"The the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) will review the risks and benefits of modified- and prolonged-release paracetamol (acetaminophen) tablets, the agency said today.
Because of the possibility of potential life-threatening CNS depression, cardiovascular collapse and/or respiratory failure, physicians must be adequately trained in intrathecal infusion therapy.
Specific instructions for programming and/or refilling the implantable pump are given by the pump manufacturers, and must be strictly adhered to. Consult pump manufacturer's literature for information on the appropriate use and care of these devices.
Because of the risks associated with the screening procedure and the adjustment of dosage following pump implantation, these procedures must be conducted in a medically supervised and adequately equipped environment (see DOSAGE AND ADMINISTRATION).
Resuscitative equipment should be available.
The pump system should not be implanted until the patient's response to bolus intrathecal injection of LIORESAL Intrathecal (baclofen injection) has been properly evaluated and found to be clinically safe and effective.
Following surgical implantation of the pump, particularly during the initial phase of pump use the patient should be monitored closely until it is certain that the patient's response to the infusion is acceptable and reasonably stable.
Whenever the dosing rate of the pump and/or the concentration of LIORESAL Intrathecal in the reservoir is adjusted, close medical monitoring is required until it is certain that the patient's response to the infusion is acceptable and reasonably stable.
It is mandatory that the patient and all those involved in the care of the patient receive adequate information regarding the risks of LIORESAL Intrathecal treatment. All medical personnel and care givers should be instructed in 1) the signs and symptoms of overdose, 2) procedures to be followed in the event of overdose and 3) proper home care of the pump and insertion site.
Inflammatory mass at the tip of implanted catheter with LIORESAL Intrathecal
Cases of inflammatory mass at the tip of the implanted catheter, have been reported in patients receiving LIORESAL Intrathecal monotherapy. The most frequent symptom associated with these masses is 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). It is known that inflammatory mass at intrathecal tip can result in pain and serious neurological impairment. Clinicians should monitor patients on LIORESAL Intrathecal therapy carefully for any new neurological signs or symptoms. 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 similar to the symptoms experienced by patients with severe spasticity from their disease. A diagnostic imaging procedure may be appropriate to confirm or rule-out inflammatory mass. Inflammatory masses have also been reported in patients receiving pharmacy compounded drugs or admixtures, including opioids. Diagnosis and management of inflammatory mass in these patients should take into consideration the pharmacology of the drugs in addition to LIORESAL.
Abrupt Drug Withdrawal
Abrupt discontinuation of LIORESAL Intrathecal, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.
Prevention of abrupt discontinuation of LIORESAL Intrathecal 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 LIORESAL withdrawal. 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 LIORESAL Intrathecal). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information. (see WARNINGS).
In the first 9 years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of LIORESAL Intrathecal therapy were reported; six patients died. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of LIORESAL Intrathecal therapy. Common reasons for abrupt interruption of LIORESAL Intrathecal therapy included malfunction of the catheter (especially disconnection), low volume in the pump reservoir, and end of pump battery life; human error may have played a causal or contributing role in some cases.
All patients receiving LIORESAL Intrathecal therapy are potentially at risk for withdrawal. Early symptoms of baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias. Some clinical characteristics of the advanced LIORESAL Intrathecal 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 and systemic effects of LIORESAL Intrathecal withdrawal. The suggested treatment for LIORESAL Intrathecal withdrawal is the restoration of LIORESAL Intrathecal 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 baclofen, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral baclofen alone should not be relied upon to halt the progression of the effects of LIORESAL Intrathecal withdrawal.
Seizures have been reported during overdose and with withdrawal from LIORESAL Intrathecal as well as in patients maintained on therapeutic doses of LIORESAL Intrathecal.
Therefore, except for serious adverse reactions and overdose related emergencies, the dose should always be reduced slowly when the drug is discontinued (over a period of approximately 1-2 weeks).
Convulsions have been reported in neonates after intrauterine exposure to oral baclofen (See PRECAUTIONS, Pregnant Women).
Patients should be infection free prior to the screening trial with LIORESAL Intrathecal (baclofen injection) because the presence of a systemic infection may interfere with an assessment of the patient's response to bolus intrathecal baclofen.
Careful monitoring of respiratory and cardiovascular functions is essential during initial test dose administration (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 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.
Following surgical implantation of the pump, particularly during the initial phases of pump 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 stable.
Pump Adjustment And Titration
In most patients, it will be necessary to increase the dose gradually over time to maintain effectiveness; a sudden requirement for substantial dose escalation typically indicates a catheter complication (i.e., catheter kink or dislodgement).
