Summary of medicine characteristics - BACLOFEN 0.05 MG / 1 ML SOLUTION FOR INJECTION
Baclofen 0.05 mg/1 ml solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
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 the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection
Clear, colourless solution for injection with pH 5.0–7.0 and osmolarity260– 320 mOsm/L.
4.1 Therapeutic indications
Adults
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 (4 to <18 years)
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.
4.2 Posology and method of administration
Method of administration
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.
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.
Dosage
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.
The testing, implantation and dosage-titration phases of the intrathecal administration must be performed under in-patient conditions in centres with specific experience with close medical supervision by suitably qualified doctors. Intensive medical care should be immediately available owing to possible life-threatening events or serious adverse reactions.
In order to establish the optimal dosage regimen for Baclofen, every patient receives an intrathecal bolus injection of Baclofen 0.05 mg/1 ml during an initial test phase before starting the long-term treatment, either via an intrathecal catheter or by lumbar puncture. This is followed by very careful patient-tailored dosage titration.
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.
Before Baclofen is administered, the subarachnoid space of patients with posttraumatic 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 ^ to 1 ampoule of Baclofen 0.05 mg/1 ml. A test dose of 25 microgram is recommended in children. 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
| Baclofen 0.05 mg/1 ml solution for injection | |
| Test dose [gg baclofen] | ml of solution corresponding to number of ampoules |
| 25 gg | 0.5 ml = ^ ampoule |
| 50 gg | 1.0 ml = 1 ampoule |
| 75 gg | 1.5 ml = m ampoules |
| 100 gg | 2.0 ml = 2 ampoules |
After every bolus injection the patient must be supervised for 4 to 8 hours.
The action of a single intrathecal dose generally sets in ^ 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 slowed CSF circulation due, for example, to blockage caused by inflammation or trauma, the delayed migration of Baclofen can reduce the antispastic efficacy and boost the adverse reactions (see section 4.3).
Renal impairment
No studies have been performed in patients with renal impairment with baclofen therapy. 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.
Hepatic impairment
No studies have been performed in patients with hepatic impairment receiving baclofen therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of baclofen. Therefore, hepatic impairment is not expected to impact the drug systemic exposure (see section 5.2).
Paediatric population
The experience in children under 6 years of age is limited.
Baclofen is not recommended for use in children below 4 years of age due to a lack of data on safety.
The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25–50 pg/day based upon age and size of the child. Patients who do not experience a response may receive a 25 pg/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 pg/day in paediatric patients.
Elderly
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).
4.3 Contraindications
Baclofen must not be administered in case of:
– hypersensitivity to the active substance or to any of the excipients listed in 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.
4.4 Special warnings and precautions for use
Intrathecal baclofen therapy is valuable but hazardous. Careful pre-operative assessment is mandatory.
The patient must be given adequate information regarding the risks of this mode of treatment, and be physically and psychologically able to cope with the pump. It is essential that the responsible physicians and all those involved in the care of the patient receive adequate instruction on the signs and symptoms of overdose, procedures to be followed in the event of an overdose and the proper home care of the pump and insertion site.
The testing, implantation and dosage-titration phases of the intrathecal treatment must be performed in hospital under close medical supervision by suitably qualified doctors in centres with specific experience in order to ensure the continuous monitoring of the patients.
Owing to possible life-threatening events or severe adverse reactions, suitable intensive medical care facilities should be immediately available. Suitable precautionary measures must be taken before the start of treatment.
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 may progress to seizures / status epilepticus, rhabdomyolysis, multiple organ failure and death.
Before the start of treatment with Baclofen, any unsatisfactory treatment with other antispastic medications should be tailed off.
Inflammatory mass at the tip of the implanted catheter
Cases of inflammatory mass at the tip of the implanted catheter that can result in serious neurological impairment, including paralysis, have been reported. Although they have been reported with baclofen, they have not been confirmed by contrast MRI or histopathology. The most frequent symptoms associated with inflammatory mass are:
1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases),
2) pain,
3) neurological deficit/dysfunction.
