Baclofen

Registered South African indications:

• Severe chronic spasticity
  - Resulting from trauma, multiple sclerosis or other spinal cord disorders in those who are unresponsive to oral baclofen or other orally administered antispastic agents and/or those patients who experience unacceptable side effects at effective oral doses

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Porphyria
• Epilepsy refractory to therapy
• Infection at the site of catheter insertion
• Intrathecal baclofen should not be administered by any route other than intrathecal

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• This medicinal product should not be administered by any route other than intrathecal

South African recommendations

• Renal impairment
• Hepatic impairment 
• Body mass (in children)
• Long-term therapy in patients with spasticity due to head injury <1 year after injury
• Slowed cerebrospinal fluid (CSF) circulation
• Pre-existing psychotic disorders, schizophrenia or Parkinson's disease
• Epilepsy
• History of autonomic dysreflexia
• Nociceptive stimulation 
• Abrupt withdrawal
• Cerebrovascular or respiratory insufficiency
• Pre-existing cardiopulmonary condition
• Pre-existing respiratory muscle weakness
• Systemic infection
• Catheter misplacement
• Non-aseptic conditions
• Filling pump reservoir
• Direct injection into the catheter
• Where spasticity contributes to functional maintenance
• Transcutaneous catheter insertion during the pump implantation (in children)
• Presence of a percutaneous endoscopic gastrostomy (PEG) tube (in children)
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment 
• Elderly
• Long term therapy in patients with spasticity due to head injury <1 year after injury
• Slowed cerebrospinal fluid (CSF) circulation
• Pre-existing epilepsy or other cerebral seizure illnesses
• Bulbar paralytic symptoms or partial paralysis of the respiratory musculature
• Acute or chronic confusional states
• Pre-existing psychotic states, schizophrenia or Parkinson's disease
• History of dysreflexia of the autonomic nervous system
• Cerebrovascular and respiratory failure
• Pre-existing cardiopulmonary conditions
• Pre-existing respiratory muscle weakness
• Pre-existing hypertension of the bladder sphincter
• Peptic ulcers
• Suicidal risk factors
• Systemic infection
• Non-aseptic conditions
• Filling pump reservoir
• Injection via the access port directly into the catheter
• Level of spasticity
• Pre-existing scoliosis
• Abrupt withdrawal
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inf, inj

South African registered indications and dosages

Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by medical practitioners with the necessary knowledge and experience

Severe chronic spasticity
- Resulting from trauma, multiple sclerosis or other spinal cord disorders in those who are unresponsive to oral baclofen or other orally administered antispastic agents and/or those patients who experience unacceptable side effects at effective oral doses

Test phase

• Intrathecal: Initial: 25μg or 50μg injected over ≥1min via barbotage; Titrate by 25μg at intervals of ≥24hrs until a response lasting approx. 4-8hrs is obtained; Max: 100μg/24hrs 

Maintenance via continuous infusion
Spasticity of spinal genesis

• Intrathecal: 10-1200μg, dly (with an adequate response being achieved between 300-800μg for most patients)

Spasticity of cerebral origin 

• Intrathecal: 22-1400μg, dly (Mean dose: 276μg/day at 12 months and 307μg/day at 24 months)

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Switching of a patient from oral to intrathecal therapy or initiation of therapy up to achieving a stable maintenance phase of treatment should be done in hospital care setting with full resuscitation care, ventilation facilities and under supervision of a medical practitioner or physiotherapists

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Maintenance: Spasticity of spinal genesis: Adequate response is achieved in most patients with 300-800μg/day

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

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Patients with spasticity due to traumatic brain injury should wait at least 1 year before considering long-term intrathecal therapy

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Baclofen should not be administered by any route other than intrathecal

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Discontinuation of treatment: Except in emergency cases associated with an overdose, treatment should be discontinued gradually with successive dose reductions. Baclofen should not be abruptly discontinued

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Every ampoule is exclusively single-use. Any remaining product must be disposed of. Do not resterilize

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Baclofen must be visually inspected prior to use. Only clear solutions practically free from particles should be used

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To obtain concentrations other than 0.05, 0.5 or 2mg/ml of baclofen, baclofen must be diluted under aseptic conditions with sterile and preservative-free sodium chloride solution for injection

