Consumer medicine information

Sintetica Baclofen Intrathecal

Baclofen

BRAND INFORMATION

Brand name

Sintetica Baclofen Intrathecal

Active ingredient

Baclofen

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sintetica Baclofen Intrathecal.

What is in this leaflet

Please read this leaflet carefully before you are given Sintetica Baclofen Intrathecal.

This leaflet answers some common questions about Sintetica Baclofen Intrathecal. It does not contain all the available information. The most up-to-date Consumer Medicine Information can be downloaded from www.ebs.tga.gov.au.

Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of giving you Sintetica Baclofen Intrathecal against the benefits this medicine is expected to have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What Sintetica Baclofen Intrathecal is used for

Sintetica Baclofen Intrathecal is used to reduce tension in your muscles which causes spasms. These spasms happen in various illnesses such as multiple sclerosis, cerebral palsy and other diseases or injuries of the spinal cord or brain.

Because this medicine reduces spasms and the pain that goes with them, it helps to make you more mobile. This helps you to manage your daily activities and makes physiotherapy easier.

Sintetica Baclofen Intrathecal belongs to a group of medicines called muscle relaxants. It contains the active ingredient, baclofen, in a solution for injection or infusion. It is used when medicines taken by mouth do not work well enough or when they cause too many side effects.

The solution in the ampoule is injected into your back (spinal canal) using a special pump. From the pump, a constant amount of baclofen goes into the space surrounding your spinal cord through a tiny tube.

This medicine can be used for adults and for children aged four years or older.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor if you have any questions about why it has been prescribed for you.

Sintetica Baclofen Intrathecal is only available with a doctor's prescription. Sintetica Baclofen Intrathecal is not addictive.

Before you are given Sintetica Baclofen Intrathecal

Sintetica Baclofen Intrathecal is not suitable for everyone.

When you must not be given it

You must not be given Sintetica Baclofen Intrathecal if you have epilepsy not controlled by treatment, e.g. if you continue to have fits or convulsions despite medication.

You must not be given Sintetica Baclofen Intrathecal if you are allergic to any medicine containing baclofen or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include hives or an itchy skin rash, flushing of the face, swelling of the face, lips or tongue, faintness, tight feeling in the chest, wheezing or difficulty breathing.

Sintetica Baclofen Intrathecal must not be used after the expiry date (EXP) printed on the pack, or if the packaging is torn or shows signs of tampering. The solution must be clear before use.

If you are not sure whether you should be given Sintetica Baclofen Intrathecal, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to any other medicines, foods, preservatives or dyes.

Get urgent medical help if you observe that your implanted device is not working and you also notice withdrawal symptoms (see "If the medicine must be stopped").

Tell your doctor if you have or have had any medical conditions, especially the following:

  • an infection of any kind
  • schizophrenia or other mental illness, especially if it makes you feel confused at times
  • Parkinson’s disease
  • seizures due to epilepsy or any other reason
  • autonomic dysreflexia, an emergency condition associated with extremely high blood pressure, intense headaches, profuse sweating, blurred vision and other symptoms
  • problems with blood flow to the brain
  • heart or lung disease
  • kidney disease
  • liver disease
  • breathing problems
  • stomach ulcer now or at any time in the past
  • thoughts of suicide or self harm at any time. Speak to your doctor immediately or go to the Emergency Department of the nearest hospital for help. Ask your family, a friend or carer to monitor your behaviour and tell you if they are worried about any changes in your behaviour. Ask them to read this leaflet.

Your doctor may need to do tests, e.g. spinal imaging, before treating you with Sintetica Baclofen Intrathecal to check if there is any reason you should not be given it.

Tell your doctor if you are pregnant or breastfeeding. There are no studies using Sintetica Baclofen Intrathecal in women who are pregnant or breastfeeding. Your doctor will discuss the possible risks and benefits of you being given Sintetica Baclofen Intrathecal during pregnancy and breastfeeding.

Tell your doctor if you are over 65 years old. Elderly persons may be more sensitive to side effects which your doctor can manage by changing the dose gradually.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given Sintetica Baclofen Intrathecal.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Tell any healthcare professional who is prescribing a new medicine for you that you are using Sintetica Baclofen Intrathecal.

Some medicines and Sintetica Baclofen Intrathecal may interfere with each other. These include:

  • levodopa, carbidopa and other similar medicines known as DDC inhibitors (used to treat Parkinson’s disease)
  • general anaesthetics used to put you to sleep during surgery, such as fentanyl and propofol
  • morphine or other opiates, used to control pain
  • some antidepressants, known as tricyclics
  • medicines used to treat high blood pressure
  • benzodiazepines, used to treat anxiety, insomnia, seizures or muscle spasms
  • any medicine or drug which affects the Central Nervous System (brain or spinal cord).

The above medicines may be affected by Sintetica Baclofen Intrathecal, or may affect how well it works. You may need different amounts of Sintetica Baclofen Intrathecal or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using Sintetica Baclofen Intrathecal.

How Sintetica Baclofen Intrathecal is given

How it is given

This medicine can only be given by experienced doctors using special medical equipment. You will need to stay in hospital, at least at the beginning of treatment.

Your doctor will inject a small amount of Sintetica Baclofen Intrathecal into your spinal canal to see if it improves your muscle spasms.

If it does, then a special pump will be implanted under the skin of your abdomen. The pump will give you a small amount of medicine all the time.

You will be monitored closely in a fully equipped and staffed environment after the first injection and following pump implant. You will be assessed after each change of dose for possible side effects or evidence of infection. The functioning of the pump will also be checked.

You or the person caring for you will be shown how to look after the pump at home and how to keep the skin where it has been implanted free from infection.

How much will be given

Your doctor will decide how much Sintetica Baclofen Intrathecal you will be given. It may take several days to find the amount of medicine that suits you best. Your doctor will keep a close watch on you during this time.

After that, your doctor will still want to see you regularly to check your progress and make sure your pump is working well.