Clinicians should monitor patients on intraspinal therapy carefully for any new neurological signs or symptoms. Clinicians should use their medical judgement regarding the most appropriate monitoring specific to their patients' medical needs to identify prodromal signs and symptoms for inflammatory mass especially if using pharmacy compounded drugs or admixtures that include opioids. In patients with new neurological signs or symptoms suggestive of an inflammatory mass, consider a neurosurgical consultation since many of the symptoms of inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an inflammatory mass.
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.
Pump implantation
The patients should be free from infection prior to the test phase with Baclofen 0.05 mg/1 ml, as systemic infections may increase the risk of surgical complications. Moreover, a systemic infection may complicate attempts to adjust the dose. A local infection or catheter malplacement can also lead to drug delivery failure, which may result in sudden Baclofen withdrawal and its related symptoms (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).
Reservoir refilling
Reservoir refilling must be performed by trained and qualified personnel in accordance with the instructions provided by the pump manufacturer. Refills should be timed to avoid excessive depletion of the reservoir, as this would result in the return of spasticity or potentially life-threatening symptoms of Baclofen withdrawal (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).
When refilling the pump care should be taken to avoid discharging the contents of the catheter into the intrathecal space.
Strict asepsis is required to avoid microbial contamination and infection.
Extreme caution must be taken when filling a pump equipped with an injection port that allows direct access to the intrathecal catheter as a direct injection into the catheter through the access port could cause a life-threatening overdose.
Additional notes on dosage adjustment
Occasionally a certain level of spasticity is necessary to maintain body posture and balance or other functions. In order to avoid excessive weakness and thus to prevent the patient from falling over, Baclofen should be administered with care in these cases. A certain level of muscle tone and occasional spasms may also be necessary to support circulatory function and prevent deep-vein thrombosis.
Discontinuation phenomena
Abrupt discontinuation of Baclofen, regardless of cause, manifested by increased spasticity as a rebound effect, pruritis, paraesthesia (tingling or burning) and hypotension has resulted in sequelae including a hyperactive state with rapid and uncontrolled spasms, hyperthermia and symptoms consistent with malignant neuroleptic syndrome, e.g. 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.
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.
Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the signs and symptoms of baclofen withdrawal particularly those seen early in the withdrawal syndrome (e.g. priaprism).
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, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reason for the abrupt interruption of intrathecal administration is malfunctions of the catheter (especially problems with the connection), low volume in the pump reservoir and end of pump battery life.
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), that is to say essentially ‘sodium-free’.
Precautions in special patient populations
In patients with abnormal CSF flow the circulation of drug and hence antispastic activity may be inadequate.
Psychotic disorders, schizophrenia, confusional states or Parkinson's disease may be exacerbated by treatment with oral baclofen. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance. Special attention should be given to patients known to suffer from epilepsy as seizures have occasionally been reported during overdose with, and withdrawal from, Baclofen as well as in patients maintained on therapeutic doses.
Intrathecal baclofen should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of Baclofen may precipitate an autonomic dysreflexic episode.
Baclofen should be used with caution in patients with cerebrovascular or respiratory insufficiency.
An effect of Baclofen on underlying, non-CNS related diseases is unlikely because its systemic availability is substantially lower than after oral administration.
Observations after oral baclofen therapy suggest that caution should be exercised in patients with a history of peptic ulcers and pre-existing sphincter hypertonia.
Precautions in paediatric patients
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.
Renal impairment
After oral baclofen dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering baclofen in patients with renal impairment.
In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral baclofen.
Elderly patients >65 years
Elderly patients may be more susceptible to the side effects of oral baclofen in the titration stage and this may also apply to baclofen.
Scoliosis
The onset of scoliosis or worsening of a pre-existing scoliosis has been reported in patients treated with Baclofen. Signs of scoliosis should be monitored during treatment with Baclofen.
4.5 Interaction with other medicinal products and other forms of interaction
No interactions studies with other medications have been performed.
The co-administration of other intrathecal agents with Baclofen SUN is not recommended.
An attempt should be made to reduce or discontinue concomitant oral antispastic medications, preferably before initiating baclofen infusion. However, abrupt reduction or discontinuation during chronic intrathecal baclofen therapy should be avoided.
There is little experience with the use of baclofen in combination with systemic medications to predict specific drug-drug interactions, although it is suggested that the low baclofen systemic exposure observed after intrathecal administration could reduce the potential for pharmacokinetic interactions (see section 5.2).