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Posology, test phase, titration phase and maintenance therapy: See additional prescribing points

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Administration: Particular specifications: See additional prescribing points

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Method of administration: See additional prescribing points

Paed. forms avail. in SA and covered in this monograph: inf, inj

South African registered indications and dosages

Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience

Severe chronic spasticity
- Of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) in those who are unresponsive to orally administered antispastics (including oral baclofen) and/or who experience unacceptable side effects at effective oral doses

Younger than 4 years 

• Not established for use

Between 4-<18 years

Screening phase

• Intrathecal: 25-50μg, dly based upon age and size of the child; Titrate by 25μg at intervals of 24hrs if no response is experienced; Max: 100μg/24hrs 

Initial maintenance dosage for long-term continuous infusion

• Intrathecal: 25-200μg, dly (Median dose: 100μg/day)

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The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1000μg/day

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Patients with spasticity due to traumatic brain injury should wait at least 1 year before considering long-term intrathecal therapy

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Baclofen should not be administered by any route other than intrathecal

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Discontinuation of treatment: Except in emergency cases associated with an overdose, treatment should be discontinued gradually with successive dose reductions. Baclofen should not be abruptly discontinued

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Every ampoule is exclusively single-use. Any remaining product must be disposed of. Do not resterilize

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Baclofen must be visually inspected prior to use. Only clear solutions practically free from particles should be used

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To obtain concentrations other than 0.05, 0.5 or 2mg/ml of baclofen, baclofen must be diluted under aseptic conditions with sterile and preservative-free sodium chloride solution for injections

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

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Posology, test phase, titration phase and maintenance therapy: See additional prescribing points

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Administration: Particular specifications: See additional prescribing points

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Method of administration: See additional prescribing points

Pregnancy

South African recommendations

• Contraindicated
• Safety in pregnancy has not been established. Baclofen crosses the human placental barrier. Studies in animals have shown that baclofen is embryotoxic in rats, following oral administration. The clinical relevance of these findings in humans is not known

Recommendations in other jurisdictions

• Caution; not recommended
• 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. Baclofen crosses the placenta and has shown reproduction toxicity. Baclofen should not be used during pregnancy unless the expected benefit for the mother outweighs the possible risks for the child

Breastfeeding

South African recommendations

• Contraindicated 
• Safety during breastfeeding has not been established. It is not known whether measurable levels of the product can be detected in the maternal milk of breastfeeding mothers treated with baclofen. At oral therapeutic doses, the active substance passes into breast milk. Mothers who are receiving baclofen are advised not to breastfeed their infants

Recommendations in other jurisdictions

• Caution 
• 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. Baclofen can be used during breastfeeding

Fertility

South African recommendations

• Ovarian cysts have been found by palpation in about 4% of the multiple sclerosis patients who were treated with oral baclofen for up to one year. In most cases these cysts disappeared spontaneously while patients continued to receive the medicine

Recommendations in other jurisdictions

• Animal studies have shown that intrathecal baclofen is unlikely to have an adverse effect on fertility

South African recommendations

• Caution; dose adjustment recommended 
  No studies have been performed in patients with renal impairment receiving baclofen therapy. Because baclofen is primarily excreted unchanged by the kidneys it should be given with special care and caution in patients with impaired renal function. In patients with impaired renal function, the dosage may need to be reduced to take account of the clinical condition or the level of reduced renal clearance

Recommendations in other jurisdictions

• Caution; dose adjustment recommended 
  No studies have been performed in patients with renal impairment receiving baclofen therapy. In patients with impaired renal function, the dosage may need to be reduced to take account the clinical condition and the level of reduced renal function

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended 
  No studies have been performed in patients with hepatic impairment receiving baclofen therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of baclofen. Therefore, hepatic impairment is not expected to impact the systemic exposure of baclofen

South African recommendations

• No dose adjustment recommended 
• Several patients over the age of 65 years have been treated with intrathecal baclofen during clinical trials, without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
• As part of clinical studies, some patients over 65 years of age have been treated with baclofen without specific problems being observed. Experience with baclofen tablets shows, however, that adverse reactions can occur more frequently in this patient group. Older patients should therefore be monitored carefully for the development of adverse reactions

