Baclofen 0.05 mg/1 ml solution for injection

1 ampoule with 1 ml solution for injection contains 0.05 mg baclofen.

1 ampoule with 1 ml solution for injection contains 3.5 mg sodium.

For a full list of excipients, see section 6.1.

Solution for injection

Clear, colourless solution for injection with pH 5.0-7.0 and osmolarity260- 320 mOsm/L.

For testing the response to intrathecal baclofen administration in severe chronic spasticity associated with multiple sclerosis, with injuries to the spinal cord or of cerebral origin that cannot be treated successfully with a standard treatment.

Paediatric population

Baclofen is indicated in patients aged 4 to <18 years with severe chronic spasticity of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) who are unresponsive to orally administered antispastics (including oral baclofen) and/or who experience unacceptable side effects at effective oral doses.

Baclofen is intended for administration in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable pumps suitable for continuous administration of intrathecal baclofen into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to. This procedure is necessary because of the large differences between the therapeutically effective dosages required by different patients. Long-term administration is achieved by means of an implantable pump for continuous delivery of baclofen solution to the cerebrospinal fluid using Baclofen 10 mg/20 ml or Baclofen 10 mg/5 ml.

The efficacy of Baclofen has been demonstrated in clinical studies using the SyncroMed infusion system. This system is a delivery system with a refillable reservoir that is implanted subcutaneously, usually in the abdominal wall. The instrument is connected to an intrathecal catheter that also runs subcutaneously into the subarachnoid space. There is as yet no confirmed experience with other implantable pump systems.

Before Baclofen is administered, the subarachnoid space of patients with post-traumatic spasticity should be investigated by myelography. If radiological signs of arachnoiditis are found, treatment with Baclofen should not be instituted.

Before administration of Baclofen , the solution should be checked for clarity and colourlessness. Only clear solutions practically free from particles should be used. If clouding or discoloration is evident, then the solution should not be used and should be discarded.

The solution contained in the ampoule is stable, isotonic, pyrogen-free and antioxidant-free, and has a pH of 5 to 7.

Every ampoule is intended only for single use.

Baclofen 0.05 mg/1 ml solution for injection:

Test phase (under in-patient conditions)

Before starting the phase of long-term infusion of Baclofen , the reaction of the patient to baclofen must first be investigated in a test phase. This is done using Baclofen 0.05 mg/1 ml solution for injection. The test dose is usually administered undiluted by an intrathecal catheter or lumbar puncture. The usual test dose is initially 25 microgram to 50 microgram of baclofen, corresponding to ½ to 1 ampoule of Baclofen 0.05 mg/1 ml. The dosage should be administered by mixing with the Cerebrospinal fluid (CSF) (barbotage) over 1 minute (or longer). At intervals of 24 hours, the dosage can then be increased in increments of 25 microgram to a maximum test dosage of 100 microgram as follows:

Table 1

After every bolus injection the patient must be supervised for 4 to 8 hours.

The action of a single intrathecal dose generally sets in ½ to 1 hour after administration. The maximum spasmolytic effect sets in about 4 hours after administration and lasts about 4 to 8 hours. The time to onset of action, the peak action and the duration of action vary from patient to patient and are dependent on the dosage, on the severity of symptoms, and on the mode and speed of administration. A clinically relevant reduction in the muscle tone or in the frequency or severity of spasms must be detectable in order to classify the reaction as a response to the treatment. If a test dose of 2 ampoules of Baclofen 0.05 mg/1 ml (corresponding to 100 microgram of baclofen) is not sufficient, the dosage should not be raised further, and treatment should not progress to continuous intrathecal infusion.

The tolerability of the test dosage can vary from individual to individual. As overdosing symptoms (coma) have previously occurred in one patient after a single test dose of 25 microgram of baclofen, treatment should be started only under inpatient conditions with immediate availability of intensive medical care facilities.

Special patient groups

In patients with impaired renal function, the dosage may need to be reduced to take account of the clinical condition or the level of reduced renal clearance.

Paediatric population

Screening phase

The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25-50 μg/day based upon age and size of the child. Patients who do not experience a response may receive a 25 μg/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 μg/day in paediatric patients.

Dose Titration phase

No proposed changes.

The safety and efficacy of Baclofen for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established (also see section 4.4).