Experience with oral baclofen would suggest that:
Alcohol and other compounds affecting the CNS
There may be increased sedation where Baclofen SUN is taken concomitantly with other drugs acting on the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) or with alcohol.
In particular, the concomitant intake of alcohol should be avoided as the interactions with alcohol are unpredictable.
Tricyclic Antidepressants
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.
Antihypertensives
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.
Morphine
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.
Anesthetics
Concomitant use of intrathecal baclofen and general anesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anesthetics are administered to patients receiving intrathecal baclofen.
Levodopa/DDC inhibitor
Concomitant use of oral baclofen and levodopa/dopa-decarboxylase (DDC) inhibitor resulted in increased risk of adverse events like visual hallucinations, confusional state, headache and nausea. Worsening of the symptoms of Parkinsonism has also been reported. Thus, caution should be exercised when intrathecal baclofen is administered to patients receiving levodopa/DDC inhibitor therapy.
There is hitherto no information on the concomitant administration of Baclofen with other intrathecally administered medications.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is limited data on the use of baclofen in pregnant women. After intrathecal administration of baclofen small amounts of baclofen can be detected in maternal plasma (see section 5.2). Baclofen crosses the placenta and has shown reproductive toxicity (see section 5.3). In contrast to oral administration, intrathecally infused baclofen was not teratogenic in mice, rats and rabbits (See section 5.3). Baclofen should not be used during pregnancy, unless the expected benefit for the mother outweighs the possible risks for the child.
Breastfeeding
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 expected benefit for the mother outweighs the possible risks for the child.
Fertility
Animal studies have shown that intrathecal baclofen is unlikely to have an adverse effect on fertility under clinically-relevant conditions (see section 5.3).
4.7 Effects on ability to drive and use machines
The ability to drive or operate machinery may be considerably impaired during treatment with Baclofen. Alcohol consumption increases this impairment still further.
Central nervous system (CNS) depressant effects such as somnolence and sedation have been reported in some patients on baclofen. Other listed events include ataxia, hallucination, diplopia, vision blurred and withdrawal symptoms. Operating equipment or machinery may be hazardous.
In patients treated with inthrathecal baclofen, the ability to continue driving or operating complex machinery should be routinely evaluated by the treating physician.
4.8 Undesirable effects
Some of the adverse reactions listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse reactions that are more frequent in either population are indicated below.
Adverse drug reactions (Table 2) from clinical trials are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category 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).
Table 2
| Metabolism and nutrition disorders | |
| Uncommon: | Dehydration. |
| Psychiatric disorders | |
| Common: | Depression, Agitation, Anxiety. |
| Uncommon: | Suicidal ideation, Suicide attempt, Paranoia, Hallucinations, Euphoric mood. |
| Not known: | Dysphoria |
| Nervous system disorders | |
| Very common: | Somnolence. |
| Common: | Convulsion, Confusional State, Disorientation, Lethargy, Dysarthria, Headache, Paraesthesia, Insomnia, Sedation, Dizziness. |
| Uncommon: | Ataxia, Memory impairment, Nystagmus. |
| Convulsion and headache occur more frequently in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin. | |
| Eye disorders | |
| Common: | Accommodation disorders, vision blurred, diplopia. |
| Cardiac disorders | |
| Uncommon: | Bradycardia. |
| Vascular disorders | |
| Common: | Orthostatic hypotension |
| Uncommon: | Deep vein thrombosis, Hypertension, Flushing, Pallor. |
| Respiratory, thoracic and mediastinal disorders | |
| Common: | Respiratory depression, Aspiration Pneumonia, Dyspnoea. |
| Not known: | Bradypnoea |
| Gastrointestinal disorders | |
| Common: | Vomiting, Constipation, Diarrhoea, Nausea, Dry mouth, Decreased appetite, Increased salivation |
| Uncommon: | Ileus, Dysphagia, Hypogeusia. |
| Nausea and vomiting occur more frequently in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin | |
| Skin and subcutaneous tissue disorders | |
| Common: | Urticaria, Pruritus, Oedema peripheral and/or Face oedema. |
| Uncommon: | Alopecia, Hyperhidrosis. |
| Musculoskeletal and connective tissue disorders | |
| Very common: | Hypotonia. |
| Common: | Hypertonia. |
| Not known: | Scoliosis |
| Renal and urinary disorders | |
| Common: | Urinary retention, Urinary incontinence. |
| Urinary retention occurs more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin. | |
| Reproductive system and breast disorders | |
| Common: | Sexual dysfunction (Baclofen may compromise erection and ejaculation. This effect is usually reversible on withdrawal of Baclofen). |
| Not known: | Erectile dysfunction |
| General disorders and administration site conditions | |
| Common: | Asthenia, Pain, Pyrexia, Chills. |
| Uncommon: | Hypothermia |
| Rare: | Life-threatening withdrawal symptoms due to drug delivery failure (see section 4.4). |
Adverse events associated with the delivery system
These can include inflammatory mass at the tip of the catheter, dislocation/kinking/rupture (tearing) of the catheter with possible complications, 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, whereby in some cases a causal relationship with baclofen cannot be excluded (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store.
