SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Baclofen Aguettant 0.05mg/ml solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Baclofen Aguettant 0.05 mg/ml solution for injection

l ml of solution for injection contains 0.05 mg (50 micrograms) baclofen, 3.5mg sodium.

l ampoule contains 0.05 mg (50 micrograms) baclofen, 3.5 mg sodium.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear and colourless solution in ampoules.

The pH of the solution is between 5.5 and 6.8.

The osmolarity of the solution is between 270 and 300 mOsm/kg.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Baclofen Aguettant is indicated in patients with severe chronic spasticity resulting from trauma, multiple sclerosis or other spinal cord disorders, who are unresponsive to oral baclofen or other orally administered antispastic agents and/or those patients who experience unacceptable side effects at effective oral doses.

Baclofen Aguettant is effective in adult patients with severe chronic spasticity of cerebral origin, resulting, for example, from cerebral palsy, brain trauma or cerebrovascular accident; however, clinical experience is limited.

Paediatric population

Baclofen Aguettant 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

Intrathecal 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 baclofen into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with an 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.

Efficacy of intrathecal baclofen has been demonstrated in controlled randomised studies with an EU certified pump. This is an implantable administration system: a refillable reservoir is implanted beneath the skin, mostly into the abdominal wall. This system is connected to an intrathecal catheter that passes subcutaneously into the subarachnoid space.

Posology

Test phase.

Prior to administering baclofen as a continuous intrathecal infusion, patients must show a positive response to administration of an intrathecal test dose in an initial test phase. Usually, a bolus test dose is administered via lumbar puncture or an intrathecal catheter, in order to provoke a response. Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response. The initial dose is generally 25 or 50 micrograms; the dose is generally increased in increments of 25 micrograms at intervals of at least 24 hours, until a response lasting approximately 4 to 8 hours is obtained. The dose must be injected over at least one minute via barbotage.

Low-dose ampoules (0.05 mg/ml) are available for this test phase.

Resuscitative equipment must be on hand during injection of the first dose.

Patients are considered to be positive responders if they show a significant decrease in muscle tone and/or frequency and/or severity of spasms.

There is much variability with regard to sensitivity to intrathecal baclofen.

Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25 micrograms.

Patients who do not respond to a 100 microgram test dose must not be given further doses and are not eligible for continuous intrathecal infusions.

Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depressions.

Paediatric population

Screening phase

The initial lumbar puncture test dose for patients 4 to <18 years of age should be 2550 micrograms/day based upon age and size of the child. Patients who do not experience a response may receive a 25 micrograms/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 micrograms/day in paediatric patients.

Titration phase

Once the patient's response to Intrathecal Baclofen has been established as positive via test doses, intrathecal infusion with a suitable administration system is introduced. Infection may increase the risk of surgical complications and complicate attempts to adjust the dose.

Following implantation, the initial total daily dose should be determined by doubling the dose that gave a positive effect in the test phase and administering it over a 24-hour period, unless the effect of the bolus dose is maintained for more than 12 hours. In this latter case, the initial daily dose should be similar to the dose in the test phase and should be administered over a 24 hour period. The dose must not be increased during the first 24 hours. After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed l0-30%.

Patients with spasticity of cerebral origin: After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed 5 - 15%.

If a programmable pump is used, dosage should only be increased once every 24 hours. For non-programmable pumps attached to a 76 cm catheter and with a delivery rate of 1 ml/day, it is recommended that the response should only be evaluated at 48 hour intervals. If the daily dosage has been significantly increased without any clinical effect having been observed, pump functioning and catheter permeability should be verified.

Only limited experience is available with doses exceeding 1,000 micrograms/day.

During the test phase, as well as during the titration period following implantation, patients should be closely monitored at an institution with all the necessary equipment and personnel. Resuscitative equipment must be on immediate stand-by in the event of any reaction that threatens the vital prognosis, or onset of very serious undesirable effects. In order to limit risks in the perioperative phase, the pump must only be implanted at centres with experienced personnel.

Maintenance therapy.

The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of “paralysis” on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis.

In patients with spasticity of spinal origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom control. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%).