Central Nervous System Disorders

• Depression
• Confusional state
• Disorientation
• Agitation
• Anxiety
• Suicidal ideation
• Suicide attempt
• Paranoia
• Hallucinations
• Dysphoria
• Euphoric mood
• Somnolence
• Seizure (more frequently in cerebral spasticity patients)
• Lethargy
• Dysarthria
• Headache (more frequently in cerebral spasticity patients)
• Paraesthesia
• Insomnia
• Sedation
• Dizziness
• Light-headedness
• Ataxia
• Memory impairment
• Asthenia

Cardiovascular Disorders 

• Bradycardia
• Orthostatic hypotension
• Hypertension
• Flushing
• Decreased blood pressure

Respiratory Disorders 

• Respiratory depression
• Aspiration pneumonia
• Dyspnoea
• Bradypnoea

Gastrointestinal Disorders 

• Nausea and vomiting (more frequently in cerebral spasticity patients)
• Constipation
• Diarrhoea
• Dry mouth
• Salivary hypersecretion
• Ileus
• Dysphagia

Genitourinary Disorders

• Urinary retention (more frequently in cerebral spasticity patients)
• Urinary incontinence
• Sexual dysfunction
• Erectile dysfunction

Endocrine and Metabolic Disorders 

• Decreased appetite
• Dehydration

Musculoskeletal Disorders 

• Hypotonia
• Hypertonia
• Scoliosis
• Muscle weakness

Skin and Subcutaneous Tissue Disorders 

• Pallor
• Urticaria
• Pruritus
• Alopecia
• Hyperhidrosis

Immune, Blood and Lymphatic System Disorders 

• Peripheral oedema
• Face oedema
• Pyrexia
• Chills
• Hypothermia
• Deep vein thrombosis
• Inflammation

Sensory Disorders 

• Nystagmus
• Accommodation disorders
  - Blurred vision
  - Diplopia
• Hypogeusia

Others

• Adverse events due to the infusion system
  - Inflammatory mass at the tip of the catheter
  - Dislocation/kinking/rupture (tearing) of the catheter with possible complications
  - Implantation site infection
  - Meningitis
  - Septicaemia
  - Pump-pocket seroma
  - Haematoma with a possible risk of inflammation
  - Failure of the pump function
  - Cerebrospinal fluid (CSF) leakage
  - Skin perforation
  - Overdosing or underdosing
• Pain
• Life-threatening withdrawal symptoms due to drug delivery failure

• Oral antispastic agents
• Central nervous system (CNS) depressants
• Analgesics
• Neuroleptics
• Barbiturates
• Benzodiazepines
• Anxiolytics
• Tricyclic antidepressants
• Antihypertensives
• Levodopa/ dopa decarboxylase inhibitor
• Morphine
• Opiates 
• Benzodiazepines
• General anaesthetics 
• Fentanyl
• Propofol

Other interactions

• Alcohol

None routine. Specific cases may require

• Electroencephalogram (EEG)
• Respiratory function
• Cardiac function
• Blood pressure

Additional observations

• Signs and symptoms of baclofen withdrawal (oral or intrathecal)
  - Altered mental status
  - Exaggerated rebound spasticity
  - Hallucination
  - High fever
  - Hypertension
  - Hyperthermia
  - Muscle rigidity
  - Tachycardia
  - Seizure
  - Agitation
  - Confusion
  - Delusions
  - Insomnia
  - Paranoid ideation
• Signs and symptoms of overdose (during the initial screening, dose-titration phase, and reintroduction of therapy)
  - Drowsiness
  - Dizziness
  - Somnolence
  - Hypothermia
  - Respiratory depression
  - Seizures
  - Rostral progression of hypotonia
  - Loss of consciousness progressing to coma
• Programming of the infusion system, refill scheduling and procedures as well as pump alarms (during the initial phase of pump use and when titrating the dosing rate and/or the concentration in the reservoir)

