GABLOFEN 1 MG / ML SOLUTION FOR INJECTION/INFUSION IN PRE-FILLED SYRINGE - patient leaflet, side effects, dosage

1. what gablofen is and what it is used for

Gablofen contains the active substance Baclofen. It belongs to the group of medicines called muscle relaxants.

Gablofen is administered by injection into the spinal canal directly into the spinal fluid (intrathecal injection) and relieves severe muscle rigidity (spasticity).

Gablofen is used to treat severe, long-lasting muscle tension (spasticity) occurring in various illnesses, such as:

• brain or spinal cord injuries or diseases
• multiple sclerosis, which is a progressive brain and spinal cord nerve disease with physical and mental symptoms

Gablofen is used in adults and children aged 4 years and above. It is used when other orally taken medicines, including baclofen, have been unsuccessful or caused unacceptable side effects.

2. what you need to know before you are given gablofendo not use gablofen if you are allergic to baclofen or any of the other ingredients of this medicine (listed in section 6)

• if you have untreatable epilepsy

• by any other route of administration than via the spinal canal
  
  Warnings and precautions

  Talk to your doctor before you are given Gablofen if you are/have:

• any infection
• had a head injury; for patients with spasticity due to head injury, it is recommended not to proceed to intrathecal Gablofen therapy until the symptoms of spasticity are stable and can be reliably assessed
• had autonomic dysreflexia: a reaction of the nervous system to overstimulation, causing sudden severe high blood pressure
• reduced circulation of liquid contained in the brain and spinal cord as a result of obstructed passage, for example caused by inflammation or injuries
• treatable epilepsy
• had a stomach or intestinal ulcer
• overactive bladder sphincter muscle
• acute or chronic confusional states
• psychotic disorder, or schizophrenia (mental disease)
• Parkinson's disease
• reduced kidney function or a liver disease
• inadequate blood flow in the brain (cerebrovascular insufficiency)
• heart or breathing difficulties
• Monitoring of heart and breathing function is essential during the initial test phase, particularly if you have heart or breathing difficulties.
• scoliosis (increase in sideways curvature of the spine)
• diabetes
• to undergo an operation

Contact your doctor immediately if you think that Gablofen is not working as well as usual. It is important to make sure that there are no problems with the pump.

You will be monitored closely in a fully equipped and staffed environment during the screening phase and dose-finding period immediately following pump implant. You will regularly be assessed for your dosage requirements, for possible side effects or evidence of infection. The functioning of the delivery system will also be checked.

Treatment with Gablofen must not stop suddenly because of the risk of withdrawal effects. Make sure that you do not miss hospital visits when the pump reservoir is being refilled.

Children

Gablofen is not recommended for children under 4 years. Older children must have sufficient body mass to accommodate the implantable pump. There is limited clinical data in children under the age of four.

Elderly patients

Some patients over the age of 65 years have been treated with intrathecal baclofen during the clinical trials without specific problems. Experience with baclofen tablets shows however, that this patient group may be more susceptible to side effects. Older patients should therefore be carefully monitored for the occurrence of side effects.

Other medicines and Gablofen

Tell your doctor or pharmacist if you are using or have recently used or might use any other medicines, including medicines obtained without a prescription.

Inform your doctor if you are using any of the following medicines as they can affect or be affected by Gablofen:.

• other medicines to treat muscle spasm condition

If possible, your doctor may slowly discontinue other medicines which treat muscle spasm.

• medicines to treat depression
• medicines to treat high blood pressure
• levodopa, carbidopa: medicines to treat Parkinson's disease
• strong pain relief medicines, such as morphine
• medicines which slow down the function of the central system, such as sleep inducing medicines
• other medicines administered into the spine
• Administration of other medicines into the spine is not recommended during Gablofen treatment.

Concomitant use of general anaesthetics may increase the risk of cardiac disturbances and seizures.