In both cases the daily dose may also be reduced by 10-20% if patients suffer side effects.

If a significant dose increase should suddenly be necessary, this is indicative of a catheter complication (kink or dislodgement) or pump malfunction.

For long-term maintenance treatment via continuous infusion, the intrathecal baclofen dosage for patients with spasticity of spinal origin is between 12 and 2,300 micrograms/day, with an adequate response being achieved in most patients with 300800 micrograms/day.

In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22 to 1,400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.

Around 5% of patients receiving long-term treatment become refractory to dose escalation. This may be due to therapeutic failure. There is insufficient experience available to make any recommendations on dealing with treatment failure. However, this phenomenon has occasionally been treated in hospital by a "drug holiday" consisting of the gradual reduction of intrathecal baclofen over a period of 2 to 4 weeks and switching to alternative methods of spasticity therapy (e.g. intrathecal preservative-free morphine sulphate). After this period, sensitivity to intrathecal baclofen may be re-established: treatment should be resumed at the initial continuous infusion dose, followed by a titration phase to avoid overdose.

Caution should be exercised when switching from Intrathecal Baclofen to morphine and vice versa (see "Interactions").

Regular clinical monitoring is needed to assess the patient's dosage requirements, to check that the administration system is working properly and to note any undesirable effects or the presence of infection.

Paediatric population

In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of Intrathecal Baclofen ranges from 25 to 200 micrograms/day (median dose: 100 micrograms/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.

The safety and efficacy of Intrathecal 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).

Discontinuation of treatment.

Except in emergency cases associated with an overdose, treatment should be discontinued gradually with successive dose reductions. Intrathecal Baclofen should not be abruptly discontinued (see "Special warnings and precautions").

Administration: particular specifications.

Ampoules of 10mg/5ml, 40mg/20ml and l0mg/20ml Baclofen Aguettant have been specially developed for infusion pumps.

The exact concentration to be selected depends on the total daily dose needed, as well as the minimum infusion rate of the pump. Please refer to the pump manufacturer's manual, which contains all specific recommendations.

Method of administration.

In most cases, Intrathecal Baclofen is administered as a continuous infusion directly after implantation. Once the patient is stabilised in terms of daily dosage and functional aspects, and provided that the pump allows it, a switch can be made to a more complex method of administration, to allow optimal control over spasticity at different times of the day. For example, patients with increased night-time spasms may require a 20% increase in the hourly infusion rate. This altered rate of infusion must be programmed about 2 hours in advance of the expected clinical effect.

Each ampoule is exclusively single-use. Do not resterilise.

The medicinal product has to be visually inspected prior to use. Only clear solutions practically free from particles should be used.

For instructions on dilution of the product before administration, see section 6.6.

Special populations Renal impairment

No studies have been performed in patients with renal impairment receiving Intrathecal Baclofen therapy. Because baclofen is primarily excreted unchanged by the kidneys it should be given with special care and caution in patients with impaired renal function.

Hepatic impairment

No studies have been performed in patients with hepatic impairment receiving Intrathecal 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.

Elderly population

Several patients over the age of 65 years have been treated with Intrathecal Baclofen during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Epilepsy refractory to therapy.

The drug should not be administered by any route other than intrathecal.

4.4 Special warnings and precautions for use

Medical management.

The pump should only be implanted after strict evaluation of the patient's response to intrathecal baclofen bolus injections and/or dose titration. Given the risks associated with initial administration and dose adjustment of intrathecal baclofen (general depression of CNS functions, cardiovascular collapse and/or respiratory depression), these steps must only be performed under medical surveillance at a centre with the required equipment, in compliance with the directives given in section "Posology and method of administration". Resuscitative equipment must be on immediate stand-by in the event of overdose symptoms that threaten the vital prognosis. Doctors must be adequately experienced in the chronic treatment with intrathecal infusions.

Patient surveillance.

The patient must be closely monitored after surgical implantation of the pump, especially during the initial phase of pump use and each time that its delivery rate and/or the baclofen concentration in the reservoir are readjusted, until the patient's response to the infusion is acceptable and stabilised within reasonable limits.