Elderly patients

As part of clinical studies, some patients over 65 years of age have been treated with Baclofen without specific problems being observed. Experience with baclofen tablets shows, however, that adverse reactions can occur more frequently in this patient group. Elderly patients should therefore be monitored carefully for the development of adverse reactions.

Discontinuation of treatment

No specific limit to the duration of treatment is foreseen.

Except in emergencies due to overdosing or following development of serious adverse reactions, the treatment should always be discontinued by gradual reduction in the dosage. Baclofen must not be abruptly discontinued. In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases these may progress to seizures/status epilepticus, rhabdomyolysis, multiorgan failure and death (see section 4.4).

Abrupt discontinuation of Baclofen , especially at doses above the normal range, can lead to an intolerable increase in spasticity. Abrupt discontinuation of baclofen tablets has also been followed by confusion, sensory disturbances, disturbed mood states with hallucinations, seizures/status epilepticus, and sometimes increased spasticity, particularly after long-term therapy.

Withdrawal symptoms

In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases these may progress to seizures/status epilepticus, rhabdomyolysis, multiorgan failure and death (see section 4.4).

Discontinuation symptoms can possibly be confused with poisoning symptoms. They also require inpatient admission of the patient.

Therapy in the event of occurrence of withdrawal symptoms

A rapid correct diagnosis and treatment in an emergency medical or intensive care unit are important to prevent the possibly life-threatening central nervous and systemic effects of withdrawal of intrathecal baclofen (see section 4.4).

Baclofen must not be administered in case of:

- hypersensitivity to the active substance or to any of the excipients (see section 6.1),

- therapy-resistant epilepsy.

Baclofen should be administered only into the subarachnoid space. Baclofen must not be administered by the intravenous, intramuscular, subcutaneous or epidural routes.

Baclofen may be administered only with special caution to patients with:

- impaired CSF circulation due to passage constriction,

- epilepsy or other cerebral seizure illnesses,

- bulbar paralytic symptoms or partial paralysis of the respiratory musculature,

- acute or chronic confusional states,

- psychotic states, schizophrenia or Parkinson's disease,

- a history of dysreflexia of the autonomic nervous system,

- cerebrovascular and respiratory failure,

- pre-existing hypertension of the bladder sphincter,

- impaired renal function,

- peptic ulcers,

- severe hepatic dysfunction.

For patients with spasticity due to head injury, it is recommended not to proceed to long-term Baclofen therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of Baclofen in the paediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use of Baclofen in children under the age of four years.

Before the start of treatment with Baclofen , any unsatisfactory treatment with other antispastic medications should be tailed off.

Medical Support

The first intrathecal administration, the implantation of the infusion system, and the first infusion and dosage-titration of Baclofen are associated with risks such as CNS suppression, cardiovascular collapse and respiratory failure. These steps must therefore be performed under in-patient conditions with the availability of intensive medical care, and the instructions on dosage must be observed. The necessary facilities and support for immediate resuscitation in cases of life-threatening symptoms of severe overdosing should be available. The treating doctor must have specific experience in dealing with intrathecal administration and related infusion systems.

Monitoring the patients

The patient must be monitored closely until his condition is stable. The treating doctor, the patient and the hospital staff as well as other persons involved in the care of the patient must be adequately informed about the risks of this method of treatment. In particular, the symptoms of overdosing or sudden withdrawal, the measures to be taken in these cases, and the care of the pump and of the implantation site must be known.

Test phase

The respiratory and cardiovascular functions should be carefully monitored following administration of the initial test doses. This is especially true for patients with heart or lung diseases and with weakness of the respiratory musculature. Attention should be paid to an increased risk of respiratory depression in patients who are receiving concurrent benzodiazepines or opiates.

The patients should be free from infection prior to the test phase with Baclofen 0.05 mg/1 ml, as systemic infections can impair the assessment of the reaction by the patient to the intrathecal bolus injection.

Additional notes on dosage adjustment

Discontinuation phenomena

Abrupt discontinuation of Baclofen , regardless of cause, may manifest itself in increased spasticity as a rebound effect, pruritis, paraesthesia (tingling or burning) and hypotension. This can lead to sequelae such as a hyperactive state with rapid and uncontrolled spasms, to elevated body temperature, and to symptoms similar to those of a malignant neuroleptic syndrome such as changes in mental state and muscle rigidity. In rare cases these symptoms have developed further to seizures/ status epilepticus, muscle degradation (rhabdomyolysis), clotting disorders (coagulopathy), multiple organ failure and death.