Gablofen with alcohol

Avoid drinking alcohol during treatment with Gablofen as this may lead to an undesirable intensification or unpredictable change in the effects of the medicine.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

There is limited experience on the use of intrathecal baclofen during pregnancy or while breastfeeding. Gablofen should not be used during pregnancy or while breast-feeding, unless the expected benefit for the mother outweighs the potential risk for the child. Gablofen passes into breast milk, but low levels are expected after intrathecal administration. Consequently, Gablofen can be used during breast-feeding.

Driving and using machines

During treatment with Gablofen your ability to drive or use machines may be considerably impaired.

Some people may feel drowsy, dizzy, have problems with their eyes, difficulties in controlling movements or have hallucinations while being treated with Gablofen. Do not drive or anything that requires you to be alert until these effects have worn off, if this applies to you. Before driving or using machines you should consult your physician.

Gablofen contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per maximum daily dose i.e. essentially “sodium-free”.

3. how to use gablofen

Gablofen may only be administered by a specially qualified doctor.

The dose varies, dependent upon each person's condition. The doctor will decide your dose after testing your response to this medicine.

Firstly, the doctor will give you single doses of Gablofen, to find out if it is suitable for you. During this period your heart and lung functions will be closely monitored. If your symptoms improve, a special pump which continuously delivers Gablofen will be implanted into your chest or abdominal wall. The doctor will provide you with all necessary instructions for using the pump and dosage information. Make sure that you understand everything.

Your dose depends upon your response to the medicine. Beginning with a low dose, this is gradually increased over a few days under doctor's super­vision, until you have the right dose.

Side effects are more likely if the starting dose is too high or the dose is increased too quickly. To avoid these effects, which may be serious, it is important that your pump does not run out. Ensure that you do not miss your hospital appointments.

It is extremely important that you keep your appointments with the doctor to refill the pump, otherwise spasms may recur because you are not getting a high enough dose of Gablofen.

Your muscle spasms may worsen as a result.

If your muscle spasticity is not improving or if you start having spasms again, either gradually or suddenly, contact your doctor immediately.

If treatment with Gablofen is interrupted

It is very important that you, and those caring for you, are able to recognise signs of Gablofen withdrawal. These may appear suddenly or slowly for example because the pump is not working properly due to battery problems, catheter problems or alarm dysfunction.

The signs of withdrawal are:

• – increased spasticity, too much muscle tone

• – difficulty with muscle movements

• – increase in heart rate or pulse

• – itching, tingling, burning sensation or numbness (paraesthesia) in your hands or feet

• – priapism (persistent painful erection of the penis)

• – palpitations

• – anxiety

• – high body temperature

• – low blood pressure

• – altered mental conditions for example agitation, confusion, hallucinations, abnormal thinking and behaviour, convulsions

If you have any of the above signs, tell your doctor straight away. These signs may be followed by more serious side effects unless you are treated immediately.

Route of administration

Gablofen may only be administered into the spinal canal (intrathecal use).

Duration of use

To be decided by the doctor.

During long-term treatment, some patients find that Gablofen becomes less effective. Your doctor

may recommend occasional breaks in treatment to counteract this.

If you are given more Gablofen than you should

It is very important that you and your carer can recognise the signs of overdose. This may occur if the pump is not working properly.

Inform your doctor immediately if this applies to you or you experience any overdose signs, such as:

• unusual muscle weakness
• sleepiness, clouding or loss of consciousness
• dizziness, light-headedness
• excessive salivation, abnormal low body temperature
• nausea or vomiting
• breathing difficulties, respiratory arrest
• seizures

If you stop using Gablofen

If this medicine must be stopped, this may only be done by your doctor who will reduce the dose gradually to avoid side effects. Suddenly stopping intrathecal Gablofen can cause withdrawal symptoms which in some cases have proven fatal.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

These occur more often at the start of treatment during your hospital stay, but they may also occur later. Many of these side effects are also known to be associated with the specific medical condition for which you are being treated.