It is essential that the risks of such a method of treatment are precisely known by the patient, doctors in charge of him/her and all caregivers. All persons participating in the treatment or care given to the patient must be clearly informed about the symptoms of under- and overdosing, procedures to be implemented in the event of intoxication, as well as the measures to be taken at home with regard to the pump and the insertion site.

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

Test phase.

Close monitoring of respiratory and cardiovascular functions is essential during the initial test phase, particularly in the presence of a cardiopulmonary condition or respiratory muscle weakness, as well as in patients concomitantly receiving benzodiazepine- or opiate-type medications, as the risk of respiratory depression is increased in such cases.

Any infection must be excluded prior to the test phase with Intrathecal Baclofen, as a systemic infection might falsify the evaluation of the patient's response to the Intrathecal Baclofen injection.

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 Intrathecal 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

Pump implantation.

The patient must be free from infection prior to pump implantation, as the risk of postoperative complications would be increased. Furthermore, a systemic infection could complicate dose adjustment. A local infection or catheter misplacement can also cause interruption of drug delivery, which may result in abrupt Intrathecal Baclofen withdrawal, accompanied by its symptoms (see "Interruption of treatment").

Filling the reservoir.

This must be performed by trained and fully qualified personnel, in accordance with the manufacturer's instructions. Intervals between each refill should be carefully calculated to avoid depletion of the reservoir, which would lead to severe recurrence of spasticity or potentially life-threatening symptoms of Intrathecal Baclofen withdrawal (see "Interruption of treatment"). Filling should be performed under strictly aseptic conditions, in order to avoid any microbial contamination or any serious CNS infection. There should be an observation period, adapted to the clinical situation, after each refill or handling of the reservoir.

Extreme caution is required when filling an implantable pump fitted with a port with direct access to the intrathecal catheter, as direct injection into the catheter may lead to an overdose threatening the vital prognosis.

Dose adjustment: additional comments.

Intrathecal Baclofen must be used with caution to avoid excessive weakness or a fall when a certain degree of spasticity is needed for standing up and gait balance, or whenever spasticity contributes to functional maintenance. It may be important to retain a certain amount of muscle tone and to tolerate occasional spasms, in order to facilitate circulatory function and prevent possible formation of deep vein thrombosis.

Whenever possible, all concomitant oral antispasmodic medications shouId be discontinued to avoid a possible overdose or undesirable interactions; preferably prior to initiating the Intrathecal Baclofen infusion and under close medical surveillance. However, any abrupt reduction or discontinuation of the concomitant antispasmodic medication should be avoided during chronic treatment with Intrathecal Baclofen.

Precautions in special populations.

Precautions in paediatric patients

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use of Intrathecal 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 Intrathecal Baclofen in children under the age of four years.

Trascutaneous catheter insertion during the pump implantation and the presence of a PEG tube increase the incidence of infections in children.

Special patient groups

In patients with slowed CSF circulation due, for exampIe, to blockage caused by inflammation or trauma, the delayed migration of Intrathecal Baclofen can reduce the antispastic efficacy and boost the adverse reactions.

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.

Patients with psychotic disorders, schizophrenia, confusional states or Parkinson's disease must be cautiously treated with Intrathecal Baclofen and undergo strict surveillance whenever exacerbation of such conditions has been observed following oral baclofen administration. Patients with epilepsy must be particularly monitored, as seizures may occasionally occur in the event of an overdose or withdrawal of the medication and even during maintenance treatment at therapeutic doses of Intrathecal Baclofen.

Intrathecal Baclofen must be used with caution in patients with a history of autonomic dysreflexia. Nociceptive stimulation or abrupt withdrawal of Intrathecal Baclofen may precipitate such episodes.

The same caution is required in the presence of cerebrovascular or respiratory insufficiency, as baclofen can aggravate such states.

Intrathecal Baclofen is unlikely to have any effect on underlying, non-CNS related diseases, as systemic bioavailability of the product following intrathecal administration is considerably lower than with the oral route.