Reservoir refilling must be performed by fully trained and qualified personnel following the directions provided by the pump manufacturer. Refill intervals should be carefully calculated to prevent depletion of the reservoir, as this would result in the return of severe spasticity and possibly symptoms of withdrawal. Depending on individual daily dose requirements and the flow rate of the pump, refill intervals generally vary between one and three months.
Strictly aseptic filling is required to avoid microbial contamination and serious infection. A period of observation appropriate to the clinical situation should follow each refill or manipulation of the drug reservoir.
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.
In order to prevent excessive weakness and falling, LIORESAL Intrathecal should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion or whenever spasticity is used to maintain function.
An attempt should be made to discontinue concomitant oral antispastic medication to avoid possible overdose or adverse drug interactions, preferably before initiating baclofen infusion, with careful monitoring by the physician. However, abrupt reduction or discontinuation of concomitant antispastics during chronic intrathecal therapy with baclofen should be avoided.
Driving And Using Machines
Central nervous systems (CNS) depressant effects, such as somnolence and sedation have been reported in some patients on intrathecal baclofen. Other listed events include ataxia, hallucinations, diplopia and withdrawal symptoms (see ADVERSE REACTIONS). Patients should be cautioned regarding the operation of automobiles or dangerous machinery, and activities made hazardous by decreased alertness. Patients should also be cautioned that the central nervous system effects of baclofen may be additive to those of alcohol and other CNS depressants.
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.
The safety and efficacy of LIORESAL Intrathecal has not been studied in patients under 18 years of age. Its use in pediatric patients is not recommended unless the benefits outweigh the risk.
There are no adequate and well-controlled studies of LIORESAL Intrathecal in pregnant women. LIORESAL Intrathecal has been detected in maternal plasma (see CLINICAL PHARMACOLOGY) and is known to cross the placental barrier (see Toxicology). Post-marketing reports on mothers who used LIORESAL Intrathecal during pregnancy suggest a higher than expected rate of preterm delivery and delivery by caesarian section. Further, these preterm births have resulted in low birth weights according to what would be expected for gestational age. Therefore, LIORESAL Intrathecal should not be used during pregnancy unless the potential benefits to the mother outweigh the potential risk to the fetus.
Infants exposed to LIORESAL through maternal oral dosing during pregnancy are at risk of experiencing baclofen withdrawal at birth; identification of this condition may be confounded due to delayed appearance of withdrawal symptoms in this population. One case of suspected withdrawal reaction (generalized convulsions) has been reported in a week-old infant whose mother had taken oral baclofen during pregnancy. The convulsions, which were refractory to different anticonvulsants, ceased within 30 minutes of giving baclofen to the infant.
Oral baclofen at therapeutic doses passes into breast milk. LIORESAL Intrathecal should not be used in nursing women unless the potential the benefit outweigh the risk.
Patients With Special Diseases And Conditions
In patients with abnormal CSF flow, the spread of the drug and therefore, the distribution of antispastic activity may be inadequate.
Patients suffering from psychotic disorders, schizophrenia, confusional states, or Parkinson's disease should be treated cautiously with LIORESAL Intrathecal and kept under careful surveillance as exacerbations of these conditions have been observed with oral baclofen administration.
Special attention should be given to patients known to suffer from epilepsy as seizures have been reported during overdose with, and withdrawal from, LIORESAL Intrathecal, as well as in patients maintained on therapeutic doses of LIORESAL Intrathecal.
LIORESAL Intrathecal should be used with caution in patients with a history of autonomic dysreflexia. The presence of nociceptive stimuli or abrupt withdrawal of LIORESAL Intrathecal may cause an autonomic dysreflexic episode.
Interaction of intrathecal baclofen with 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, and impaired hepatic function.
No studies have been performed in patients with renal impairment receiving LIORESAL Intrathecal therapy. After oral LIORESAL dosing, severe neurological outcomes including clinical manifestations of toxic encephalopathy (e.g. somnolence, depressed level of consciousness and coma) have been reported in patients with renal impairment. Caution should be exercised while administering LIORESAL Intrathecal in patients with renal impairment because baclofen is primarily excreted unchanged through the kidneys. Patients with severe renal impairment should be treated with extra caution, as they are in general more sensitive to therapeutic effects/adverse effects of drugs. Severely renal impaired patients should be closely monitored for prompt diagnosis of early signs and/or symptoms of toxicity (see Symptoms And Treatment Of Overdosage).
No studies have been performed in patients with hepatic impairment receiving LIORESAL Intrathecal therapy. As baclofen does not undergo predominant hepatic metabolism, its pharmacokinetics is unlikely to be altered to a clinically significant level in patients with hepatic impairment.
However, the patients with severe hepatic impairment should be treated with caution, as they are in general more sensitive to therapeutic effects/adverse effects of drugs.
In rare instances, elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral baclofen.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/10/2014
Additional Lioresal Intrathecal Information
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