Side effects can occur with the following frequencies:

Very common, may affect more than 1 in 10 people

• drowsiness
• reduced muscle tension

Common, may affect up to 1 in 10 people

• sedation, dizziness, light-headedness
• pain, fever, chills
• abnormal sensation such as tingling
• problems with eyesight with vision blurred or double-vision
• slurred speech
• lethargy, weakness
• breathing difficulties (respiratory depression, dyspnoea, bradypnoea), lung inflammation (aspiration pneumonia)
• sleeplessness
• confusion, disorientation, anxiety, restlessness, depression
• low blood pressure
• constipation, diarrhoea
• dry mouth, decreased appetite, excessive saliva
• rash, itching
• tissue swelling in the face, hands or feet
• urinary incontinence
• increased muscle tension, muscle weakness
• sexual problems, such as impotence

The following side effects occur more frequently in patients with cerebral spasticity:

Seizures, headache, nausea, vomiting and difficulties in urinating

Uncommon, may affect up to 1 in 100 people

• feeling abnormally cold
• involuntary eye movement (nystagmus)
• difficulties in controlling movements (ataxia)
• reduced memory
• disturbed mood, euphoria, paranoia, hallucinations, suicidal thoughts and attempts
• bowel obstruction, difficulty in swallowing, loss of taste, dehydration
• high blood pressure, slow heartbeat
• deep vein thrombosis
• flushed or pale skin, excessive sweating
• hair loss

Rare, may affect up to 1 in 1000 people

• Life-threatening withdrawal symptoms due to drug delivery failure.

Not known , frequency cannot be estimated from the available data

• Scoliosis (increase in sideways curvature of the spine)
• Erectile dysfunction

For a description of the signs of withdrawal, see “If treatment with Gablofen is interrupted”.

For a description of the signs of overdose, see “If you are given more Gablofen than you should”.

There have been reports of problems associated with the pump and delivery system such as infections, inflammation of the lining around the brain and spinal cord (meningitis) or inflammation at the tip of the delivery tube.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via Yellow Card Scheme, Website: or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

5. how to store gablofen

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the outer carton and on the prefilled syringe.

The expiry date refers to the last day of that month.

Do not store above 30°C. Do not freeze.

After first opening: the product should be used immediately.

Do not use this medicine if you notice that the solution is not clear or free from particles. As it is limited to hospital use the disposal of unused medicine is carried out directly by the hospital.

6. contents of the pack and other informationwhat gablofen contains the active substance is baclofen.

• Each ml contains 1 mg (1000 microgram) baclofen.

Each 20 ml pre-filled syringe contains 20 mg (20000 microgram) baclofen.

• The other ingredients are sodium chloride and water for injection.

What Gablofen looks like and contents of the pack

Gablofen is a clear, colourless solution for injection.

Gablofen is available in packs containing one syringe of 20 ml.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Piramal Critical Care Limited, Suite 4, Ground Floor, Heathrow Boulevard – East Wing, 280 Bath Road, West Drayton, UB7 0DQ, United Kingdom, Tel : 00441670562400

• Manufacturer

Laboratoire Aguettant, 1 rue Alexander Fleming, Parc Scientifique Tony Garnier, LYON, 69007, France

This medicinal product is authorised in the Member States of the EEA under the following names:

Belgium SPACYR

Denmark Gablofen

France SPACYR

Germany Gablofen

Italy Baclofene Piramal

Netherlands Gablofen

Spain SPACYR

Sweden Gablofen

United Kingdom Gablofen

This leaflet was last revised in 11/2019

GA/UK/I/011/02

Sodium

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

• 4.5 Interaction with other medicinal products and other forms of interaction

No interactions studies have been performed.

There is little experience with the use of intrathecal baclofen in combination with systemic medicinal products 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).

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

Alcohol and other compounds affecting the CNS

The concomitant administration of baclofen and other medicinal products that have a suppressing effect on functions of the central nervous system (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) can enhance the action of baclofen. 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 medicinal products 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

As concomitant use of oral baclofen and antihypertensive medicinal products may increase any fall in blood pressure, it may prove necessary to monitor blood pressure. If applicable, the dosage of the antihypertensive medication must be reduced.

Levodopa/Dopa decarboxylase inhibitor

Concomitant use of oral baclofen and levodopa/Dopa decarboxylase 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/Dopa decarboxylase inhibitor therapy.

Morphine

The combined use of morphine and intrathecal baclofen has been responsible for hypotension in one patient.

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.

Anaesthetics

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.

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 intrathecal baclofen in pregnant women. After intrathecal administration, small amounts of baclofen can be detected in maternal plasma (see section 5.2). Baclofen crosses the placenta and has shown reproduction toxicity (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, however clinically relevant levels are not expected due to the low plasma concentration of baclofen in mothers treated with intrathecal baclofen. Gablofen can be used during breastfeeding.

Fertility

Animal studies have shown that intrathecal baclofen is unlikely to have an adverse effect on fertility (see section 5.3).

• 4.7 Effects on ability to drive and use machines

The ability to drive or use machines may be considerably impaired during treatment with intrathecal 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 intrathecal baclofen. Other listed events include ataxia, hallucinations, diplopia and withdrawal symptoms.

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

• 4.8 Undesirable effects

Adverse reactions 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 (frequency cannot be estimated from the available data).

Metabolism and nutrition disorders
Common:	Decreased appetite.
Uncommon:	Dehydration.
Psychiatric disorders
Common:	Depression, Confusional state, Disorientation, Agitation, Anxiety.
Uncommon:	Suicidal ideation, Suicide attempt, Paranoia, Hallucinations, Dysphoria, Euphoric mood.
Nervous system disorders
Very common:	Somnolence.
Common:	Convulsion, Lethargy, Dysarthria, Headache, Paraesthesia, Insomnia, Sedation, Dizziness. Convulsion and headache occur more frequently in patients with cerebral spasticity.
Uncommon:	Ataxia, Hypothermia, Dysphagia, Memory impairment, Nystagmus.
Eye disorders
Common:	Accommodation disorders with vision blurred or 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, Bradypnoea.
Gastrointestinal disorders
Common:	Vomiting, Constipation, Diarrhoea, Nausea, Dry mouth, Salivary hypersecretion. Nausea and vomiting occur more frequently in patients with cerebral spasticity
Uncommon:	Ileus, Hypogeusia.
Skin and subcutaneous tissue disorders
Common:	Urticaria, Pruritus.
Uncommon:	Alopecia, Hyperhidrosis.
Musculoskeletal and connective tissue disorders
Very common:	Hypotonia.
Common:	Hypertonia, Asthenia.
Not known:	Scoliosis
Renal and urinary disorders
Common:	Urinary retention, Urinary incontinence. Urinary retention occurs more frequently in patients with cerebral spasticity.
Reproductive system and breast disorders
Common:	Sexual dysfunction.
Not known:	Erectile dysfunction
General disorders and administration site conditions
Common:	Oedema peripheral, Face oedema, Pain, Pyrexia, Chills.
Rare:	Life-threatening withdrawal symptoms due to drug delivery failure

A reliable causal connection between the observed adverse events and the administration of intrathecal 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.

Seizures, headache, nausea, vomiting and urinary retention occur more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin.

Ovarian cysts have been found by palpation in about 5% 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 medicinal product. Ovarian cysts are known to occur spontaneously in a proportion of the normal female population.

Adverse events due to the infusion 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, Website: or search for MHRA Yellow Card in the Google Play or Apple App Store.

• 4.9 Overdose

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

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 during reintroduction of baclofen after an interruption of therapy.

Signs of overdose may appear suddenly or insidiously.

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 intrathecal baclofen.

Symptoms of overdose: excessive muscular hypotonia, light-headedness, dizziness, somnolence, sedation, convulsions, loss of consciousness, hypothermia, excessive salivation, nausea and vomiting.

Respiratory depression, apnoea and coma occur in the event of a major overdose. Seizures may occur with increasing dosage or, more commonly, during recovery from an overdose.

Treatment

There is no specific antidote for the treatment of overdosing with baclofen. In general, the following steps should be undertaken:

• Residual intrathecal baclofen solution should be removed from the pump as soon as possible.
• Patients with respiratory depression should be intubated if necessary until baclofen is eliminated.
• If lumbar puncture is not contraindicated, 30 to 40 ml of CSF may be drawn off in the early stage of intoxication in order to reduce the concentration of baclofen in the CSF.
• Maintenance of cardiovascular function.
• If spasms occur, diazepam intravenous should be administered carefully.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: Musculo-skeletal system; Muscle-relaxants, centrally acting agents; other centrally acting agents

ATC code: M03BX01

Mechanism of action

The precise mechanism of action of baclofen as a muscle relaxant and antispasticity medicinal product is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABA receptors. Baclofen is a chemical analogue of the inhibitory neurotransmitter gammaaminobutyric 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 patient mobility, providing them with greater autonomy, and facilitates physiotherapy. In humans, as well as in animals, baclofen has been shown to have general depressant properties on the central nervous system, causing sedation, somnolence, and respiratory and cardiovascular depression. In addition, a dose-dependent inhibitory effect on male erectile function due to stimulation of the GABA receptor has been demonstrated.

Intrathecal bolus

The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately 4 hours after dosing and effects may last 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

Intrathecal baclofen's an­tispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours.

• 5.2 Pharmacoki­netic properties

When considering the pharmacokinetic data on baclofen intrathecal, 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.

Baclofen when introduced directly into the intrathecal space permits effective CNS concentrations to be achieved with resultant plasma concentrations at least 100 times lower than those occurring with oral administration.

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.

During continuous intrathecal infusion of daily doses between 95 to 190 microgram, 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 medicinal product's action on the brain centres.

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. During intrathecal infusion the plasma concentrations do not exceed 5 ng/ml, confirming that baclofen passes only slowly across the blood-brain barrier.

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 ranges from 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 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.

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 patients 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 active substance 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.

Following 3 months intrathecal infusion in sheep, a mild inflammatory mass was observed during histopathological examination without resulting in any clinical observations.

Genotoxicity and carcinogenicity

In vivo and in vitro genotoxicity tests have shown no mutagenic effect.

A 2-year study in rats (oral route) has shown that baclofen is not carcinogenic. This study showed a dosedependent 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.

Reproduction toxicity

Baclofen had no effect on the fertility of female rats. Possible effects on male fertility have not been investigated. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Orally administered baclofen has been shown to increase the incidence of omphaloceles (ventral hernias) in foetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not observed in mice or rabbits.

Oral baclofen has been shown to delay foetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat foetuses at a high intraperitone­al dose.

Intrathecal baclofen is unlikely to have adverse effects on prenatal or postnatal development based on oral studies in rats.

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Sodium chloride

Water for injections

• 6.2 Incompati­bilities

Glucose 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

3 years

After first opening: the product should be used immediately.

• 6.4 Special precautions for storage

Do not store above 30°C.

Do not freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

• 6.5 Nature and contents of container

Clear, colourless pre-filled syringes of glass type I (Ph. Eur.). Stoppers are made from halobutyl rubber. Each syringe is packed into a plastic tray (intermediate packaging).

Pack size

1 pre-filled syringe of 20 ml.

• 6.6 Special precautions for disposal and other handling

Each syringe is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The medicinal product and fluid pathway are sterile; the outside of the syringe is not sterile.

• 7. MARKETING AUTHORISATION HOLDER

Piramal Critical Care Limited

Suite 4, Ground Floor

Heathrow Boulevard – East Wing, 280 Bath Road, West Drayton

UB7 0DQ

United Kingdom

Tel : 00441670562400

• 8. MARKETING AUTHORISATION NUMBER(S)

PL 37071/0010

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 15/01/2016

Date of latest renewal: 13/03/2020

• 10. DATE OF REVISION OF THE TEXT

Black

16. 50 inch