All patients receiving intrathecal baclofen therapy are potentially at risk for abrupt withdrawal. For this reason, the patients and their caregivers must be informed about the need to observe the set appointments for re-filling the pump and be instructed about the signs and symptoms of baclofen withdrawal, especially those that occur in an early phase.

The early symptoms of baclofen withdrawal include recurrence of the spasticity originally present, itching, low blood pressure and paraesthesia. Some clinical signs of advanced withdrawal syndrome resemble those of autonomic dysreflexia, infection or sepsis, malignant hyperthermia, malignant neuroleptic syndrome or other conditions that accompany a hypermetabolic state or extensive rhabdomyolysis.

Other symptoms of abrupt discontinuation can be: hallucinations, psychotic, manic or paranoid states, severe headaches and sleeplessness. An autonomic crisis with heart failure has been observed in one case of a patient with a syndrome resembling stiff-man syndrome.

In most cases the withdrawal symptoms set in within hours or a few days after interruption of the intrathecal administration. Common reason for the abrupt interruption of intrathecal administration is malfunctions of the catheter (especially problems with the connection). In some cases, human error may also be involved.

Therapy of discontinuation/withdrawal symptoms

Rapid and correct confirmation of the diagnosis and treatment in an emergency medical or intensive care unit are important to prevent the possibly life-threatening CNS and systemic effects of withdrawal of intrathecal baclofen. The recommended treatment is resumption of the intrathecal baclofen administration at the same or approximately the same dosage as before interruption of the intrathecal baclofen delivery. However, if intrathecal baclofen administration can be resumed only after a delay, treatment with GABA-agonists such as oral or enteral baclofen or oral, enteral or intravenous benzodiazepines can prevent the potentially fatal sequelae. However, there is no guarantee that mere administration of oral or enteral baclofen is sufficient to prevent the progression of the symptoms of withdrawal of intrathecal baclofen.

Baclofen 0.05 mg/1 ml solution for injection contains less than 1 mmol sodium (23 mg) per maximum dose of 2 ml (corresponding to 100 microgram baclofen), see section 4.2.

No interactions studies with other medications have been performed.

Experience so far with the use of Baclofen in combination with other medications is not sufficient to predict interactions in individual cases.

Baclofen should not be administered concomitantly with other antispastic agents, so as to avoid possible adverse reactions.

The concomitant administration of Baclofen and other medications that have a suppressing effect on functions of the central nervous system can enhance the action of Baclofen . In particular, the concomitant intake of alcohol should be avoided as the interactions with alcohol are unpredictable.

When taken concomitantly with baclofen tablets, some specific medications for the treatment of depression (tricyclic antidepressants) can potentiate the effect, and as a result considerable muscle relaxation may occur. For this reason, such an interaction during concomitant administration of Baclofen and tricyclic antidepressants cannot be excluded.

The combination of baclofen tablets and antihypertensive medication can result in an enhanced reduction in blood pressure. For this reason, blood pressure should be checked regularly in the event of concomitant administration of Baclofen and medications for lowering blood pressure. If applicable, the dosage of the antihypertensive medication must be reduced.

When Baclofen is combined with morphine, a drop in blood pressure has occurred in one case. It cannot be excluded that in such cases respiratory disturbances or CNS disturbances may also occur. For this reason, an increased risk of these disturbances should be borne in mind during concomitant administration of opiates or benzodiazepines.

There is hitherto no information on the concomitant administration of Baclofen with other intrathecally administered medications.

Pregnancy

No experience is available relating to the use of Baclofen during pregnancy. Baclofen crosses the placenta and has shown reproductive toxicity (see section 5.3). Baclofen should not be used during pregnancy, unless the advantages of the therapy for the mother outweigh the possible risks to the child.

Lactation

Baclofen is excreted in breast milk. No statement concerning breast milk concentration can be made as there is insufficient data available. Baclofen should not be used during lactation, unless the advantages of the therapy for the mother outweigh the possible risks to the child.

The ability to drive or operate machinery may be considerably impaired during treatment with Baclofen . Alcohol consumption increases this impairment still further.

In patients treated with inthrathecal baclofen, the ability to continue driving or operating complex machinery should be routinely evaluated by the treating physician.