Posology 

South African recommendations

• Switching of a patient from oral to intrathecal therapy or initiation of therapy up to achieving a stable maintenance phase of treatment should be done in hospital care setting with full resuscitation care, ventilation facilities and under supervision of a medical practitioner or physiotherapists
• Baclofen is intended for administration in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, in implantable pumps suitable for continuous administration of baclofen into the intrathecal space (suitably SAHPRA certified pumps)
• Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individual dose titration prior to maintenance therapy. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to
• Efficacy of baclofen intrathecal has been demonstrated in controlled randomised studies using certified implantable administration infusion pumps. This is an implantable administration system: a refillable reservoir is implanted beneath the skin, mostly into the abdominal wall. This system is connected to an intrathecal catheter that passes subcutaneously into the subarachnoid space

Recommendations in other jurisdictions

• Baclofen 50μg/1ml 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 500μg/ml, 1000μg/ml, or 2000μg/ml into the intrathecal space (EU certified pumps). Establishment of the optimum dose schedule requires that each patient undergoes an initial screening phase with intrathecal bolus, followed by a very careful individualized dose titration prior to maintenance therapy
• The testing, implantation and dosage-titration phases of the intrathecal administration must be performed under in-patient conditions in centres with specific experience with close medical supervision by suitably qualified physicians. Intensive medical care should be immediately available owing to possible life-threatening events or serious adverse reactions
• Only pumps constructed of material known to be compatible with the product and incorporating an in-line bacterial retentive filter should be used
• Before baclofen is administered, the subarachnoid space of patients with post-traumatic spasticity should be investigated by an appropriate imaging technique (myelography) as clinically indicated. If radiological signs of arachnoiditis are found, treatment with baclofen should not be instituted
• Before administration of baclofen, the solution should be checked for clarity and colourlessness. Only clear solutions practically free from particles should be used. If clouding or discolouration is evident, then the solution should not be used and should be discarded
• The solution it contains is stable, isotonic, pyrogen and antioxidant-free and has a pH value of 5.5-7.5. Every vial is intended for single use only

Screening phase (4-<18 years)

South African manufacturer recommendations

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

Recommendations in other jurisdictions

• The recommended initial lumbar puncture test dose for patients 4-<18 years of age is 25-50μg/day which is administered slowly into the intrathecal space by barbotage over a period of not less than one minute. Patients who do not experience a response may receive a 25μg/day dose escalation every 24 hours. The maximum screening dose should not exceed 100μg/day in paediatric patients

Test phase (>18 years)

South African recommendations

• Prior to administering baclofen as a continuous intrathecal infusion, patients must show a positive response to administration of an intrathecal test dose in an initial test phase. A bolus test dose is administered via lumbar puncture or an intrathecal catheter, in order to provoke a response
• Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response. The initial dose is generally 25μg or 50μg; the dose is generally increased in increments of 25μg at intervals of at least 24 hours, until a response lasting approximately 4-8 hours is obtained. The dose must be injected over at least one minute via barbotage. Low-dose ampoules (Baclofen 0.05mg/ml) are available for this test phase. Resuscitative equipment must be on hand during injection of the first dose. Patients are considered to be positive responders if they show a significant decrease in muscle tone and/or frequency and/or severity of spasms
• There is much variability with regard to sensitivity to intrathecal baclofen. Signs of severe overdose (coma) have been observed after a single test dose of 25μg
• Patients who do not respond to a 100μg test dose must not be given further doses and are not eligible for continuous intrathecal infusions
• Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depressions

Recommendations in other jurisdictions

• Prior to pump implantation and initiation of chronic infusion of baclofen, patients must demonstrate a positive response to intrathecal test dose in an initial test phase. Usually, a bolus test dose is administered via lumbar puncture or an intrathecal catheter, in order to provoke a response. Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response. The initial test phase must only be performed with low concentration solution containing 50μg baclofen in 1ml
• The screening procedure is as follows. The usual initial test dose in adults is 25μg or 50μg which is administered slowly into the intrathecal space by barbotage (alternating intrathecal baclofen administration and distraction of cerebrospinal fluid to obtain an appropriate mixture) over a period of not less than one minute. A positive response consists of a significant decrease in muscle tone and/or frequency and/or severity of spasms. At intervals of at least 24 hours the dosage can be increased by increments of 25μg to a maximum test dosage of 100μg if the response is less than desired. After every bolus injection the patient must be supervised for 4-8 hours
• The action of a single intrathecal dose generally sets in 30-60 minutes after administration. The maximum spasmolytic effect sets in about 4 hours after administration and lasts about 4-8 hours. The time to onset of action, the peak action and the duration of action vary from patient to patient and are dependent on the dosage, on the severity of symptoms, and on the mode and speed of administration
• There is much variability with regard to sensitivity to intrathecal baclofen between patients. Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25μg
• Patients who do not respond to a 100μg test dose should not be given further dose increments and treatment should not progress to continuous intrathecal infusion
• Resuscitative equipment and trained staff must be available during screening, dose titration, and refills
• Monitoring of respiratory and cardiac function is essential during this phase, especially in patients with cardiopulmonary disease and respiratory muscle weakness or those being treated with benzodiazepine-type preparations or opiates, who are at higher risk of respiratory depression