This dose will depend on your condition and how your body responds to the treatment. It is usually between 276-800 micrograms a day. Children under 12 years of age usually require lower doses than older patients.

Ask your doctor or pharmacist if you would like more information about how your dose is managed.

How often you will be given it

Your doctor will work out how often you need to return to have the pump filled with additional Sintetica Baclofen Intrathecal before it runs out. It is important that the pump not be allowed to run out because you can have a serious reaction if you stop treatment suddenly.

Follow closely the instructions given to you by the hospital staff and discuss with your doctor first before changing any of your treatment appointments.

If the medicine must be stopped

If this medicine must be stopped for any reason, your doctor will reduce the dose gradually to avoid unwanted side effects. Suddenly stopping Sintetica Baclofen Intrathecal or rapidly reducing the dose can cause serious side effects which in a few rare cases have been fatal.

Do not stop Sintetica Baclofen Intrathecal suddenly or allow the pump to run out of medicine. If it should happen, tell your doctor immediately and watch out for the symptoms listed below. These symptoms can lead to more severe side effects unless treated immediately.

Stopping this medicine suddenly may cause:

  • severe and uncontrolled muscle spasms
  • difficulty in muscle movements
  • dizziness or light-headedness due to low blood pressure
  • severe itching and numbness or tingling in hands and feet
  • convulsions (seizures)
  • persistant painful erection of the penis (priapism)
  • high fever
  • altered mental conditions, for example anxiety, agitation, confusion, hallucination, abnormal thinking and behaviour or convulsions (seizures), persistent
  • painful erection of the penis (priapism) and infection (sepsis).
  • Problems with the pump, for example, due to battery problems, catheter problems, alarm dysfunction or device malfunctions may also cause withdrawal symptoms.
  • If you have any of the above signs, tell your doctor immediately. These signs may be followed by more serious side effects (including death) unless you are treated immediately.

While you are using Sintetica Baclofen Intrathecal

Things you must do

Follow your doctor's instructions carefully. Make sure the pump and the site where the pump was inserted are looked after properly. If not, the pump may not work properly or you could get a serious skin infection. If you’re not sure what to do, or if you’re not sure if there’s a problem, talk to your doctor.

Keep all of your doctor’s appointments so that your medicine can be refilled and your progress can be checked. It is very important that your pump is refilled before your medicine runs out as it is not safe to stop treatment suddenly. Also, your doctor needs to check on your progress to make sure you are on the right dose.

See your doctor if you feel that your condition is not improving or is getting worse. Your dose may need adjusting or there might be a problem with the pump.

If any adjustments to the pump are needed, including to the pump flow rate (dose), make sure this is supervised by a doctor. Errors in adjusting the pump can lead to serious side effects.

If your muscle spasms come back, either suddenly or gradually, tell your doctor. Your doctor may be able to change the dose of Sintetica Baclofen Intrathecal to make it work better for you.

Tell your doctor immediately if you have pain in your back, shoulders, neck and buttock during treatment.

See your doctor immediately if your condition is worsening and you experience unusual itching, dizziness, light-headedness or tingling in the hands or feet. There may be a problem with the pump that is stopping you getting your medicine. This can be life-threatening and you may need immediate medical attention.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are using Sintetica Baclofen Intrathecal. Likewise, tell any other doctors, dentists and pharmacists who are treating you that you are being given this medicine.

If you are going to have surgery, tell the surgeon and anaesthetist that you are using this medicine. It may affect other medicines used during surgery.

If you become pregnant while using this medicine, tell your doctor immediately.

Things you must not do

Do not stop Baclofen Sintetica Intrathecal suddenly. See "If the medicine must be stopped" for more information.

Do not give this medicine to anyone else, even if their symptoms seem to be the same as yours.

Things to be careful of

Be careful driving or operating machinery until you know how Sintetica Baclofen Intrathecal affects you. It may cause sleepiness, dizziness, problems with coordination or vision, and hallucinations in some people. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you feel less alert. If you drink alcohol, or take strong pain killers or barbiturates, the effects may be worse.

Be careful drinking alcohol until you know how Sintetica Baclofen Intrathecal affects you. Alcohol may have a greater effect on you if you are being treated with Sintetica Baclofen Intrathecal. You may feel more sleepy or dizzy than usual.

Be careful on stairs and uneven surfaces to avoid falling. Sintetica Baclofen Intrathecal works by reducing muscle tone. It may cause weakness and affect reflexes and coordination. Talk to your doctor if you are having problems as they may need to change your dose.

In case of overdose

If you are given too much

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you may have been given too much Sintetica Baclofen Intrathecal.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

People vary in their sensitivity to Sintetica Baclofen Intrathecal. Some people may have signs of overdose at doses that are safe for other people.

Take care particularly at the start of treatment, after a dose change or after restarting treatment if you have had a break. It is very important that you and those caring for you know the signs of overdose that can happen. Symptoms of an overdose may include extreme weakness, unusual drowsiness, light-headedness, dizziness, sleepiness, excessive saliva, nausea or vomiting. More severe symptoms include fits, difficulty breathing, slow heartbeat, loss of consciousness, coma and death.

Signs of overdose may happen suddenly or more slowly (for example, because the pump is not working properly).

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Sintetica Baclofen Intrathecal.

Like all medicines, Sintetica Baclofen Intrathecal may occasionally cause side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Some side effects could be associated with the delivery system.

Ask your doctor or pharmacist to answer any questions you may have. Tell your doctor if you notice any of the following and they worry you:

  • drowsiness, tiredness or lack of energy
  • dizziness or feeling light-headed
  • headache
  • feeling sick or vomiting
  • loss of appetite, weight loss
  • constipation
  • numbness or tingling in the hands and feet
  • muscle weakness, spasms or pain or change in muscle tone
  • problems with coordination and balance
  • slurred speech
  • blurred or double vision
  • feeling anxious, confused, disorientated or unable to sleep
  • problems with concentration or memory
  • dry mouth, decreased sense of taste
  • diarrhoea
  • increase in saliva
  • problems with sexual function
  • hair loss.