Renal impairment

Based on observations made during baclofen treatment via the oral route, caution is recommended in the following cases: history of gastro-duodenal ulcers, pre-existing sphincter hypertonia, renal impairment.

With oral baclofen, rare cases of elevated SGOT (AST), alkaline phosphatase and blood glucose levels have been recorded.

Elderly Patients

Several patients over 65 years of age have been treated with intrathecal baclofen during clinical studies without any specific problems. Elderly patients are more likely to experience undesirable effects with oral baclofen in the titration phase and this may also apply to Intrathecal Baclofen. However, as optimal dose finding is individualised, treatment of elderly patients is unlikely to pose any specific problems.

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, i.e. essentialIy "sodium free".

Interruption of treatment.

Abrupt discontinuation of intrathecal baclofen, for whatever reason, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has given rise to sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia and symptoms consistent with neuroleptic malignant syndrome (NMS), e.g. confused mental state and muscle rigidity. In rare cases, this has progressed to epileptic seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients receiving treatment with intrathecal baclofen are potentially at risk during withdrawal. Some clinical characteristics associated with intrathecal baclofen withdrawal can resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome (NMS) or other conditions associated with status hypermetabolicus or extensive rhabdomyolysis.

Patients and their caregivers must be advised of the importance of keeping a timetable for refill visits and must be alerted to the signs and symptoms of baclofen withdrawal, particularly those that appear early on during the withdrawal syndrome.

In most cases, withdrawal symptoms appeared within a few hours after discontinuation of intrathecal baclofen treatment. Common reasons for abrupt withdrawal of intrathecal baclofen treatment included catheter malfunctioning (especially disconnection), excessively low volume in the pump reservoir and end of pump battery life; in some cases, human error may have been to blame or played a contributing role. Prevention of abrupt withdrawal of intrathecal baclofen requires careful attention to programming and surveillance of the infusion system, refill scheduling/procedures and pump alarms.

The suggested treatment for Intrathecal Baclofen withdrawal is the restoration of Intrathecal Baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral Baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral Baclofen alone should not be relied upon to halt the progression of Intrathecal Baclofen withdrawal.

It is extremely important that the manufacturer's instructions for implantation, pump programming and/or refilling of the reservoir should be strictly followed.

4.5 Interaction with other medicinal products and other forms of interaction

Available experience is not systematic enough to predict what would be the specific interactions of Intrathecal Baclofen with other medications.

Whenever possible, all concomitant oral antispasmodic medications should be discontinued, to prevent a possible overdose or undesirable interactions; preferably prior to initiating an Intrathecal Baclofen infusion and under close medical surveillance.

However, any abrupt reduction or discontinuation of the concomitant antispasmodic medication should be avoided during chronic treatment with Intrathecal Baclofen.

A combination of morphine and intrathecal baclofen has caused hypotension in one patient. The potential for dyspnoea or other central nervous symptoms cannot be excluded during concomitant medication.

Co-administration with other agents via the intrathecal route has been tested to a limited extent and little is known about the safety of such combinations.

The CNS-depressant effect of alcohol and other compounds acting at this level may be additive to those of Intrathecal Baclofen.

Concomitant treatment with oral baclofen and tricycIic antidepressants may enhance the effect of baclofen and induce marked muscle hypotonia. Caution is advised when using Intrathecal Baclofen in this type of combinations.

As concomitant use of oral baclofen and antihypertensive agents may increase any fall in blood pressure, it may prove necessary to monitor blood pressure and readjust the antihypertensive dosage.

During concomitant administration with levodopa, there is a risk of increasing the undesirable effects associated with the latter (mental confusion, hallucinations, agitation).

Concomitant use of intrathecal baclofen and general anaesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anaesthetics are administered to patients receiving Intrathecal Baclofen.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and sufficiently controlled studies in pregnant women. Baclofen crosses the placental barrier. Intathecal Baclofen must not be used during pregnancy, unless the potential benefits outweigh the possible risks to the foetus. Studies in animals have shown a teratogenic effect of baclofen by oral administration (See section 5.3).