Titration phase 

South African recommendations

• Once the patient’s response to baclofen has been established as positive via test doses, intrathecal infusion with a suitable administration system is introduced. Infection may increase the risk of surgical complications and complicate attempts to adjust the dose
• Following implantation, the initial total daily dose should be determined by doubling the dose that gave a positive effect in the test phase and administering it over a 24-hour period, unless the effect of the bolus dose is maintained for more than 12 hours. In this latter case, the initial daily dose should be similar to the dose in the test phase and should be administered over a 24-hour period. The dose must not be increased during the first 24 hours. After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed 10-30%. Patients with spasticity of cerebral genesis: After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect. To avoid any overdose, increments must not exceed 5-15 %
• If a programmable pump is used, dosage should only be increased once every 24 hours. For non-programmable pumps attached to a 76cm catheter and with a delivery rate of 1ml/day, it is recommended that the response should only be evaluated at 48-hour intervals. If the daily dosage has been significantly increased without any clinical effect having been observed, pump functioning and catheter permeability should be verified
• Only limited experience is available with doses exceeding 1000μg/day
• During the test phase, as well as during the titration period following implantation, patients should be closely monitored at an institution with all the necessary equipment and personnel. Resuscitative equipment must be on immediate stand-by in the event of any reaction that threatens the vital prognosis, or onset of very serious undesirable effects. In order to limit risks in the perioperative phase, the pump must only be implanted at centres with experienced personnel

Recommendations in other jurisdictions

• Once the patient's responsiveness to baclofen has been established, an intrathecal infusion may be introduced. Baclofen is most often administered using an infusion pump which is implanted in the chest wall or abdominal wall tissues. Implantation of pumps should only be performed in experienced centres to minimise risks during the perioperative phase
• Infection may increase the risk of surgical complications and complicate attempts to adjust the dose
• A very careful patient-tailored dosage titration is necessary because of the potential for large response differences with a given dose among patients
• Following implantation, if the duration of action of the test dose is more than 12 hours, this is taken as the initial daily dose. If the duration of action of the test dose is shorter than 12 hours, then the initial daily dose is double the test dose. The dose must not be increased during the first 24 hours. After the first 24 hours the dose is adjusted slowly on a daily basis, to obtain the desired effect
• The antispastic action of baclofen sets in 6-8 hours after the start of continuous infusion and reaches its maximum within 24-48 hours
•  For indication of spasticity of spinal cord origin (>18 years): After the first 24 hours, for adult patients, the daily dosage should be increased slowly by 10%-30% increments and only once every 24 hours, until the desired clinical effect is achieved
• For indication of spasticity of cerebral origin (>18 years): After the first 24 hours, the daily dose should be increased slowly by 5%-15% only once every 24 hours, until the desired clinical effect is achieved
• When using a programmable pump, it is advisable to adjust the dosage only once in any 24-hour period. With nonprogrammable pumps with a 76cm catheter that release 1ml of solution per day, intervals of 48 hours are recommended in order to be able to assess the reaction to the dosage. If a considerable rise in the daily dosage does not increase the clinical action, then the pump function and the catheter permeability should be verified
• During the test phase, as well as during the titration period following implantation, patients should be closely monitored at an institution with all the necessary equipment and personnel. Resuscitative equipment must be on immediate standby in the event of any reaction that threatens the vital prognosis, or onset of very serious undesirable effects. In order to limit risks in the perioperative phase, the pump must only be implanted at centres with experienced personnel