Adverse reactions (Table 1) are ranked under headings of frequency, the most frequent first, using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

In approximately 5 % of female patients with multiple sclerosis who have been treated with baclofen tablets for up to one year, ovarian cysts have been established by palpation. In most cases, these cysts disappeared spontaneously despite continuation of therapy. It is known that a part of the healthy female population develop ovarian cysts spontaneously.

A reliable causal connection between the observed adverse events and the administration of Baclofen is not always possible as some of the observed adverse events could also be symptoms of the underlying illness being treated. Particularly frequently occurring adverse events such as dizziness, light-headedness, somnolence, headache, nausea, drop in blood pressure, and muscle weakness are usually due to the medication.

Adverse events due to the infusion system

These can include dislocation/kinking/rupture (tearing) of the catheter, infection of the implantation site, meningitis, septicaemia, pump-pocket seroma and haematoma with a possible risk of inflammation, failure of the pump function and CSF leakage, as well as skin perforation after a long time, and overdosing or underdosing due to incorrect handling.

At the first signs of overdosing with Baclofen , the patient should be admitted to inpatient care if being treated as an outpatient.

Attention should be paid to symptoms of overdosing throughout the period of treatment, but especially during the test phase and the dosage adjustment phase and on restarting Baclofen after a pause in treatment.

Overdosing can occur, for example, as a result of accidental delivery of the contents of the catheter during checking of the patency or position of the catheter. Other possible causes are errors in the programming, extremely rapid dosage increment, concurrent oral administration of baclofen or malfunction of the pump.

In one case, an adult patient showed signs of severe overdosing (coma) after injection of a single dose of 25 microgram of baclofen (Baclofen ). Conversely, daily dosages of 4000 microgram have been required and tolerated in isolated cases (German studies). The lowest lethal dose reported in German studies is 4000 microgram, and the highest recorded dose survived without sequelae is 20000 microgram of baclofen (Baclofen ).

Symptoms of poisoning

Increasing muscle hypotension, dizziness, sedation, convulsion, loss of consciousness, salivary hypersecretion, nausea and vomiting.

Respiratory depression, apnoea and coma may occur in acute massive overdosing.

Therapy in overdosing There is no known specific antidote for the treatment of overdosing with Baclofen . In general the following measures should be performed:

• Removal as rapidly as possible of the remaining baclofen solution from the pump.

• Patients with respiratory depression should be intubated until baclofen has been eliminated.

There are observations that indicate that intravenously administered physostigmine can counteract the actions on the central nervous system, especially drowsiness and respiratory depression.

Administration of a total intravenous dose of 1 to 2 mg of physostigmine over 5 to 10 minutes may be attempted in adult patients. During this time, the patients should be monitored closely, especially for signs of induction of seizures, bradycardia and cardiac conduction disturbances. If the therapy proves effective, repeat doses of 1 mg of physostigmine at intervals of 30 to 60 minutes can be administered to maintain respiration and consciousness.

In children, a dose of 0.02 mg of physostigmine per kg bodyweight can be administered intravenously at a rate not exceeding 0.5 mg/minute. The dose can be repeated at intervals of 5 to 10 minutes until the therapeutic effect is achieved. The maximum dose should not exceed 2 mg.

Physostigmine on its own may not be sufficient to treat high overdoses, and in these cases the patient must be artificially ventilated.

If lumbar puncture is not contraindicated, 30 to 40 ml of CSF may be drawn off in the initial phase of poisoning in order to lower the concentration of baclofen in the CSF.

Support of the cardiovascular function. If spasms occur, diazepam intravenous should be administered carefully.

Pharmacotherapeutic group: muscle-relaxants, other centrally acting agents, ATC code: M03BX01

Baclofen is a p-chlorophenyl derivative of gamma-aminobutyric acid (GABA), which is ubiquitous in the central nervous system and is the most important inhibitory transmitter in the CNS. The exact mechanism of action of baclofen is not yet fully elucidated. It stimulates GABA_B-receptors that are located pre- and postsynaptically. Its action is based on boosting of the presynaptic inhibition starting mainly in the spinal marrow, which leads to damping of the stimulus transmission. This causes a reduction in the spastic muscle tone and in the pathological mass reflexes in spasticity. Being a centrally acting muscle relaxant, baclofen does not affect the neuromuscular stimulus transmission.

In humans as in animals, baclofen can cause general suppression of the central nervous system, and this can lead to sedation and somnolence as well as to respiratory and cardiovascular suppression.