Breast-feeding

It is not known whether measurable levels of the product can be detected in the maternal milk of lactating mothers treated with Intrathecal Baclofen. At oral therapeutic doses, the active substance passes into breast milk, but in amounts so small that the infant will probably not experience any undesirable effects.

Fertility

Ovarian cysts have been found by palpation in about 4 % of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the drug. Ovarian cysts are known to occur spontaneously in a proportion of the normal female population.

4.7 Effects on ability to drive and use machines

Onset of drowsiness has been reported in some patients on intrathecal baclofen treatment. Patients must be urged to exercise caution when driving their car, using hazardous machinery or performing any potentially hazardous activity in case of reduced alertness.

4.8 Undesirable effects

In many cases, a causal link between the effects observed and baclofen administration cannot be established, as most of the undesirable effects reported may also be associated with the underlying disease. Nevertheless, some commonly reported reactions (somnolence, dizziness, headache, nausea, hypotension, hypotonia) seem to be drug-related. These effects are mostly transient and primarily occur during the test phase or with changes in concentrations.

Table 1.

Adverse drug reactions are listed according to system organ classes in MedDRA.

Undesirable effects are ranked according to system class and frequency, within each frequency grouping, undesirable effects are presented in order of decreasing seriousness and according to 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)

Metabolism and nutritional disorders
Uncommon:	dehydration
Psychiatric disorders
Common	depression, anxiety, agitation
Uncommon	suicidal ideation, suicide attempt, hallucinations, paranoia, euphoric mood
Not known	dysphoria
Nervous system disorders
Very common	somnolence (especially during the test phase)
Common	convulsion, sedation, dizziness/ light-headedness, epileptic seizures (especially upon abrupt discontinuation of treatment), headache, paraesthesia, dysarthria, lethargy, insomnia,

	confusion/ disorientation.
Uncommon	ataxia, impaired memory nystagmus
Convulsion and headache occur more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin
Eye disorders
Common	accommodation disorders, vision blurred, diplopia
Cardiovascular disorders
Uncommon	bradycardia
Vascular disorders
Common	hypotension.
Uncommon	hypertension, deep vein thrombosis, flushing, pallor.
Respiratory, thoracic and mediastinal disorders
Common	respiratory depression, pneumonia, dyspnoea
Not known	bradypnoea
Gastrointestinal disorders
Common	nausea/vomiting, constipation, dry mouth, diarrhoea decreased appetite, increased salivation.
Uncommon	ileus, dyshalgia, hypoageusia.
Nausea and vomiting occur more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin
Skin and subcutaneous tissue disorders
Common	urticaria, pruritus, facial or peripheral oedema.
Uncommon	alopecia, hyperhydrosis.
Musculoskeletal and connective tissue disorders
Very common	muscular hypotonia (especially during the test phase - transient effects).
Common	muscular hypertonia.
Renal and urinary disorders
Common	urinary incontinence, urinary retention
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 (Intrathecal Baclofen may compromise erection and ejaculation. This effect is usually reversible on withdrawal of Intrathecal Baclofen)
General disorders and administration site conditions
Common	asthenia, pyrexia, pain, chills
Uncommon	hypothermia
Rare	potentially life-threatening withdrawal symptoms, as a result of sudden interruption of drug delivery (see “Interruption of treatment”)

Undesirable effects due to the administration system (e.g. inflammatory mass at the tip of the implanted catheter, catheter dislodgement, local infection, meningitis, overdose due to incorrect manipulation of the system) are not mentioned here.

In a screening trial the presence of a PEG tube increased the incidence of deep infections in children.

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 :

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The patient must be closely monitored for any signs and symptoms of overdose throughout the entire treatment, particularly during the initial test phase and titration phase, but also when administration of Intrathecal Baclofen is resumed after brief suspension.

Signs of overdose may appear suddenly or insidiously.

Symptoms of overdose: excessive muscular hypotonia, drowsiness, lightheadedness, dizziness, sedation, epileptic seizures, loss of consciousness, ptyalism, nausea and vomiting.

Respiratory depression, apnoea and coma occur in the event of a major overdose.

