Baclofen Sintetica

/ Biomed - JR

Intrathecal administration of baclofen through an implanted delivery system should only be undertaken by physicians with the necessary knowledge and experience. Specific instructions for implantation, programming and/or refilling of the implantable pump are given by the pump manufacturers, and must be strictly adhered to.
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 10 mg/5 ml and 40 mg/20 ml into the intrathecal space. 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.
Respiratory function should be monitored and appropriate resuscitation facilities should be available during the introduction of treatment with baclofen. Only pumps constructed of material known to be compatible with the product and incorporating an in-line bacterial retentive filter should be used.
Adult Screening Phase:
Prior to initiation of a chronic infusion, the patient’s response to intrathecal bolus doses administered via a catheter or lumbar puncture must be assessed. Low concentration ampoules containing 500 micrograms baclofen in 1 ml are available for the purpose. Patients should be infection-free prior to screening, as the presence of a systemic infection may prevent an accurate assessment of the response.
The usual initial test dose in adults is 25 or 50 micrograms, increasing step-wise by 25 microgram increments at intervals of not less than 24 hours until a response of approximately 4 to 8 hours duration is observed. Each dose should be given slowly (over at least one minute). In order to be considered a responder the patient must demonstrate a significant decrease in muscle tone and/or frequency and/or severity of muscle spasms.
The variability in sensitivity to intrathecal baclofen between patients is emphasised. Signs of severe overdose (coma) have been observed in an adult after a single test dose of 25 micrograms. It is recommended that the initial test dose is administered with resuscitative equipment on hand.
Patients who do not respond to a 100 micrograms test dose should not be given further dose increments or considered for continuous intrathecal infusion.
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.
Pediatric population Screening Phase:
The initial lumbar puncture test dose for patients 4 to <18 years of age should be 25-50 micrograms/day based upon age and size of the child. Patients who do not experience a response may receive a 25 microgram/day dose escalation every 24 hours. The maximum screening dose should not exceed 100 micrograms/day in pediatric patients.
Dose-Titration Phase:
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 centers to minimize risks during the perioperative phase.
Infection may increase the risk of surgical complications and complicate attempts to adjust the dose.
The initial total daily infused dose is determined by doubling the bolus dose which gave a significant response in the initial screening phase and administering it over a 24 hour period.
However, if a prolonged effect (i.e. lasting more than 12 hours) is observed during screening the starting dose should be the unchanged screening dose delivered over 24 hours. No dose increases should be attempted during the first 24 hours.
After the initial 24 hour period dosage should be adjusted slowly to achieve the desired clinical effect. If a programmable pump is used the dose should be increased only once every 24 hours; for non-programmable multi-dose reservoir pumps intervals of 48 hours between dose adjustments are recommended. In either case increments should be limited as follows to avoid possible overdosage:
– Patients with spasticity of spinal origin: 10-30% of the previous daily dose.
– Patients with spasticity of cerebral origin:  5-15% of the previous daily dose.
If the dose has been significantly increased without apparent clinical effect pump function and catheter patency should be investigated.
There is limited clinical experience using doses greater than 1,000 micrograms/day.
It is important that patients are monitored closely in an appropriately equipped and staffed environment during screening and immediately following pump implantation. Resuscitative equipment should be available for immediate use in case of life-threatening adverse reactions.
Adult Maintenance Therapy:
The clinical goal is to maintain as normal a muscle tone as possible, and to minimize 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 maintenance dosing for long-term continuous infusions of intrathecal baclofen has been found to range from 12 to 2,003 micrograms/day, with most patients being adequately maintained on 300 to 800 micrograms/day.
In patients with spasticity of cerebral origin maintenance dosage has been found to range from 22 to 1,400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.
Pediatric population Maintenance Therapy
In children aged 4 to <18 years with spasticity of cerebral and spinal origin, the initial maintenance dosage for long-term continuous infusion of baclofen ranges from 25 to 200 micrograms/day (median dose: 100 micrograms/day). The total daily dose tends to increase over the first year of therapy, therefore the maintenance dose needs to be adjusted based on individual clinical response. There is limited experience with doses greater than 1,000 micrograms/day.
The safety and efficacy of baclofen for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established.
Delivery specifications:
Ampoules of 20 ml containing 500 micrograms/ml and 5 ml / 20 ml containing 2 mg (2,000 micrograms)/ml are intended for use with infusion pumps. The concentration to be used depends on the dose requirements and size of pump reservoir. Use of the more concentrated solution obviates the need for frequent re-filling in patients with high dosage requirements.
Delivery regimen:
This medicinal product is most often administered in a continuous infusion mode immediately following implant. After the patient has stabilized with regard to daily dose and functional status, and provided the pump allows it, a more complex mode of delivery may be started to optimize 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 side effects.
A sudden requirement for substantial dose escalation is indicative of a catheter complication (i.e. a kink 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.
During long-term treatment approximately 5% of patients become refractory to increasing doses due to tolerance or drug delivery failure. This “tolerance” may be treated by gradually reducing baclofen dose over 2 to 4 week period and switching to alternative methods of spasticity management (e.g. Intrathecal preservative-free morphine sulphate). Baclofen should be resumed at the initial continuous infusion dose. Caution should be exercised when switching from baclofen  to morphine and vice versa.
Discontinuation:
Except in overdose-related emergencies, the treatment with baclofen should always be gradually discontinued by successively reducing the dosage. Baclofen should not be discontinued suddenly.