Maintenance therapy 

South African recommendations

• The clinical goal is to maintain as normal a muscle tone as possible, and to minimise the frequency and severity of spasms without inducing intolerable side effects. The lowest dose producing an adequate response should be used. The retention of some spasticity is desirable to avoid a sensation of “paralysis” on the part of the patient. In addition, a degree of muscle tone and occasional spasms may help support circulatory function and possibly prevent the formation of deep vein thrombosis
• In patients with spasticity of spinal origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom control. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%). In both cases the daily dose may also be reduced by 10-20% if patients suffer side effects
• If a significant dose increase should suddenly be necessary, this is indicative of a catheter complication (kink or dislodgement) or pump malfunction
• For long-term maintenance treatment via continuous infusion, the intrathecal baclofen dosage for patients with spasticity of spinal genesis is between 10 and 1200micrograms/day, with an adequate response being achieved in most patients with 300-800micrograms/day. In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22-1400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months
• Around 5% of patients receiving long-term treatment become refractory to dose escalation. This may be due to therapeutic failure. There is insufficient experience available to make any recommendations on dealing with treatment failure. However, this phenomenon has occasionally been treated in hospital by a “medicine holiday” consisting of the gradual reduction of baclofen intrathecal over a period of 2-4 weeks and switching to alternative methods of spasticity therapy (e.g. intrathecal preservative-free morphine sulphate). After this period, sensitivity to baclofen intrathecal may be re-established: treatment should be resumed at the initial continuous infusion dose, followed by a titration phase to avoid overdose
• Caution should be exercised when switching from baclofen intrathecal to intrathecal preservative-free morphine sulphate and vice versa
• Regular clinical monitoring is needed to assess the patient’s dosage requirements, to check that the administration system is working properly and to note any undesirable effects or the presence of infection

Recommendations in other jurisdictions

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

Method of administration 

South African recommendations

• In most cases, baclofen is administered as a continuous infusion directly after implantation. Once the patient is stabilised in terms of daily dosage and functional aspects, and provided that the pump allows it, a switch can be made to a more complex method of administration, to allow optimal control over spasticity at different times of the day. For example, patients with increased night-time spasms may require a 20% increase in the hourly infusion rate. This altered rate of infusion must be programmed about 2 hours in advance of the expected clinical effect
• Every ampoule is exclusively single-use. Any remaining product must be disposed of. Do not resterilize
• Baclofen intrathecal must be visually inspected prior to use. Only clear solutions practically free from particles should be used

Recommendations in other jurisdictions

• Baclofen is most often administered in a continuous infusion mode immediately following implant. 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 increased 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 desired onset of clinical effect
• Most patients require gradual dose increases to maintain optimum response during chronic therapy due to decreased responsiveness or disease progression. In patients with spasticity of spinal origin the daily dose may be increased gradually by 10-30% to maintain adequate symptom control. Where the spasticity is of cerebral origin any increase in dose should be limited to 20% (range: 5-20%)
• In both cases the daily dose may also be reduced by 10-20% if patients suffer undesirable effects
• If a significant dose increase should suddenly be necessary, this is indicative of a catheter complication (kink, tear or dislodgement) or pump malfunction. In order to prevent excessive weakness the dosage of baclofen should be adjusted with caution whenever spasticity is required to maintain function

Withdrawal symptoms

Recommendations in other jurisdictions

• In the event of abrupt discontinuation of intrathecal administration of baclofen, sequelae such as high fever, changes in mental state, increased spasticity as a rebound effect and muscle rigidity may occur regardless of the cause of the discontinuation, and in rare cases these may progress to seizures/status epilepticus, rhabdomyolysis, multiorgan failure and death 
• Discontinuation symptoms can possibly be confused with poisoning symptoms. They also require inpatient admission of the patient
• Around 5% of patients receiving long-term treatment become refractory to dose escalation. This may be due to therapeutic failure. There is insufficient experience available to make any recommendations on dealing with treatment failure. However, this phenomenon has occasionally been treated in hospitals by a “drug holiday” consisting of the gradual reduction off baclofen intrathecal over a period of 2-4 weeks and switching to alternative methods of spasticity therapy (e.g. intrathecal preservative-free morphine sulphate). After this period, sensitivity to baclofen intrathecal may be re-established: treatment should be resumed at the initial continuous infusion dose, followed by a titration phase to avoid overdose. This should again be performed under inpatient conditions
• Caution should be exercised when switching from baclofen to morphine and vice versa 
• Through the treatment period, regular checks for therapeutic and adverse effects of baclofen are appropriate. These checks may occur more frequently during the titration phase of therapy than during the chronic maintenance phase. The functioning of the infusion system must be checked regularly. A local infection or a malfunction of the catheter can cause interruption of the intrathecal delivery of baclofen with life-threatening consequences