Serious overdose may occur, for example, if the catheter contents inadvertently pass into the intrathecal space during verification of catheter permeability/positioning. Programming errors, excessively rapid dose increases and concomitant treatment with oral Baclofen represent other possible causes of overdose. Pump malfunction should also be investigated.

Treatment

There is no specific antidote for the treatment of overdose with Intrathecal Baclofen. The following measures are usually taken:

1)    Drain any remaining baclofen from the pump as quickly as possible.

2)    If necessary, intubate patients with respiratory depression, until the drug is eliminated.

Certain reports suggest that physostigmine is capable of abolishing the central nervous effects, particularly drowsiness and respiratory depression.

However, caution must be exercised when intravenously injecting physostigmine, as it might induce epileptic seizures, bradycardia and cardiac conduction disturbances. A test can be performed with 1-2 mg physostigmine IV over a period of 5 to 10 minutes. During this time, patients should be subject to strict surveillance. Repeated doses of 1 mg can be given at 30 to 60 minute intervals, in order to maintain adequate ventilation and vigilance if the patient responds favourably.

Physostigmine may be ineffective in cases of massive overdose and the patient may have to be placed under artificial ventilation.

Provided that lumbar puncture is not contraindicated, evacuation of 30-40 ml CSF can be considered at an early stage of intoxication, in order to reduce the baclofen concentration within the CSF.

Maintenance of cardiovascular function. During seizures: cautious IV injection of diazepam.

Physostigmine is only recommended for severe toxicity not responsive to supportive measures.

In children a dose of 0.02 mg/kg physostigmine may be administered IV at a rate not exceeding 0.5 mg per minute. This dose may be repeated at 5 to l0 minute intervals until a therapeutic effect is obtained or a total dose of 2 mg has been administered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antispastic with a spinal site of attack Muscle Relaxants, Other Centrally Acting Agents ATC code: M03B X01

Mechanism of action

Baclofen slows down mono- and polysynaptic reflex transmission in the spinal cord, by stimulating GABA_b receptors.

Pharmacodynamics effects:

The chemical structure of baclofen is analogous to that of gamma-aminobutyric acid (GABA), which is a neurotransmitter inhibitor.

Neuromuscular transmission is not altered by baclofen. Baclofen has an antinociceptive action. In neurological diseases accompanied by musculoskeletal spasms, the properties of baclofen manifest not only in the form of an effect on reflex muscle contractions, but also as a marked reduction in the intensity of painful spasms and clonus. Baclofen improves patient mobility, providing them with greater autonomy, and facilitates physiotherapy.

Baclofen depresses the CNS in general, causing sedation, somnolence, as well as respiratory and cardiovascuIar depression.

Intrathecal Baclofencan be regarded as an alternative to destructive neurosurgical procedures.

Baclofen, introduced directly into the intrathecal space, allows treatment of spasticity at doses at least 400 to 1,000 times lower than they would be via the oral route.

Intrathecal bolus.

The medicinal product usually starts to act half an hour to one hour after administration of a single intrathecal dose. The peak spasmolytic effect manifests around 4 hours post-dose and its action lasts for 4 to 8 hours. Onset of action, peak response and duration of effect can vary between individual patients, depending on the dose, severity of symptoms and the method and rate of administration.

Continuous infusion.

The antispasmodic effect of baclofen starts 6 to 8 hours following initiation of the continuous infusion and reaches its peak within 24 to 48 hours.

5.2 Pharmacokinetic properties

The intrathecal nature of administration and decelerated circulation of cerebrospinal fluid (CSF) must be taken into account when interpreting the following kinetic parameters.

Absorption.

Direct infusion into the cerebrospinal fluid allows absorption processes to be avoided and allows the substance to come into contact, via adsorption, with receptor sites in the dorsal horn of the spinal cord.

Distribution.

Following a single intrathecal bolus injection/short-term infusion, the volume of distribution is between 22 and 157 ml, calculated from levels present in the CSF. When given as continuous intrathecal infusions, daily doses of 50 to 1,200 micrograms produce baclofen steady-state concentrations of 130 - 1,240 ng/ml in lumbar CSF. According to the half-life measured in the CSF, steady state CSF concentrations are reached within 1 to 2 days. During intrathecal infusion, plasma concentrations do not exceed 5 ng/ml, which confirms that the passage of baclofen through the blood-brain barrier is slow.