Tell your doctor immediately if you notice any of the following:

  • slow or difficult breathing, or chest tightness, pain or congestion
  • fever, chills or other signs of infection, pneumonia
  • swelling of the face, ankles, feet or lower legs
  • pain, numbness or heavy feeling in the legs
  • unusually slow heart beat
  • seizures (fits)
  • depression or other severe mood or mental disorders (paranoia)
  • difficulty in swallowing
  • rash or itching of skin
  • continuous uncontrollable eye movements
  • loss of bladder (urine) control or other bladder problems
  • severe vomiting, diarrhoea or constipation
  • increase in sideways curvature of the spine (a type of spinal deformity called scoliosis)
  • feeling of extreme happiness (euphoria)
  • confusion, disorientation
  • suicidal ideas and suicide attempt
  • hallucinations
  • extreme sleepiness

The above side effects could be serious. You may need medical attention.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After being given Sintetica Baclofen Intrathecal

Storage

Sintetica Baclofen Intrathecal will be stored in the pharmacy or on the ward under the recommended storage conditions.

It must be kept in a cool dry place, protected from light, where the temperature stays below 25°C. Do not refrigerate or freeze.

Disposal

Any Sintetica Baclofen Intrathecal which has passed its expiry date, or is left in the container after use, will be disposed of in a safe manner by your doctor, nurse or pharmacist.

Product description

What it looks like

Sintetica Baclofen Intrathecal is a clear, colourless solution for injection or infusion. It is available in clear glass ampoules in the following sizes:

  • 1 mL containing 50 microgram baclofen – 10 ampoules in each pack
  • 5 mL containing 10 mg baclofen – 1 ampoule and 10 ampoules in each pack
  • 20 mL containing 10 mg baclofen – 1 ampoule in each pack
  • 20 mL containing 40 mg baclofen – 1 ampoule in each pack.

Not all presentations may be marketed.

Ingredients

Active ingredient:

  • baclofen

Inactive ingredients:

  • sodium chloride
  • water for injections.

Sponsor details

Boucher & Muir Pty Ltd
Level 9, 76 Berry Street
North Sydney NSW 2060
Ph: 1800 627 680

Sintetica Baclofen Intrathecal:

50 microgram/1 mL: AUST R 271172

10 mg/20 mL: AUST R 271173

10 mg/5 mL: AUST R 271174

40 mg/20 mL: AUST R 271175

Date of preparation

This leaflet was prepared on 17 November 2020.

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Sintetica Baclofen Intrathecal

Active ingredient

Baclofen

Schedule

S4

 

1 Name of Medicine

Baclofen.

2 Qualitative and Quantitative Composition

Sintetica Baclofen Intrathecal contains 50 microgram baclofen per 1 mL ampoule (50 microgram/mL), 10 mg baclofen per 20 mL ampoule (500 microgram/mL), 10 mg baclofen per 5 mL ampoule (2 mg/mL) and 40 mg baclofen per 20 mL ampoule (2 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sintetica Baclofen Intrathecal is a solution for intrathecal injection and intrathecal infusion. It is a clear, colourless solution.
Sintetica Baclofen Intrathecal does not contain preservatives.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Sintetica Baclofen Intrathecal 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 solution into the intrathecal space.
For patients with spasticity due to head injury, it is recommended not to proceed to long-term Sintetica Baclofen Intrathecal therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).
Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with test doses by intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. This is due to the great variability in the effective individual therapeutic dose.
Patients must be monitored closely in a fully equipped and staffed environment during the screening phase and dose-titration period immediately following implant. Resuscitative equipment should be available for immediate use in case of life-threatening or intolerable adverse reactions. Implantation of pumps should only be performed by experienced clinicians in properly equipped centres in order to minimise the risks in the perioperative phase (see Section 4.4 Special Warnings and Precautions for Use).
Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implanting, programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to.

Screening phase.

Prior to initiation of chronic infusion of intrathecal baclofen, patients must demonstrate a response to an intrathecal bolus of baclofen in a screening trial. A bolus test dose of baclofen is usually administered via a lumbar puncture or an intrathecal catheter to elicit a response. In adults, the usual initial test dose is 25 microgram or 50 microgram and is stepped up by 25 microgram increments at least 24 hours apart, until a response lasting approximately 4 to 8 hours is observed; the dose should be given by barbotage over at least one minute. In children, the recommended initial test dose is 25 microgram. For the test dose, low concentration ampoules of 50 microgram/mL are available.
The first dose should be performed with resuscitative equipment on stand-by. Patients should demonstrate a significant decrease in muscle tone and/or frequency and/or severity of spasms in order to be considered responders to treatment.
There is great variability in sensitivity to intrathecal baclofen. Signs of severe overdose (coma), have been observed in an adult patient after a single test dose of 25 microgram.
Patients who do not respond to a 100 microgram test dose should not be given further increases of the dose or be considered for continuous intrathecal infusion.

Dose titration phase.

After confirmation that the patient is responsive to intrathecal baclofen by means of bolus test doses, intrathecal infusion is established using a suitable delivery system.
To determine the initial total daily dose of intrathecal baclofen following implant, the screening dose which gave a positive effect should be doubled and administered over a 24 hour period, unless the efficacy of the bolus dose was maintained for more than 12 hours. In this case the starting daily dose should be the screening dose delivered over a 24 hour period. No dose increases should be administered in the first 24 hours.

Patients with spasticity of spinal origin.

After the first 24 hours, the dosage should be adjusted slowly on a daily basis to achieve the desired clinical effect, with dosage increments limited to 10-30% to avoid possible overdosing.

Patients with spasticity of cerebral origin.

