intrathecal at the same or approximately the same dose. If resumption of therapy by intrathecal administration is delayed, oral or parenteral administration of GABA receptor agonists such as the liorasal drug with intravenous administration of benzodiazepines may prevent the development of fatal complications. Oral or parenteral isolated administration of the drug Liorasal does not provide a delay in the symptoms of discontinuation of baclofen.

Formation of a granuloma at the end of an intrathecal catheter. Cases of granuloma on the end of an implanted catheter, leading to various serious neurological diseases, including paralysis, are described.Although the occurrence of catheter granulomas is associated with the appointment of the drug Lioresal® Intrathecal, studies using MRI with contrasting and histopathological methods. With the appointment of baclofen as monotherapy, there were no cases of catheter-induced granulomas. The most frequent symptoms of catheter granulomas were: a decrease in therapeutic efficacy (increased spasticity, spasticity resumption with previously achieved positive result of therapy, development of withdrawal syndrome, decreased effectiveness of the drug with frequent or significant increase in dose), pain, neurological disorders / dysfunctions. Special attention should be paid to patients when any new neurological symptoms appear, as well as to detect prodromal symptoms of catheter granulomas, especially in the case of joint use of narcotic analgesics. When any new neurologic symptoms appear that resemble the symptoms and signs of a catheter granuloma, the consultation of a neurosurgeon is advised, since the symptoms of a catheter granuloma are similar to those of severe spasticity.In some cases, diagnostic imaging is required to confirm or exclude a catheter granuloma.




Effect on the ability to drive transp. cf. and fur:
It was reported that a number of patients who received drug therapy developed symptoms of CNS depression, such as drowsiness and sedation, as well as ataxia, hallucinations, diplopia and signs of discontinuation of treatment. Patients should be warned that during the treatment period,
caution at management of transport means and engaging in potentially hazardous activities requiring increased attention.
Form release / dosage:The solution for intrathecal administration is 0.05 mg / ml, 0.5 mg / ml, 2 mg / ml.
Packaging:
Solution for intrathecal administration 0.05 mg / ml: 1 ml per ampoule of glass of hydrolytic class 1. 5 ampoules together with instructions for use in a cardboard box with a cardboard holder for ampoules.
Solution for intrathecal administration of 0.5 mg / ml: 20 ml per ampoule of hydrolytic class 1 glass. 1 ampoule together with instructions for use in a cardboard box with a cardboard holder for the ampoule.
Solution for intrathecal injection of 2 mg / ml: 5 ml per ampoule of glass hydrolytic class 1. 1 ampoule together with instructions for use in a cardboard box with a cardboard holder for the ampoule.
Storage conditions:
The drug should not be frozen and sterilized with high temperatures.
At a temperature of no higher than 30 ° C.
Keep out of the reach of children.
Shelf life:
3 years
Do not use the drug after the expiration date.
Terms of leave from pharmacies:On prescription
Registration number:LSR-008524/10
Date of registration:23.08.2010
The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
Manufacturer: & nbsp
Representation: & nbspNOVARTIS CONSUMER HELS S.A. (part of Novartis groups) NOVARTIS CONSUMER HELS S.A. (part of Novartis groups) Switzerland
Information update date: & nbsp18.12.2014
Illustrated instructions
    Instructions
    Up