The systemic availability of baclofen after intrathecal administration (Baclofen ) is considerable less than after oral administration (baclofen tablets).

When considering the pharmacokinetic data on Baclofen , the effects of the slow CSF circulation should be taken into account.

Absorption

Infusion directly into the spinal subarachnoid space circumvents absorption processes and allows access to the receptor sites in the posterior horn of the spinal cord.

The direct delivery of baclofen to the cerebrospinal space allows effective treatment of the spasticity with doses that are at least 100 times lower than those of oral therapy (baclofen tablets).

Distribution

After a single intrathecal bolus injection/rapid infusion, the distribution volume calculated from the concentration in the CSF ranges from 22 to 157 ml. The mean of about 75 ml corresponds approximately to the human CSF volume, and indicates that it is this in which the baclofen is mainly distributed. With continuous intrathecal infusion of daily doses of between 50 to 1200 microgram, steady-state concentrations of baclofen in the CSF of the lumbar region of 130 to 1240 nanogram/ml are reached within 1 to 2 days. In the steady state with continuous intrathecal infusion of daily doses between 95 to 190 microgram, a mean baclofen concentration gradient from lumbar to cisternal of 4:1 (range 8.7:1-1.8:1) is found. This is independent of the body position of the patient. All three strengths of baclofen solution (density: 1.003 ± 0.001 g/cm³ at 23°C) are practically isobaric to human CSF (density: 1.006-1.008 g/cm³). The baclofen plasma concentrations under intrathecal infusion of clinically used doses of baclofen are below 5 nanogram/ml ( 10 nanogram/ml in children) and are thus below the analytical quantitation limits. From this it can be concluded that baclofen crosses the blood-brain barrier only slowly and becomes systemically available only in very small quantities.

Elimination

The elimination half-life from the CSF after administration of a single intrathecal bolus injection/ rapid infusion of 50 to 135 microgram of baclofen is 1 to 5 hours. Both after a single bolus injection and after continuous infusion into the spinal subarachnoid space using an implanted pump, the mean clearance from the CSF is about 30 ml/hour (corresponding to the physiological turnover rate of the CSF). Thus the amount of baclofen infused over 24 hours is eliminated almost completely with the CSF over the same period of time. Systemic baclofen is eliminated almost completely renally in the unaltered form. A metabolite (beta-(p-chlorophenyl)-gamma-hydroxybutyric acid) formed in small amounts in the liver by oxidative desamination is inactive. Investigations suggest baclofen is not metabolised in the CSF. Other routes of elimination are not considered significant according to the information currently available.

From animal experiments it is evident that the active substance cumulates in the CSF after administration of high doses. It has not been investigated to what extent this finding is relevant for humans and what consequences should be expected.

Histological investigations in studies with continuous intrathecal infusion of baclofen to rats (2-4 weeks) and dogs (2-4 months) have revealed no signs of a local reaction or inflammation due to baclofen. Reactions are ascribed to the irritation due to the infusion catheter.

Baclofen was not mutagenic in in-vivo and in-vitro studies.

A 2-year study on rats with oral administration showed that baclofen is not carcinogenic. A dose-dependent rise in the incidence of ovarian cysts and a less pronounced rise in the incidence of enlarged and/or haemorrhagic adrenal glands was observed in female rats treated for two years with baclofen. The findings suggest endocrine effects of baclofen, and the basis for this could be an action on hypothalamic hormones. These effects occur in test animals (and presumably also in humans) possibly only in conjunction with age-related hormonal changes.

After a dose equivalent to about 13 times the maximum oral dose recommended for humans, rat foetuses showed a raised incidence of omphaloceles. This malformation was not observed in mice or rabbits.

Baclofen had no effect on the fertility of female rats. Possible effects on male fertility have not been investigated.

Sodium chloride

Water for injections

Baclofen solution for injection must not be mixed with other infusion or injection solutions.

Shelf-life in unopened containers:

2 years

The product should be used immediately after opening.

This medicinal product does not require any special storage conditions.

Clear, colourless ampoules of glass type I (Ph.Eur.) containing 1 ml of solution for injection.

Packs of 1 and 5 ampoules.

Not all pack sizes may be marketed.

Any unrequired fraction must be destroyed.

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

PL 31750/0003

15 /02/2010

June 2011