After the first 24 hours, the dosage should be adjusted slowly on a daily basis to achieve the desired clinical effect, with dosage increments limited to 5-15% to avoid possible overdosing.
With programmable pumps, the dose should be increased only once every 24 h. For non-programmable pumps with a 76 cm catheter delivering 1 mL/day, intervals of 48 hours are suggested for evaluation of response. If the daily dose has been substantially increased and no clinical effect is achieved, check for proper pump function and catheter patency.
There is limited experience with doses greater than 1000 micrograms/day.

Maintenance therapy.

The clinical goal is to maintain muscle tone as close to normal as possible and to minimise the frequency and severity of spasms without inducing intolerable side effects, or to titrate the dose to the desired degree of muscle tone for optimal function when patients with cerebral spasticity are treated. The lowest dose producing an adequate response should be used.

Patients with spasticity of spinal origin.

The daily dose may be gradually increased in steps of 10-30% to maintain adequate symptom control by adjusting the dosing rate of the pump and/or the concentration of baclofen in the reservoir. The daily dose may also be reduced by 10-20% if patients experience side effects.

Patients with spasticity of cerebral origin.

The daily dose may be gradually increased by 5-20%, but no more than 20%, to maintain adequate symptom control by adjusting the dosing rate of the pump and/or the concentration of baclofen in the reservoir. The daily dose may also be reduced by 10-20% if patients experience side effects.
A sudden requirement for substantial dose escalation suggests a catheter complication (i.e. catheter kink or dislodgement) or pump malfunction.
Most patients require gradual increases in dose over time to maintain optimum response during chronic therapy due to decreased responsiveness to therapy or due to disease progression.
Maintenance dosage for long-term continuous infusion of intrathecal baclofen in patients with spasticity of spinal origin ranges from 10 microgram/day to 1200 microgram/day, most patients being adequately maintained on 300-800 microgram/day.
In patients with spasticity of cerebral origin, the maintenance dosage for long-term continuous infusion of intrathecal baclofen ranges from 22 microgram/day to 1400 micrograms/day, with a mean daily dose of 276 microgram/day at 12 months and 307 microgram/day at 24 months. Paediatric patients under twelve years of age generally require lower dosages than do older patients; the dose ranges from 24-1199 microgram/day, with a mean daily dose of 274 microgram/day.
Regular clinical review remains necessary throughout, to assess dosage requirements, functioning of the delivery system, and to watch for possible adverse drug reactions or evidence of infection.

Delivery regimen.

Intrathecal baclofen is most often administered in a continuous infusion mode immediately after pump implantation. However, after the patient has stabilised with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimise control of spasticity at different times of the day. For example, patients who have greater spasm at night may require a 20% increase in their hourly infusion rate. Changes in flow rate should be programmed to start two hours before the time of desired clinical effect.

Development of tolerance.

During long-term treatment approximately 5% of patients become refractory to increasing doses. There is not sufficient experience to make firm recommendations for management of tolerance. After a few days cessation of baclofen the sensitivity to baclofen may be restored. Treatment should be resumed at the initial continuous infusion dose, followed by a titration phase to avoid accidental overdose. This must be performed in a hospital unit (see Section 4.4 Special Warnings and Precautions for Use, Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction)). Caution should be exercised when switching from Sintetica Baclofen Intrathecal to morphine and vice versa (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Special populations.

Renal impairment.

No studies have been performed in patients with renal impairment with Sintetica Baclofen Intrathecal 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 (see Section 4.4 Special Warnings and Precautions for Use).

Instructions for use/handling.

Ampoule specifications.

Sintetica Baclofen Intrathecal is intended for intrathecal injection and continuous intrathecal infusion. Each ampoule is intended for single use in one patient only. Discard any unused portion. Do not freeze. Do not heat-sterilise.
Sintetica Baclofen Intrathecal contains no preservatives. To reduce microbiological hazard use as soon as practicable after opening.
Sintetica Baclofen Intrathecal ampoules containing 50 microgram/mL are available for administering low dose bolus injections during the screening phase.
Sintetica Baclofen Intrathecal ampoules containing 10 mg/5 mL, 10 mg/20 mL and 40 mg/20 mL are available for use with infusion pumps. The concentration chosen for use depends upon the total daily dose required as well as the delivery rate of the pump. Please consult the pump manufacturer's manual for specific recommendations.

Dilution instructions.

For patients who require concentrations other than 50 microgram/mL, 500 microgram/mL or 2 mg/mL, Sintetica Baclofen Intrathecal must be diluted, under aseptic conditions, with sterile preservative-free sodium chloride for injection. To reduce microbiological hazard use as soon as practicable after preparation.

Incompatibilities.

Sintetica Baclofen Intrathecal ampoules for intrathecal administration should not be mixed with other infusion or injection solutions. Glucose solutions are incompatible due to a chemical reaction with baclofen.

Pump specification.

Evidence demonstrating the efficacy of baclofen intrathecal injection was obtained in randomised, controlled investigations conducted by Medtronic, Inc., using the Medtronic SynchroMed Infusion System Model 8610 and 8611H. Additional experience was gained with the Infusaid 400 Infusion System. These devices are implantable drug delivery systems with refillable reservoirs, which are implanted in a subcutaneous pocket usually on the abdominal wall. The devices are connected to an intrathecal catheter which passes subcutaneously to the subarachnoid space.
Use of Sintetica Baclofen Intrathecal is recommended only with implantable pumps that have been approved for intrathecal use by the Therapeutic Goods Administration (TGA).

Stability of Sintetica Baclofen Intrathecal in the infusion pump.

Sintetica Baclofen Intrathecal was tested and found to be stable in the implanted Medtronic-SynchroMed II Infusion System for 180 days. The maximum time the injection solution may be held in the pump reservoir is 180 days. The pump must be completely emptied before refilling in accordance with directions provided by the pump manufacturer.
Baclofen may be used with subsequent models that the pump manufacturer specifies to be compatible with baclofen intrathecal injection and which have been approved for intrathecal use by the TGA. Parenteral drug products should be inspected for particulate matter and discolouration prior to administration whenever solution and container permit.