Patients with severe chronic spasticity resulting from trauma, multiple sclerosis or other spinal cord disorders, who are unresponsive to oral baclofen or other orally administered antispastic agents and/or those patients who experience unacceptable side effects at effective oral doses.
Baclofen is effective in adult patients with severe chronic spasticity of cerebral origin, resulting e.g. from cerebral palsy, brain trauma or cerebrovascular accident; however, clinical experience is limited.

Known hypersensitivity to baclofen or any of its excipients.
The drug should not be administered by any route other than intrathecal.

Intrathecal baclofen therapy is valuable but hazardous. Careful pre-operative assessment is mandatory.
The patient must be given adequate information regarding the risks of this mode of treatment, and be physically and psychologically able to cope with the pump. It is essential that the responsible physicians and all those involved in the care of the patient receive adequate instruction on the signs and symptoms of overdose, procedures to be followed in the event of an overdose and the proper home care of the pump and insertion site.
Inflammatory mass at the tip of the implanted catheter:
cases of inflammatory mass at the tip of the implanted catheter that can result in serious neurological impairment, including paralysis, have been reported. Although they have been reported with baclofen, they have not been confirmed by contrast MRI or histopathology. The most frequent symptoms associated with inflammatory mass are: 1) decreased therapeutic response (worsening spasticity, return of spasticity when previously well controlled, withdrawal symptoms, poor response to escalating doses, or frequent or large dosage increases), 2) pain, 3) neurological deficit/dysfunction. Clinicians should carefully monitor patients on intraspinal therapy for any new neurological signs or symptoms. Clinicians should use their medical judgment 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 an inflammatory mass are not unlike the symptoms experienced by patients with severe spasticity from their disease. In some cases, performance of an imaging procedure may be appropriate to confirm or rule-out the diagnosis of an inflammatory mass.
Pump Implantation:
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 baclofen withdrawal and its related symptoms.
Reservoir refilling:
Reservoir refilling must be performed by trained and qualified personnel in accordance with the instructions provided by the pump manufacturer. Refills should be timed to avoid excessive depletion of the reservoir, as this would result in the return of spasticity or potentially life-threatening symptoms of baclofen withdrawal.
When refilling the pump care should be taken to avoid discharging the contents of the catheter into the intrathecal space.
Strict asepsis is required to avoid microbial contamination and infection.
Extreme caution must be taken when filling a pump equipped with an injection port that allows direct access to the intrathecal catheter as a direct injection into the catheter through the access port could cause a life-threatening overdose.
Precautions in pediatric patients:
For patients with spasticity due to head injury, it is recommended not to proceed to long-term baclofen therapy until the symptoms of spasticity are stable (i.e. at least one year after the injury).
Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Use in the pediatric population should be only prescribed by medical specialists with the necessary knowledge and experience. There is very limited clinical data regarding the safety and efficacy of the use in children under the age of four years .
Precautions in special patient populations:
In patients with abnormal CSF flow the circulation of drug and hence antispastic activity may be inadequate.
Psychotic disorders, schizophrenia, confusional states or Parkinson’s disease:
Exacerbation by treatment with oral baclofen. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.
Close supervision of patients with additional risk factors for suicide should accompany therapy with this medicinal product. Patients (and caregivers of patients) should be alerted about the need to monitor for clinical worsening, suicidal behavior or thoughts or unusual changes in behavior and to seek medical advice immediately if these symptoms present.
Special attention should be given to patients known to suffer from epilepsy as seizures have occasionally been reported during overdose with, and withdrawal from, baclofen as well as in patients maintained on therapeutic doses.
Baclofen should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of baclofen may precipitate an autonomic dysreflexic episode.
Baclofen should be used with caution in patients with cerebrovascular or respiratory insufficiency.
An effect of baclofen on underlying, non-CNS related diseases is unlikely because its systemic availability is substantially lower than after oral administration. Observations after oral baclofen therapy suggest that caution should be exercised in patients with a history of peptic ulcers and pre-existing sphincter hypertonia.
Renal impairment:
After oral baclofen dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering baclofen in patients with renal impairment.
In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral baclofen.
Treatment withdrawal (including associated with catheter or device malfunction)
Abrupt discontinuation of this medicinal product, regardless of cause, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has resulted in sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia, tachycardia and symptoms consistent with neuroleptic malignant syndrome, e.g. altered mental status and muscle rigidity. In rare cases this has advanced to seizures/status epilepticus, rhabdomyolysis, coagulopathy, multiple organ failure and death. All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal.
Some clinical characteristics associated with intrathecal baclofen withdrawal may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.
Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the signs and symptoms of baclofen withdrawal particularly those seen early in the withdrawal syndrome (e.g. priapism).
In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of baclofen therapy. Common reasons for abrupt interruption of intrathecal baclofen therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, end of pump battery life and device malfunction. Device malfunction resulting in altered drug delivery leading to withdrawal symptoms including death has been reported.
Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. The suggested treatment for intrathecal baclofen withdrawal is the restoration of intrathecal baclofen at or near the same dosage as before therapy was interrupted. However, if restoration of intrathecal delivery is delayed, treatment with GABA-ergic agonist drugs such as oral or enteral baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.
Scoliosis:
The onset of scoliosis or worsening of a pre-existing scoliosis has been reported in patients treated with baclofen. Signs of scoliosis should be monitored during treatment with baclofen.
See prescribing information for full details

Very Common: Somnolence, hypotonia.
Common: Depression, anxiety, agitation, convulsion, confusional state, sedation, dizziness, headache, paraethesia, dysarthria, lethargy, insomnia, disorientation, accommodation disorder, vision blurred, diplopia, hypotension, respiratory depression, pneumonia, dyspnea, nausea/vomiting, constipation, dry mouth, diarrhoea, decreased appetite,increased salivation, urticaria/pruritus, facial and/or peripheral oedema, hypertonia, urinary incontinence, urinary retention, sexual dysfunction (Intrathecal baclofen may compromise erection and ejaculation, asthenia, pyrexia, pain, chills.