Interruption of treatment

South African recommendations

• Abrupt discontinuation of baclofen intrathecal, for whatever reason, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has given rise to sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia and symptoms consistent with neuroleptic malignant syndrome (NMS), e.g. confused mental state and muscle rigidity. In rare cases, this has progressed to epileptic seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death
• All patients receiving treatment with intrathecal baclofen are potentially at risk for withdrawal
• Some clinical characteristics associated with intrathecal baclofen withdrawal can resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome (NMS) or other conditions associated with hypermetabolic state or extensive rhabdomyolysis
• Patients and their caregivers must be advised of the importance of keeping a timetable for refill visits and must be alerted to the signs and symptoms of baclofen withdrawal, particularly those that appear early on during the withdrawal syndrome
• In most cases, withdrawal symptoms appeared within a few hours after discontinuation of intrathecal baclofen treatment
• Common reasons for abrupt withdrawal of intrathecal baclofen treatment included catheter malfunctioning (especially disconnection), excessively low volume in the pump reservoir and end of pump battery life; in some cases, human error may have been to blame or played a contributing role. Prevention of abrupt withdrawal of intrathecal baclofen requires careful attention to programming and surveillance of the infusion system, refill scheduling/procedures and pump alarms
• The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist medicines such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal
• It is extremely important that the manufacturer’s instructions for implantation, pump programming and/or refilling of the reservoir should be strictly followed

Administration: particular specifications 

South African recommendations

• Baclofen ampoules containing 0.5mg/ml (20ml), 2mg/ml (5ml) and 2mg/ml (20ml) baclofen have been specially developed for infusion pumps. The exact concentration to be selected depends on the total daily dose needed, as well as the minimum infusion rate of the pump. Please refer to the manufacturer’s manual, which contains all specific recommendations

Recommendations in other jurisdictions

• Baclofen 500μg/ml, 1000μg/ml, and 2000μg/ml are intended for use with infusion pumps. The concentration to be used depends on the dose requirements and size of pump reservoir. Please refer to the manufacturer's manual, which contains all specific recommendations. The necessary concentration of baclofen when filling the pump depends on the total daily dose and on the rate of delivery of the pump. If baclofen concentrations other than 50μg/ml, 500μg/ml, 1000μg/ml or 2000μg/ml are required, baclofen in vials may be diluted to a lower concentration; dilution must be performed under aseptic conditions with sterile preservative-free sodium chloride solution for injections. The instructions of the pump manufacturer should be observed here. Dilution of baclofen in vials: If users wish to obtain concentrations other than 500, 1000 or 2000μg/ml, baclofen must be diluted under aseptic conditions in a sterile and preservative-free sodium chloride 9mg/ml solution for injections

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 gamma-aminobutyric acid GABA_B receptors. Baclofen is a chemical analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Neuromuscular transmission is not affected by baclofen. Baclofen exerts an antinociceptive effect. In neurological diseases associated with spasm of the skeletal muscles, the clinical effects of baclofen take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Baclofen improves 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_B 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 4-8 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 6-8 hours after initiation of continuous infusion. Maximum activity is observed in 24-48 hours.

Infusion (per ml) 0.5mg

Bacentra Intrathecal 0.5mg/ml (Umsebe Healthcare)

Infusion (per ml) 2mg

Bacentra Intrathecal 2mg/ml (Umsebe Healthcare)

Injection (per ml) 0.05mg

Bacentra Intrathecal 0,05mg/ml (Umsebe Healthcare)

Also available in the following forms: tablets.