4.3 Contraindications

Known hypersensitivity to baclofen or to any of the excipients.
Administration by the intravenous, intramuscular, epidural or subcutaneous routes.
Epilepsy refractory to therapy.

4.4 Special Warnings and Precautions for Use

Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction).

Except in overdose-related emergencies, treatment with Sintetica Baclofen Intrathecal should always be gradually discontinued by successively reducing the dosage. Sintetica Baclofen Intrathecal should not be discontinued suddenly.
Abrupt withdrawal of intrathecal baclofen, regardless of the cause, has resulted in sequelae that included high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity that in rare cases progressed to seizures/status epilepticus, coagulopathy, rhabdomyolysis, multiple organ-system failure and death. In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of baclofen therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy.
All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension and paraesthesias. Some clinical characteristics of the advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.
Rapid, accurate diagnosis and treatment in an emergency-room or intensive-care setting are important in order to prevent the potentially life-threatening central nervous system (CNS) and systemic effects of intrathecal baclofen withdrawal. 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. Seizures have been reported during overdose and with withdrawal from baclofen intrathecal injection as well as in patients maintained on therapeutic doses of baclofen intrathecal injection.
Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir and device malfunction and end of pump battery life. Device malfunction resulting in altered drug delivery leading to withdrawal symptoms including death has been reported. Human error may have played a causal or contributing role in some cases. Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to proper programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal (e.g. priapism). Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional post-implant clinician and patient information.

Safety considerations during use.

It is mandatory that the patient, the physicians responsible for the patient, and all those involved in the care of the patient receive adequate information about the risks of this mode of treatment. Physicians must be adequately trained in chronic intrathecal infusion therapy. Everyone concerned with the treatment and care of the patient should be instructed on the signs and symptoms of overdose, procedures to be followed in the event of overdose, and proper home care of the pump and insertion site.
For patients with spasticity due to head injury, it is recommended not to proceed to long-term Sintetica Baclofen Intrathecal therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).

Screening phase.

The pump system should not be implanted until the patient's response to bolus intrathecal baclofen injection and/or dose titration is adequately evaluated and found to be clinically safe and effective. Because of the risks associated with the initial administration and titration of intrathecal baclofen (CNS depression, cardiovascular collapse and/or respiratory failure), these steps must be conducted in a medically supervised and adequately equipped environment, following the instructions outlined (see Section 4.2 Dose and Method of Administration). The preliminary screening phase should be performed in a hospital and implantation of the pump system should be undertaken only in specialist units. Resuscitative equipment should be available for immediate use in case of life-threatening symptoms of severe overdose.
Careful monitoring of respiratory and cardiovascular functions is essential during administration of the initial test doses (screening phase), especially in patients with cardiopulmonary disease and respiratory muscle weakness as well as those being treated concomitantly with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depression.
Patients should be infection-free prior to the screening trial with Sintetica Baclofen Intrathecal because the presence of a systemic infection may interfere with an assessment of the patient's response to bolus intrathecal baclofen.
Before use of the drug, myelography of the subarachnoid space should be performed in patients with post-traumatic spasticity. If signs of arachnoiditis are detected, treatment should not be given.

Pump implantation and use.

Intrathecal administration of Sintetica Baclofen Intrathecal through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience in properly equipped centres in order to minimise the risks in the perioperative period. Specific instructions for implanting, programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to.
Patients should be infection-free prior to pump implantation because the presence of infection 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 Sintetica Baclofen Intrathecal withdrawal and its related symptoms (see Section 4.4 Special Warnings and Precautions for Use, Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction)).

Reservoir refilling.

Reservoir refilling must be performed by qualified and fully trained personnel following the directions provided by the pump manufacturer. Strictly aseptic filling is required to avoid microbial contamination and serious infection.
Refill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity or potentially life-threatening symptoms of withdrawal (see Section 4.4 Special Warnings and Precautions for Use, Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction)). The maximum time the injection solution may be held in the pump reservoir is 180 days (see Section 4.2 Dose and Method of Administration, Stability of Sintetica Baclofen Intrathecal in the infusion pump). The pump must be completely emptied before refilling in accordance with directions provided by the pump manufacturer.
Extreme caution must be used when filling an implantable pump equipped with an injection port that allows direct access to the intrathecal catheter. Direct injection into the catheter through the access port may cause a life-threatening overdose.

Patient monitoring after pump implantation.

Following surgical implantation of the pump, particularly during the initial phases of use and on each occasion that the dosing rate of the pump and/or the concentration of baclofen in the reservoir is adjusted, the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.

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 with baclofen intrathecal injection. Studies in animal models have demonstrated that the intrathecal infusion of some opioids can readily induce formation of an inflammatory mass, especially with high doses and/or high concentrations. However, limited experimental data in dogs suggest that intrathecal baclofen as a sole agent does not induce an inflammatory mass. 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.

Scoliosis.

The onset of scoliosis or worsening of a pre-existing scoliosis has been reported in patient treated with baclofen intrathecal. Signs of scoliosis should be monitored during treatment with Sintetica Baclofen Intrathecal.

Additional considerations pertaining to dosage adjustment.

In order to prevent excessive weakness and falling, Sintetica Baclofen Intrathecal should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion or whenever spasticity is used to obtain optimal function and care. It may be important to maintain some degree of muscle tone and allow occasional spasms to help support circulatory function and possibly prevent the formation of deep vein thrombosis.

Withdrawal of oral antispastic medication.

An attempt should be made to discontinue concomitant oral antispastic medication to avoid possible overdose or adverse drug interactions. This should preferably be done before initiating baclofen infusion and requires careful monitoring by the physician. Abrupt reduction or discontinuation of concomitant antispastics during chronic intrathecal therapy with baclofen should be avoided.

Precautions in special patient populations.