The co-administration of other intrathecal agents with baclofen is not recommended. An attempt should be made to reduce or discontinue concomitant oral antispastic medications, preferably before initiating baclofen infusion. However, abrupt reduction or discontinuation during chronic intrathecal baclofen therapy should be avoided. There is little experience with the use of baclofen in combination with systemic medications to be able to predict specific drug-drug interactions, although it is suggested that the low baclofen systemic exposure after intrathecal administration could reduce the potential for pharmacokinetic interactions.
Experience with oral baclofen would suggest that:
Alcohol and other compounds affecting the CNS: There may be increased sedation where baclofen is taken concomitantly with other drugs acting on the CNS (e.g. analgesics, neuroleptics, barbiturates, benzodiazepines, anxiolytics) or with alcohol.
Tricyclic antidepressants: During concurrent treatment with tricyclic antidepressants, the effect of baclofen may be potentiated, resulting in muscular hypotonia.
Antihypertensives: Since concomitant treatment with anti-hypertensives is likely to increase the fall in blood pressure, dosage of concomitant medications should be adjusted accordingly.
Levodopa: Concomitant use of oral baclofen and levodopa/dopa-decarboxylase (DDC) inhibitor resulted in increased risk of adverse events like visual hallucinations, confusional state, headache and nausea. Worsening of the symptoms of Parkinsonism has also been reported. Thus, caution should be exercised when intrathecal baclofen is administered to patients receiving levodopa/DDC inhibitor therapy.
Morphine: The combined use of morphine and intrathecal baclofen has been responsible for hypotension in one patient; the potential for this combination to cause dyspnoea or other CNS symptoms cannot be excluded.
Anesthetics: Concomitant use of intrathecal baclofen and general anesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anaesthetics are administered to patients receiving intrathecal baclofen.

Women of child bearing potential:
Preconceptual counselling before programmable baclofen pump placement and in women with intrathecal baclofen pumps already implanted is recommended to ensure proper preparation and management throughout pregnancy and the peripartum period.
Pregnancy:
There are limited data on the use in pregnant women.
Reproductive toxicity has been observed at high oral doses of baclofen. After intrathecal administration of baclofen small amounts of baclofen can be detected in maternal plasma. Animal data show that baclofen can cross the placental barrier. Therefore, this medicinal product should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus.
Breast-feeding:
After oral administration of baclofen at therapeutic doses, baclofen passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.
After intrathecal administration of baclofen small amounts of baclofen can be detected in maternal plasma. Therefore, no baclofen is expected to be found in the milk of the mother receiving baclofen therapy and no special recommendations are given.
Fertility:
Animal studies have shown that intrathecal baclofen is unlikely to have an adverse effect on fertility under clinically-relevant conditions.

Special attention should be given to recognising the signs and symptoms of overdosage at all times, but especially during the initial “screening” and “dose-titration” phases and also during reintroduction of baclofen after an interruption of therapy. Signs of overdose may appear suddenly or (more usually) insidiously.
Symptoms of overdose: excessive muscular hypotonia, drowsiness, light-headedness, dizziness, somnolence, seizures, loss of consciousness, hypothermia, excessive salivation, nausea and vomiting, tachycardia and tinnitus. Respiratory depression, apnoea, and coma result from serious overdosage. Seizures may occur with increasing dosage or, more commonly, during recovery from an overdose. Serious overdose may occur
through the inadvertent delivery of the catheter contents, errors in pump programming, excessively rapid dose increases or concomitant treatment with oral baclofen. Possible pump malfunction should also be investigated.
Treatment: There is no specific antidote for treating overdoses of intrathecal baclofen. Any instructions provided by the pump manufacturer should be followed, and the following steps should generally be undertaken:
• Where a programmable continuous infusion pump is used further delivery of baclofen should be halted immediately by removal of residual drug solution from the reservoir.
• If it is possible to do so without surgical intervention the intrathecal catheter should be disconnected from the pump as soon as possible, and infusion fluid allowed to drain back together with some CSF (up to 30-40 ml is suggested).
• Patients with respiratory depression should be intubated if necessary, and ventilated artificially if required. Cardiovascular functions should be supported and in the event of convulsions, i.v. diazepam cautiously administered.
• Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate should be monitored.

Store below 25°C. Do not refrigerate or freeze.
Store in the original package in order to protect from light.
After opening the product must be used immediately. Any remaining product not administered to the pump must be disposed of.
Medicines should be kept out of the reach and sight of children.