Elimination.

Following a single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms of baclofen, the CSF elimination half-life ranges from 1 to 5 hours. The CSF elimination half-life of baclofen at steady state has not been determined.

Mean CSF clearance is approximately 30 ml/h after both a single bolus injection and continuous infusion in the lumbar subarachnoid space using an implantable pump.

During continuous intrathecal infusion, once steady state has been reached, a baclofen concentration gradient is built up in the range between 1.8 : 1 and 8.7 : 1 (mean = 4 : 1) between lumbar CSF and subarachnoid cisternal CSF. This is of clinical importance, as spasticity of the lower extremities can be effectively treated without greatly influencing the upper limbs, with fewer adverse central nervous effects due to the drug's action on the brain centres.

Special populations Elderly Patients

No pharmacokinetic data is available in elderly patients after administration of Intrathecal 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.

Paediatrics

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 Intrathecal 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 Intrathecal Baclofen. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment can not be excluded.

5.3 Preclinical safety data

A 2 year study with rats (oral route) has shown that baclofen is not carcinogenic. This study showed a dose-dependent increase in the incidence of ovarian cysts and a less marked increase in the incidence of hypertrophic and/or haemorrhagic adrenal glands. The clinical relevance of these findings is not known. In vivo and in vitro mutagenesis tests have shown no mutagenic effect.

Oral baclofen increases the incidence of omphaloceles (ventral hemias) in the foetuses of rats at high doses. No teratogenic effects have been noted in mice.

An increased incidence of incomplete sternebral ossification in foetuses of rats given high doses oral baclofen was observed. High doses oral baclofen also increased the incidence of unossified phalangeal nuclei of forelimbs and hindlimbs in rabbit foetuses.

6.1 List of excipients

Sodium Chloride Water for injection

6.2 Incompatibilities

Dextrose has been shown to be incompatible with baclofen, as a chemical reaction occurs between the two substances.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

6.3 Shelf life

5 years

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Do not refrigerate or freeze.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Baclofen Aguettant 0.05 mg/ml

Type I clear colourless glass 2 ml ampoules with score-break and blue coloured ring marker.

Box of 5 and 10 ampoules containing l ml of solution.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any remaining product must be disposed of.

Instructions for use/operating instructions.

Baclofen Aguettant is designed for intrathecal injections and continuous infusions and is administered according to the specifications accompanying each infusion system.

Stability.

Intrathecal baclofen has been shown to be stable for 180 days in implantable EU certified pumps.

Wherever possible prior to administering them, medicinal products for parenteral use should be checked for the presence of particulate matter and any changes in colour.

Specific instructions for administration

The exact concentration to be selected depends on the total daily dose needed, as well as the minimum infusion rate of the pump. Please refer to the manufacturer's user manual for all specific recommendations.

Dilution.

If users wish to obtain concentrations other than 50, 500 or 2,000 micrograms/ml, Baclofen Aguettant must be diluted under aseptic conditions in a sterile and preservative-free sodium chloride solution for injections.

Administration systems.

Several systems have been used for long-term administration of intrathecal baclofen. Among these, EU certified pumps can be mentioned, which are implantable systems equipped with a refillable reservoir, and which are implanted - under local or general anaesthetic - under the skin or into a pocket mostly in the abdominal wall. These systems are connected to an intrathecal catheter that passes subcutaneously into the subarachnoid space.

Before using these systems, users should ensure that the technical specifications, as well as the chemical stability of baclofen in the reservoir, fulfil the conditions required for intrathecal administration of intrathecal baclofen.

7 MARKETING AUTHORISATION HOLDER

Laboratoire Aguettant 1, rue Alexander Fleming 69007 Lyon France

8    MARKETING AUTHORISATION NUMBER(S)

PL 14434/0024

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/06/2015

10    DATE OF REVISION OF THE TEXT

25/06/2015