In patients with abnormal CSF flow the distribution of baclofen and its antispastic activity may be inadequate.
Patients suffering from psychotic disorders, schizophrenia, confusional states or Parkinson's disease should be treated cautiously with intrathecal baclofen and kept under careful surveillance because exacerbations of these conditions have been observed with oral baclofen administration.
Close supervision of patients with additional risk factors for suicide should accompany therapy with Sintetica Baclofen Intrathecal. Patients (and caregivers of patients) should be alerted about the need to monitor clinical worsening, suicidal behaviour or thoughts, or unusual changes in behaviour and seek medical advice immediately if these symptoms present (see Section 4.8 Adverse Effects (Undesirable Effects)).
Special attention should be given to patients known to suffer from epilepsy or with a history of seizures, since seizures have been reported occasionally during overdose with, or withdrawal from, intrathecal baclofen, as well as in patients maintained on therapeutic doses of intrathecal baclofen.
Intrathecal baclofen should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli on abrupt withdrawal of Sintetica Baclofen Intrathecal may cause an autonomic dysreflexic episode (see Section 4.4 Special Warnings and Precautions for Use, Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction)).
Intrathecal baclofen should be used with caution in patients with cerebrovascular or respiratory insufficiency as these conditions may be exacerbated by baclofen.
An effect of intrathecal baclofen on underlying, non-CNS related diseases is unlikely because the systemic availability of the drug after intrathecal administration is substantially lower than after oral administration. Nevertheless, observations after oral baclofen therapy suggest that caution should be exercised in the following situations: history of peptic ulcers, pre-existing sphincter hypertonia, impaired renal function. In rare instances elevations of aspartate aminotransferase (AST), alkaline phosphatase and glucose in the serum have been recorded when using oral baclofen.

Use in renal impairment.

After oral baclofen dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering Sintetica Baclofen Intrathecal in patients with renal impairment.

Use in the elderly.

Several patients over the age of 65 years have been treated with intrathecal baclofen during the clinical trials without specific problems. Elderly patients may be more susceptible to the side effects of oral baclofen in the titration stage and this may also apply to intrathecal baclofen. However, as doses are individually titrated, there is not likely to be a particular problem in treating elderly patients.

Paediatric use.

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. There are very limited clinical data on the use of intrathecal baclofen in children under age six. The safe use of intrathecal baclofen in children under the age of four has not yet been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions.

Anticipated interactions resulting in concomitant use not being recommended.

Levodopa/DDC (DOPA decarboxylase) inhibitor.

Concomitant use of oral baclofen and levodopa/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. Therefore, in patients with Parkinson's disease receiving treatment with baclofen and levodopa plus DDC inhibitor (e.g. carbidopa), adverse events, such as mental confusion, hallucinations and agitation may occur. Thus, caution should be exercised when Sintetica Baclofen Intrathecal is administered to patients receiving levodopa/DDC inhibitor therapy.

Observed interactions to be considered.

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 Sintetica Baclofen Intrathecal.

Anticipated interactions to be considered.

The co-administration of other intrathecal agents with intrathecal baclofen has not been tested and its safety is unknown.

Morphine.

The combined use of intramuscular morphine and intrathecal baclofen was responsible for hypotension in one patient. The potential for this combination to cause dyspnoea or other CNS symptoms cannot be excluded.

Alcohol and other compounds affecting the CNS.

The central nervous system depressant effects of alcohol and other compounds affecting the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) may be additive to the effects of baclofen.

Tricyclic antidepressants.

When using oral baclofen, concurrent treatment with tricyclic antidepressants may potentiate the effect of baclofen, resulting in pronounced muscular hypotonia. Caution is advised when using Sintetica Baclofen Intrathecal in this combination.

Antihypertensives.

Since concomitant treatment with oral baclofen and antihypertensives is likely to increase the fall in blood pressure, it may be necessary to monitor blood pressure and adjust the dosage of antihypertensive medication accordingly.
Please see Section 6.2 Incompatibilities.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data available on the effect of baclofen on fertility in humans.
(Category B3)

Risk summary.

There are limited data on the use of intrathecal baclofen in pregnant women. After intrathecal administration of baclofen intrathecal, small amounts of baclofen can be detected in maternal plasma (see Section 5.2 Pharmacokinetic Properties). Animal data showed that baclofen can cross the placental barrier. Therefore, Sintetica Baclofen Intrathecal should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus.

Animal data.

In two teratogenic studies in pregnant rats, baclofen has been shown to increase the incidence of omphalocoeles (ventral hernias) in foetuses, at a dose of 20 mg/kg/day, which is maternotoxic. The relevance of this finding to humans is unknown. At the same dose there was also an increased incidence of incomplete sternebral ossification in the foetuses.
In mice, no teratogenic effects were observed at a dose of 81.5 mg/kg/day given via the diet or up to 40 mg/kg/day given by gavage. At 40 mg/kg/day by gavage, a delay in foetal growth was associated with maternal anorexia. The lack of maternotoxicity seen in the dietary study suggests that the dose used was inadequate.
Likewise, maternally given oral doses, up to 10 mg/kg/day to pregnant rabbits, were devoid of teratogenic effects. Maternotoxicity was manifested as a sedative effect. Skeletal examination of foetuses revealed a marked increase in the absence of ossification of the phalangeal nuclei of fore-limbs and hind-limbs.
There are no studies in pregnant women.
 In lactating mothers taking oral baclofen in therapeutic doses, the active substance passes into the milk, but in quantities so small that no undesirable effects on the infant are to be expected.
It is not known if detectable levels of drug are present in the milk of nursing mothers receiving intrathecal baclofen.

4.7 Effects on Ability to Drive and Use Machines

CNS depressant effects such as somnolence and sedation have been reported in some patients receiving intrathecal baclofen. Other listed events include ataxia, hallucinations, diplopia and withdrawal symptoms. Patients should be cautioned regarding the operation of automobiles or other dangerous machinery, and activities made hazardous by decreased alertness.

4.8 Adverse Effects (Undesirable Effects)

Some of the adverse events listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse events that are more frequent in either population are indicated in Tables 1 and 2.

Tabulated summary of adverse drug reactions from clinical trials.