4.9 Overdose
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.
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, hypothermia, salivary hypersecretion, nausea and vomiting.
Respiratory depression, apnoea and coma may result from serious overdosing. Serious overdose may occur through the inadvertent delivery of the catheter contents, errors in pump programming, excessively rapid dose increases or concomitant treatment with oral baclofen. Possible pump malfunction should also be investigated.
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.
Support of the cardiovascular function. If spasm occur, diazepam intravenous should be administered carefully.
Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate should be monitored.
If it is possible to do so without surgical intervention the intrathecal catheter should be disconnected from the pump as soon as possible, and infusion fluid allowed to drain back together with some CSF (up to 30–40 ml is suggested).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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.
Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABAgreceptors. Baclofen is a chemical analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of baclofen take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Baclofen improves the patient's mobility, makes it easier for him/her to manage without aid, and facilitates physiotherapy.
Consequent important gains include improved ambulation, prevention and healing of decubitus ulcers, and better sleep patterns due to elimination of painful muscle spasms. In addition, patients experience improvement in bladder and sphincter function and catheterisation is made easier, all representing significant improvements in the patient's quality of life. Baclofen has been shown to have general CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.
Baclofen when introduced directly into the intrathecal space, permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.
Intrathecal bolus
The onset of action is generally half an hour to one hour after administration of a single intrathecal dose. Peak spasmolytic effect is seen at approximately 4 hours after dosing, the effect lasting 4 to 8 hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms and the method and speed of drug administration.
Continuous infusion
Baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed within 24 to 48 hours.
5.2 Pharmacokinetic properties
The systemic availability of baclofen after intrathecal administration (Baclofen) is considerable less than after oral administration (baclofen tablets).
Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.
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.
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.
Elderly Patients
No pharmacokinetic data is available in elderly patients after administration of baclofen. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower elimination but a similar systemic exposure to baclofen compared to young adults. However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.
Paediatric population
In paediatric patients, respective plasma concentrations are at or below 10 ng/mL
Hepatic impairment
No pharmacokinetic data is available in patients with hepatic impairment after administration of baclofen. However, as liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patient with hepatic impairment.
Renal impairment
No pharmacokinetic data is available in patients with renal impairment after administration of baclofen. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment cannot be excluded.
5.3 Preclinical safety data
Local tolerance
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.
Mutagenicity and Carcinogenicity
Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. The evidence suggests that baclofen is unlikely to have mutagenic potential.
A 2-year study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or haemorrhagic adrenal glands were observed in female rats.
Reproduction toxicity
Intrathecal baclofen is unlikely to have adverse effects on fertility or on prenatal or postnatal development based on oral studies in rats and rabbits. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Baclofen given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. Baclofen dosed orally has been shown to cause delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat fetuses at a high intraperitoneal dose.
Baclofen had no effect on the fertility of female rats. Possible effects on male fertility have not been investigated.
6.1 List of excipients
Sodium chloride
Water for injection
6.2 Incompatibilities
This medicinal product must not be mixed with other infusion or injection solutions.
6.3 Shelf life
Shelf-life in unopened containers:
2 years
The product should be used immediately after opening.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAny unrequired fraction must be destroyed.
7 MARKETING AUTHORISATION HOLDER
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87
2132 JH Hoofddorp
The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 31750/0003
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
26/11/2014