Clinical trials in patients with spasticity of spinal origin. Adverse experiences reported during US studies (both controlled and uncontrolled) are shown in Table 1. None of these adverse experiences led to discontinuation of treatment.
Clinical trials in patients with spasticity of cerebral origin. Adverse experiences reported during US studies (both controlled and uncontrolled) are shown in Table 2. Nine patients discontinued long-term treatment due to adverse events.
A causal link between events observed and the administration of baclofen cannot be reliably assessed in many cases, since many of the adverse events reported are known to occur in association with the underlying conditions being treated. Nevertheless, some of the more commonly reported reactions: drowsiness/ somnolence, dizziness, headache, nausea, hypotension, hypotonia - appear to be drug-related.
Some of the adverse events listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse events that are more frequent in either population are indicated below.
Adverse events are listed by MedDRA system organ class. The corresponding frequency category is also provided for each adverse drug reaction: very common ≥ 1/10; common ≥ 1/100, < 1/10; uncommon ≥ 1/1,000, < 1/100; rare ≥ 1/10,000, < 1/1,000); very rare < 1/10,000), including isolated reports.

Central nervous system.

Very common: drowsiness/somnolence. Common: sedation, dizziness/lightheadedness, seizures, headache, paraesthesiae, accommodation disorders/blurred vision/double vision, slurred speech, lethargy, fatigue/asthenia, difficulty concentrating, respiratory depression, insomnia, confusion, disorientation, anxiety/agitation, depression. Uncommon: hypothermia, nystagmus, dysphagia, decreased coordination/ataxia, memory loss/impairment, suicidal ideation, attempted suicide (see Section 4.4 Special Warnings and Precautions for Use), euphoria, dysphoria, hallucinations, paranoia/paranoic reaction, cerebrovascular disorders.
Seizures and headache occur more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin.

Cardiovascular system.

Common: hypotension. Uncommon: hypertension, bradycardia, deep vein thrombosis, skin flushing, paleness, collapse.

Respiratory system.

Common: dyspnoea, bradypnoea, feeling of pressure in the chest (chest tightness), pneumonia.

Gastrointestinal tract.

Common: nausea/vomiting, constipation, dry mouth, diarrhoea, decreased appetite, increased salivation. Uncommon: dehydration, ileus, decreased taste sensation. 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 oedema, peripheral oedema (swelling of lower extremities). Uncommon: alopecia, diaphoresis.

Renal and urinary system.

Common: urinary incontinence, urinary retention (sluggish bladder, bladder spasm). Urinary retention occurs more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin.

Musculoskeletal system.

Very common: muscular weakness/hypotonia, disturbances of gait and balance. Common: muscular hypertonia.

Reproduction system.

Common: sexual dysfunction.

General disorders and administration site conditions.

Common: pain, fever, chills. Uncommon: septicaemia, subdural haemorrhage, accidental injury, weight loss. Rare: life-threatening withdrawal symptoms due to drug delivery failure (see Section 4.4 Special Warnings and Precautions for Use, Abrupt discontinuation or withdrawal of Sintetica Baclofen Intrathecal therapy (including associated with catheter or device malfunction)).

Adverse events associated with the delivery system.

Inflammatory mass at the tip of the catheter, dislodgement/kink/rupture of the catheter with possible complications, infection of place of implantation, meningitis, septicaemia, pump-pocket seroma and haematoma (potential risk of inflammation), pump malfunction and CSF leakages and skin ulcers after quite some time, and overdosage or underdosage due to wrong manipulation of the device have been reported, whereby in some cases a causal relationship with baclofen cannot be excluded. Device malfunction resulting in altered drug delivery leading to withdrawal symptoms including death has been reported (see Section 4.4 Special Warnings and Precautions for Use).

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with baclofen intrathecal via spontaneous case reports and literature cases. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Musculoskeletal and connective tissue disorders.

Scoliosis (see Section 4.4 Special Warnings and Precautions for Use).

Reproductive system.

Erectile dysfunction.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Deaths due to overdose of intrathecal baclofen have been reported. Special attention must be given to recognising the signs and symptoms of overdosage at all times, especially during the initial "screening" and "dose-titration" phase of treatment but also during reintroduction of intrathecal baclofen after a period of interruption of therapy. Signs of overdose may appear suddenly or insidiously.
Serious overdose may occur for example by inadvertent delivery of catheter contents during catheter patency/ position analysis. Errors in programming, excessively rapid dose increases and concomitant treatment with oral baclofen are other possible causes of overdosage. Possible pump malfunction should also be investigated. Symptoms of severe intrathecal baclofen overdose (coma) were reported in a sensitive adult patient after receiving a 25 microgram intrathecal bolus dose.

Symptoms.

Excessive muscular hypotonia, drowsiness, light-headedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea and vomiting. Respiratory depression, bradycardia, apnoea and coma result from serious overdosage.

Treatment.

There is no specific antidote for treating overdoses of intrathecal baclofen, but the following steps should generally be undertaken.
1. Residual baclofen solution should be removed from the pump as soon as possible.
2. Patients with respiratory depression should be intubated and ventilated, if necessary, until the drug is eliminated.
3. If lumbar puncture is not contraindicated, consideration should be given, in the early stage of the intoxication, to withdrawing 30-40 mL of CSF to reduce CSF baclofen concentration.
4. Cardiovascular function should be supported.
5. In the event of convulsions, diazepam may be administered cautiously i.v.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Baclofen is an antispastic agent with a spinal site of action. Baclofen also has central sites of action given the adverse event profile. Baclofen is a racemic mixture of the R, (-) and S, (+) isomers. Experimental data indicate that the pharmacological action resides in the R, (-) isomer.
The precise mechanisms of action of baclofen as a muscle relaxant and antispastic agent are not fully understood. Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals. Actions at supraspinal sites may also contribute to its clinical effect. Baclofen is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulating GABAβ receptors. Neuromuscular transmission is not affected. 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 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 Central Nervous System (CNS) depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression. It has also been shown to have a dose-dependent inhibitory effect on erectile function in men through GABAβ receptor stimulation.
Baclofen introduced directly into the intrathecal space permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.
Intrathecal baclofen may be considered an alternative to destructive neurosurgical procedures.
There is also some limited evidence of efficacy in reducing spasms in patients with tetanus.

Clinical trials.

Spasticity of spinal origin.

Evidence supporting the efficacy of baclofen intrathecal injection was obtained in randomised, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of baclofen intrathecal injection to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Baclofen intrathecal injection was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms.

Spasticity of cerebral origin.

The efficacy of baclofen intrathecal injection was investigated in three controlled clinical trials. Two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury. The first study, a randomised controlled crossover trial of 51 patients with cerebral palsy, provided strong, statistically significant results and was considered to be the pivotal study. Baclofen intrathecal injection was superior to placebo in reducing spasticity as measured by the Ashworth scale. A second crossover study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p = 0.066) and provided directionally favourable results. The last study did not provide data that could be reliably analysed. However, data on the effects of a 50 microgram dose of baclofen intrathecal injection in both the second and third studies were consistent with the results of the pivotal study.
In the USA, there were three deaths occurring among 211 patients treated with baclofen intrathecal injection in pre-marketing studies as of March 1996. These deaths were not attributed to the therapy.

5.2 Pharmacokinetic Properties

The following kinetic parameters must be interpreted in the light of intrathecal administration coupled with slow cerebrospinal fluid (CSF) circulation.

Absorption.

Direct infusion into the spinal subarachnoid space by-passes absorption processes and allows exposure to the receptor sites in the dorsal horn of the spinal cord.
Onset of action.

Intrathecal bolus.

The onset of action is generally half an hour to one hour after administration of a single intrathecal dose of baclofen. 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 severity of symptoms and the dose, method and speed of drug administration.

Continuous infusion.

Baclofen's antispasmodic action is first seen 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed within 24 to 48 hours.

Distribution.

After single intrathecal bolus injection/short-term infusion of baclofen, the volume of distribution, calculated from CSF concentrations, ranges from 22 to 157 mL. The concentrations of baclofen in plasma and the CSF after intrathecal bolus injection and intrathecal infusion have been investigated in three separate studies and the results are depicted in Table 3.
According to the half-life measured in the CSF, steady-state CSF concentrations will be reached within 1-2 days. No data are available for paediatric patients.
At steady-state conditions during continuous intrathecal infusion, a baclofen concentration gradient is built up in the range between 1.8:1 and 8.7:1 (mean: 4:1) from lumbar to cisternal CSF. This is based upon simultaneous CSF sampling via cisternal and lumbar tap during continuous baclofen infusion at the lumbar level in doses associated with therapeutic efficacy; the interpatient variability was great. This is of clinical importance insofar as spasticity in the lower extremities can be effectively treated with little effect on the upper limbs and with fewer CNS adverse reactions resulting from effects on the brain centres.
During intrathecal infusion plasma concentrations do not exceed 5 nanogram/mL, confirming that baclofen passes only slowly across the blood-brain barrier. In paediatric patients, respective plasma concentrations are at or below 10 nanogram/mL.
There is inadequate information available on the distribution of the two enantiomers.

Excretion.

The pharmacokinetics of CSF clearance of baclofen, calculated from intrathecal bolus or continuous infusion studies, approximate CSF turnover, suggesting elimination is by bulk-flow removal of CSF. After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance is about 30 mL/h.
The elimination half-life in the CSF after single intrathecal bolus injection/short-term infusion of 50 to 136 micrograms baclofen ranges from 1 to 5 hours. The elimination half-life of baclofen in the CSF at steady-state has not been determined.

5.3 Preclinical Safety Data

Subacute and subchronic studies with continuous intrathecal baclofen infusion in two species (rat, dog) revealed no signs of local irritation or inflammation on histological examination.

Genotoxicity.

Baclofen did not induce mutations in bacterial or mammalian cells in vitro, lacked DNA damaging activity in the sister chromatid exchange assay, and had no clastogenic activity in the nuclear anomaly test.

Carcinogenicity.

A two year carcinogenicity study in rats found no evidence that baclofen had carcinogenicity potential at oral doses up to 100 mg/kg/day. An apparently dose-related increase in the incidence of ovarian cysts and of enlarged and/or haemorrhagic adrenals at the highest two doses (50 and 100 mg/kg/day) was observed in female rats. The clinical relevance of these findings is not known.
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 drug. Ovarian cysts are known to occur spontaneously in a proportion of the normal female population.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sintetica Baclofen Intrathecal contains sodium chloride and water for injections.

6.2 Incompatibilities

Sintetica Baclofen Intrathecal ampoules for intrathecal administration should not be mixed with other infusion or injection solutions. Glucose solutions are incompatible due to a chemical reaction with baclofen.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate or freeze. Protect from light.

6.5 Nature and Contents of Container

Clear Type 1 glass ampoules.
50 microgram baclofen per 1 mL ampoule (50 microgram/mL); packs of 10.
10 mg baclofen per 20 mL ampoule (500 microgram/mL); packs of 1.
10 mg baclofen per 5 mL ampoule (2 mg/mL); packs of 1 and 10.
40 mg baclofen per 20 mL ampoule (2 mg/mL); packs of 1.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The active ingredient of Sintetica Baclofen Intrathecal is (3RS)-4-amino-3-(4-chlorophenyl)butanoic acid (= baclofen), a racemic mixture of the R, (-) and S, (+) isomers.
The chemical structure of baclofen is:
Baclofen is a chemical analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is an odourless or practically odourless white to off-white crystalline powder with a melting point of 206 - 208°C. Baclofen is slightly soluble in water (less than 1 mg/mL at 18°C), very slightly soluble in ethanol and practically insoluble in acetone.
Molecular formula: C10H12ClNO2.
Molecular weight: 213.7.

CAS number.

1134-47-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes