部份中文巴氯芬处方资料（仅供参考）
药品名称
力奥来素 Lioresal 巴氯芬
规格
巴氯芬片 10mg，20mg; 注射剂 2mg/ml X 5ml
药理作用
本药是一个高效的作用在脊髓部位的肌肉松弛剂，其作用机制和药理学特性均与其他肌肉松弛剂不同。巴氯芬抑制单突触和多突触反射传递，它可能是通过刺激GABAB受体，而抑制兴奋性氨基酸如谷氨酸和天门冬氨酸的释放。神经肌肉传递不受巴氯芬的影响。巴氯芬具有抗感受伤害作用，对伴有骨骼肌痉挛的神经系统疾患，本药的临床作用为缓解反射性肌肉挛缩，对痛性阵挛、自动症和阵挛有明显缓解作用。本药能改善病人的活动能力，使病人生活较易自理，更有利于主动和被动的物理治疗。
药代动力学
本药的活性物质巴氯芬在胃肠道中吸收迅速而完全，单剂量口服10mg、20mg和30mg巴氯芬，0.5-1.5小时后，其血浆峰浓度分别平均约为180、340和650 ng/mL，相应血药浓度曲线下面积(AUCs)与剂量大小成比例增加，其值分别为1140、2350和3350ng x小时/mL。巴氯芬的分布面积为0.7L/kg，脑脊液中活性物质浓度约比血浆中的低8.5倍。巴氯芬的血浆清除半衰期平均为3-4小时，其血清蛋白结合率约为30%。大部分巴氯芬以原型排出，在72小时内，摄入量中约75%经肾脏排出，其中代谢物约占5%，摄入量的其余部分，包括占5%的代谢物从粪便排出，主要代谢产物为β-(p-氨苯)-γ-羟丁酸，无药理活性。
适应症
多发性硬化症的骨骼肌痉挛状态。感染性、退行性、外伤性、肿胀或原因不明的脊髓疾病引起的痉挛状态，例如：痉挛性脊髓麻痹、肌萎缩性侧索硬化症、脊髓空洞症、横贯型脊髓炎、外伤性截瘫或麻痹、脊髓压迫、脑源性肌阵挛，特别是小儿脑性瘫痪，以及脑血管意外、肿瘤或退行性脑病引起的肌痉挛。
用法用量
应从小剂量开始，逐渐增加剂量，根据个体病情的不同，制定适当的每日剂量，既能使阵挛、屈肌和伸肌痉挛状态减轻，又能维持足够的肌张力，使病人能自主活动，并尽可能减少副反应。本药应在进餐时用少量液体送服，将每日用量分次服用，成人至少分3次，儿童分4次。
对成人患者，原则上初始剂量用每日3次，每次5 mg。应逐渐小心增加剂量，每隔3日增加剂量，每日3次，每次增加5 mg，直至所需剂量。
对该药敏感的患者，宜再降低其初始每日用量（15 mg或10 mg），并放慢增加剂量的速度。通常合适的剂量范围为每日30-75 mg，住院病人可能需要加至每日100-120 mg。
肾功能损害或长期血液透析病人，应使用特别小的剂量，即每日约5 mg。
由于老年或脑源性痉挛状态的患者更易发生副反应，对这些病例，建议极为小心地制订治疗计划，并于严密监护下用药。
儿童的用药剂量为0.75-2 mg/kg体重/日，对10岁以上儿童，每日最大剂量可达2.5 mg/kg体重。通常治疗开始时每次2.5 mg，每日4次，大约每隔3天小心增加剂量，直至达到儿童个体需要量。推荐的每日维持治疗量如下：
12个月至2岁儿童：10-20 mg；
2-10岁儿童：30-60 mg（最大量70 mg）。
任何疑问，请遵医嘱！
不良反应
副作用主要见于治疗开始时，剂量增加过快、剂量过大或年老患者。这些副作用常为暂时性，减少剂量后可减弱或消失，其程度也较轻，一般不需停药。对有神经病史患者或伴有脑血管疾病（如中风）和年老患者，副作用可能较为严重。
中枢神经系统：治疗开始时常出现日间镇静、嗜睡和恶心等副作用，偶然出现口干、呼吸抑制、头晕、无力、虚脱、精神错乱、晕眩、恶心、呕吐、头痛和失眠。
神经病学和/或精神学的表现：偶然或罕见报导有：欣快、抑郁、感觉异常、肌痛、肌无力、共济失调、震颤、眼球震颤、调节紊乱、幻觉、恶梦，上述症状常难以与疾病本身的表现相区别。可能会降低惊厥阈，并引起惊厥发作，癫痫患者尤应注意。
胃肠道：偶有轻度的胃肠功能紊乱（便秘、腹泻）。
心血管系统：偶会发生低血压、心血管功能降低。
泌尿生殖系统：偶见或罕见排尿困难、尿频、遗尿，这些常难以与疾病本身的表现相区别。
其它副作用：罕见或个别病例有视力障碍，味觉障碍、多汗、皮疹、肝功能损害。某些病人对药物可显反常的反应而表现为痉挛状态加重。可能会出现肌张力过低，使病人更难于行走或照料自己，这种情况通常在调节剂量后可缓解（如减少日间剂量，可能的话增加夜间剂量）。
禁忌症
已知对巴氯芬过敏者禁用。
注意事项
痉挛状态合并精神障碍，精神分裂症或意识错乱状态的病人，因为病情可能恶化，应慎用，并对病人进行严密监护。对伴有癫痫的痉挛状态患者，除继续使用适量的抗惊厥药治疗外，可在适当的监护下使用本药。
对于消化性溃疡或有该病史的患者，以及患有脑血管病、呼吸、肝、肾功能衰竭者，也应慎用。因神经调节紊乱而影响膀胱排空的病人，使用本药治疗期间可有改善，因此，对已患有括约肌张力过高，而可能发生急性尿潴留的病人，应慎用本药。有报告显示，使用本药特别是长期使用者突然停药，可发生焦虑、意识错乱、幻觉、精神病、躁狂或偏执状态、惊厥（癫痫持续状态）、心动过速，并且可出现反跳现象，使痉挛状态一过性加重。除非发生严重的副作用，应通过逐渐减少剂量而终止治疗（大约需1-2周以上）。
由于有报告显示，在极个别病例中可引起血谷草转氨酶、碱性磷酸酶和血糖升高，对肝病或糖尿病患者应定期作有关实验室检查，以确证上述已有的疾病与药物的诱导无关。
本药之镇静作用可使患者的反应能力受影响，应激性降低，因此患者驾驶车辆或操纵机器时应小心。
孕妇及哺乳期妇女用药
在妊娠期间，尤其在最初三个月，只有在抢救生命时才能使用本药。应仔细权衡治疗对母亲和胎儿之间的利弊。巴氯芬可通过胎盘屏障，母亲服用治疗剂量的本药，活性物质可进入乳汁，但量甚少，对婴儿影响不大。
药物相互作用
与其它作用于中枢神经系统药物或酒精合用时，可增加镇静作用。当与三环类抗抑郁药合用时，可加强本药的作用，引起明显的肌张力过低。本药和降压药合用可使血压下降作用加强。帕金森氏病（震颤麻痹）患者，同时接受本药和左旋多巴加比多巴治疗，有报告引起精神错乱、幻想和激动不安。
药物过量
体征和症状
主要表现为中枢神经抑制如嗜睡、意识模糊、呼吸抑制、昏迷，容易发生的症状还有精神错乱、幻觉、激越、调节紊乱、瞳孔反射消失；全身性肌张力过低、肌阵挛、反射消失；惊厥；周围血管扩张、低血压、心动过缓、低体温；恶心、呕吐、腹泻、流涎；乳酸脱氢酶、谷草转氨酸和碱性磷酸酶升高。如同时服用各种作用在中枢神经系统的物质或药物（例如酒精、安定、三环类抗抑郁药），可使上述情况恶化。
治疗
目前尚缺乏特异性解毒药。从胃肠清除药物（催吐、洗胃、昏迷病人在洗胃前应行气管插管）；给予活性碳，如需要，给予轻泻剂；有呼吸抑制者，给予人工呼吸，并给予心血管功能支持疗法。由于本药主要经肾脏排泄，应大量输液，如有可能，加用利尿剂。如有惊厥，应小心静脉注射安定。

Lioresal Intrathecal (baclofen injection)
for Intrathecal Baclofen Therapy
Lioresal® Intrathecal (baclofen injection) is indicated for use in the management of severe spasticity and is FDA-approved for SynchroMed® infusion systems
ITB Therapy (Intrathecal Baclofen Therapy) is indicated for use in the management of severe spasticity. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, ITB Therapy via an implantable infusion system should be reserved for patients unresponsive to oral baclofen or those who experience intolerable CNS side effects at effective doses. Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy.
Important Safety Information for ITB Therapy: Intrathecal Baclofen Withdrawal: Abrupt discontinuation of intrathecal baclofen, 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 intrathecal baclofen requires careful attention to 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. Special attention should be given to patients at 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 postimplant clinician and patient information.
This therapy is contraindicated in patients who are hypersensitive to baclofen. Implantation of the infusion system is contraindicated if the patient is of insufficient body size, requires a pump implant deeper than 2.5 cm, or, in the presence of spinal anomalies or active infection.
The most frequent drug adverse events vary by indication but include: hypotonia (34.7%), somnolence (20.9%), headache (10.7%), convulsion (10.0%), dizziness (8.0%), urinary retention (8.0%), nausea (7.3%), and paresthesia (6.7%). Pump system component failures leading to pump stall, or dosing/programming errors may result in clinically significant overdose or underdose. Acute massive overdose may result in coma and may be life threatening.
The most frequent and serious adverse events related to device and implant procedures are catheter dislodgement from the intrathecal space, catheter break/cut, and implant site infection including meningitis. Electromagnetic interference (EMI) and Magnetic resonance imaging (MRI) may cause patient injury, system damage, operational changes to the pump, and changes in flow rate.
Lioresal Intrathecal
Novartis Pharmaceuticals UK Ltd Contact details
1. Name of the medicinal product
Lioresal® Intrathecal Injection 50micrograms/1ml
Lioresal® Intrathecal Infusion 10mg/5ml
Lioresal® Intrathecal Infusion 10mg/20ml
2. Qualitative and quantitative composition
Active substance
b-(Aminomethyl)-p-chlorohydrocinnamic acid (= baclofen), a racemic mixture of the R, (-) and S, (+) isomers
One ampoule of 1 ml contains 50 micrograms baclofen, (50 micrograms/ml).
One ampoule of 5 ml contains 10 mg baclofen, (2000 micrograms/ml).
One ampoule of 20 ml contains 10 mg baclofen, (500 micrograms/ml).
For excipients see section 6.1 List of excipients.
3. Pharmaceutical form
Solutions for intrathecal injection and intrathecal infusion.
4. Clinical particulars
4.1 Therapeutic indications
Lioresal Intrathecal is indicated in patients with severe chronic spasticity of spinal or cerebral origin (associated with injury, multiple sclerosis, cerebral palsy) 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.
In patients with spasticity due to head injury a delay of at least one year before treatment with Lioresal Intrathecal is recommended, to allow the symptoms of spasticity to stabilise.
Lioresal Intrathecal may be considered as an alternative to ablative neurosurgical procedures.
Paediatric population
Lioresal Intrathecal is indicated in patients aged 4 to <18 years with severe chronic spasticity of cerebral origin or of spinal origin (associated with injury, multiple sclerosis, or other spinal cord diseases) who are unresponsive to orally administered antispastics (including oral baclofen) and/or who experience unacceptable side effects at effective oral doses.
4.2 Posology and method of administration
Intrathecal administration of Lioresal 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.
Lioresal Intrathecal 50 micrograms/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 Lioresal Intrathecal 10mg/20ml and 10mg/5ml 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 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 Lioresal Intrathecal. Intrathecal administration using an implanted delivery system should only be undertaken by physicians with appropriate knowledge and experience. Specific instructions for using the implantable pump should be obtained from the pump manufacturers. 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 50 micrograms baclofen in 1ml 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.
Paediatric 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 paediatric patients.
Dose-Titration Phase
Once the patient's responsiveness to Lioresal Intrathecal has been established, an intrathecal infusion may be introduced. Lioresal Intrathecal 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.
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 1000 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 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 maintenance dosing for long-term continuous infusions of intrathecal baclofen has been found to range from 12 to 2003 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 1400 micrograms/day, with a mean daily dosage of 276 micrograms per day at 12 months and 307 micrograms per day at 24 months.
Paediatric 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 Lioresal Intrathecal 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 Lioresal Intrathecal for the treatment of severe spasticity of cerebral or spinal origin in children younger than 4 years of age have not been established (also see section 4.4).
Delivery specifications
Lioresal Intrathecal ampoules of 20ml containing 500 micrograms/ml and 5ml containing 2mg (2000micrograms)/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
Lioresal Intrathecal 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 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 Lioresal Intrathecal 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 (see Section 4.4 – Special Warnings and Precautions for Use “Treatment Withdrawal” section). This “tolerance” may be treated by gradually reducing Lioresal Intrathecal dose over 2 to 4 week period and switching to alternative methods of spasticity management (e.g. Intrathecal preservative-free morphine sulphate). Lioresal Intrathecal should be resumed at the initial continuous infusion dose. Caution should be exercised when switching from Lioresal Intrathecal to morphine and vice versa (see section 4.5).
Discontinuation
Except in overdose-related emergencies, the treatment with Lioresal Intrathecal should always be gradually discontinued by successively reducing the dosage. Lioresal Intrathecal should not be discontinued suddenly (see section 4.4).
Special populations
Renal impairment
No studies have been performed in patients with renal impairment receiving Lioresal Intrathecal therapy. Because baclofen is primarily excreted unchanged by the kidneys (see section 5.2) it should be given with special care and caution in patients with impaired renal function (see section 4.4).
Hepatic impairment
No studies have been performed in patients with hepatic impairment receiving Lioresal Intrathecal therapy. No dosage adjustment is recommended as the liver does not play any significant role in the metabolism of baclofen after intrathecal administration of Lioresal. Therefore, hepatic impairment is not expected to impact the drug systemic exposure (see section 5.2).
Elderly population
Several patients over the age of 65 years have been treated with Lioresal Intrathecal during the clinical trials without increased risks compared to younger patients. Problems specific to this age group are not expected as doses are individually titrated.
4.3 Contraindications
Known hypersensitivity to baclofen or any of its excipients (see section 6.1).
The drug should not be administered by any route other than intrathecal.
4.4 Special warnings and precautions for use
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 Lioresal intrathecal, 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 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.
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 Lioresal Intrathecal withdrawal and its related symptoms (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).
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 Lioresal Intrathecal withdrawal (see Section 4.4 – Special Precautions for Use “Treatment Withdrawal” section).
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 paediatric patients
For patients with spasticity due to head injury, it is recommended not to proceed to long-term Lioresal Intrathecal 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 of Lioresal Intrathecal in the paediatric 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 of Lioresal Intrathecal 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 may be exacerbated by treatment with oral Lioresal. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.
Special attention should be given to patients known to suffer from epilepsy as seizures have occasionally been reported during overdose with, and withdrawal from, Lioresal Intrathecal as well as in patients maintained on therapeutic doses.
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 precipitate an autonomic dysreflexic episode.
Lioresal should be used with caution in patients with cerebrovascular or respiratory insufficiency.
An effect of Lioresal Intrathecal 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 Lioresal dosing severe neurological outcomes have been reported in patients with renal impairment. Thus caution should be exercised while administering Lioresal Intrathecal in patients with renal impairment.
In rare instances elevated SGOT, alkaline phosphatase and glucose levels in the serum have been recorded when using oral Lioresal.
Treatment withdrawal
Abrupt discontinuation of Lioresal Intrathecal, regardless of cause, manifested by increased spasticity, pruritus, paraesthesia and hypotension, has resulted in sequelae including a hyperactive state with rapid uncontrolled spasms, hyperthermia 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.
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 and end of pump battery life.
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 Lioresal withdrawal is the restoration of intrathecal Lioresal 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 Lioresal, or oral, enteral, or intravenous benzodiazepines may prevent potentially fatal sequelae. Oral or enteral Lioresal alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.
4.5 Interaction with other medicinal products and other forms of interaction
The co-administration of other intrathecal agents with Lioresal Intrathecal 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 Lioresal Intrathecal 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 (see section 5.2). Experience with oral baclofen would suggest that:
•  Alcohol and other compounds affecting the CNS: There may be increased sedation where Lioresal 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 Lioresal may be potentiated, resulting in muscular hypotonia.
• Antihypertensives: Since concomitant treatment with Lioresal and anti-hypertensives is likely to increase the fall in blood pressure, it may be necessary to reduce the dosage of antihypertensive medication.
• Levodopa: Concomitant use of oral Lioresal 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 Lioresal 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.
Anaesthetics
Concomitant use of intrathecal baclofen and general anaesthetics (e.g. fentanyl, propofol) may increase the risk of cardiac disturbances and seizures. Thus, caution should be exercised when anaesthetics are administered to patients receiving intrathecal Lioresal.
4.6 Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Oral baclofen increases the incidence of omphaloceles (ventral hernias) in the foetuses of rats at high doses. No teratogenic effects have been noted in mice or rabbits.
A dose related increase in the incidence of ovarian cysts, and a less marked increase in enlarged and/or haemorrhagic adrenals have been observed in female rats treated for 2 years. The clinical relevance of these findings is not known.
Lioresal Intrathecal should not be used during pregnancy unless the potential benefit is judged to outweigh the potential risk to the foetus. Baclofen crosses the placental barrier.
Lactation
In mothers taking oral Lioresal in therapeutic doses the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected. It is not known whether detectable levels of drug are present in the breast milk of nursing mothers receiving Lioresal Intrathecal.
4.7 Effects on ability to drive and use machines
Central nervous system (CNS) depressant effects such as somnolence and sedation have been reported in some patients receiving intrathecal baclofen, and patients should be advised to exercise due caution. Other listed events include ataxia, hallucinations, vision blurred, diplopia and withdrawal symptoms. Operating equipment or machinery may be hazardous.
4.8 Undesirable effects
Some of the adverse reactions listed below have been reported in patients with spasticity of spinal origin but could also occur in patients with spasticity of cerebral origin. Adverse reactions that are more frequent in either population are indicated below.
Adverse drug reactions (Table 1) are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked under headings of frequency, the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥1/10); common ( ≥1/100 to <1/10); uncommon ( ≥1/1,000 to <1/100); rare ( ≥1/10,000 to<1/1,000); very rare (<1/10,000), and Not known (cannot be estimated from available data).
Table 1 Adverse drug reactions

Metabolism and nutritional disorders
Uncommon:	Dehydration
Psychiatric disorders
Common:	Depression, anxiety, agitation.
Uncommon:	Suicidal ideation, suicide attempt, hallucinations, paranoia, euphoric mood.
Not known:	Dysphoria
Nervous system disorders
Very common:	Somnolence
Common:	Convulsion, confusional state, sedation, dizziness, headache, paraethesia, dysarthria, lethargy, insomnia, disorientation,
Uncommon:	Ataxia, memory impairment, nystagmus
(Convulsion and headache occur more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin).
Eye disorders
Common:	Accommodation disorder, vision blurred, diplopia.
Cardiovascular disorders
Uncommon:	Bradycardia,
Vascular disorders
Common:	Hypotension
Uncommon:	Hypertension, deep vein thrombosis, flushing, pallor.
Respiratory, thoracic and mediastinal disorders
Common:	Respiratory depression, pneumonia, dyspnoea .
Not known:	Bradypnoea
Gastrointestinal disorders
Common:	Nausea/vomiting, constipation, dry mouth, diarrhoea, decreased appetite,increased salivation.
Uncommon:	Ileus, dysphagia,hypogeusia.
(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 and/or peripheral oedema.
Uncommon:	Alopecia,hyperhydrosis.
Musculoskeletal and connective tissue disorders
Very common:	Hypotonia
Common:	Hypertonia
Renal and urinary disorders
Common:	Urinary incontinence, urinary retention
(Urinary retention occurs more often in patients with spasticity of cerebral origin than in patients with spasticity of spinal origin).
Reproductive system and breast disorders
Common:	Sexual dysfunction (Intrathecal Lioresal may compromise erection and ejaculation. This effect is usually reversible on withdrawal of Lioresal Intrathecal.)
General disorders and administration site conditions
Common:	Asthenia, pyrexia, pain, chills.
Uncommon:	Hypothermia.
Rare:	Life threatening withdrawal symptoms due to drug delivery failure (see section 4.4 – Special warnings and precautions for use “Treatment Withdrawal”).

Adverse events associated with the delivery system
Adverse events associated with the delivery system (inflammatory mass at the tip of the catheter, catheter dislocation with possible complications, pocket infection, meningitis, overdose due to wrong manipulation of the device) have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (www.mhra.gov.uk/yellowcard)
4.9 Overdose
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 Lioresal Intrathecal 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.
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 30-40ml 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, iv diazepam cautiously administered.
• Blood pressure, pulse, body temperature, cardiac rhythm and respiratory rate should be monitored.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Antispastic with a spinal site of attack: (ATC Code: M03B X01).
Baclofen depresses both monosynaptic and polysynaptic reflex transmission in the spinal cord by stimulating the GABAß 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 Lioresal take the form of a beneficial action on reflex muscle contractions and of marked relief from painful spasm, automatism, and clonus. Lioresal improves the patient's mobility, makes it easier for him/her to manage without aid, 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 CNS depressant properties, causing sedation, somnolence, and respiratory and cardiovascular depression.
Baclofen when introduced directly into the intrathecal space, permits effective treatment of spasticity with doses at least 100 times smaller than those for oral administration.
Intrathecal bolus:
The onset of action is generally half an hour to one hour after administration of a single intrathecal dose. 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 dose and severity of symptoms and the method and speed of drug administration.
Continuous infusion:
Baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum efficacy is observed within 24 to 48 hours.
5.2 Pharmacokinetic properties
Because of the slow CSF circulation and the baclofen concentration gradient from the lumbar to the cisternal CSF the pharmacokinetic parameters observed in this fluid and as described below should be interpreted considering a high inter- and intra-patients variability.
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.
Distribution
After single intrathecal bolus injection/short-term infusion the volume of distribution, calculated from CSF levels, ranges from 22 to 157 ml.
With continuous intrathecal infusion daily doses of 50 to 1200 micrograms result in lumbar CSF concentrations of baclofen as high as 130 to 1240 ng/ml at steady state. According to the half-life measured in the CSF, CSF steady-state concentrations will be reached within 1-2 days.
During intrathecal infusion the plasma concentrations do not exceed 5ng/ml, confirming that baclofen passes only slowly across the blood-brain barrier.
Elimination
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. Elimination half-life of baclofen after having reached steady-state in the CSF has not been determined.
After both single bolus injection and chronic lumbar subarachnoid infusion using an implantable pump system, the mean CSF clearance was about 30 ml/h.
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 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 due to effects on the brain centres.
Special populations
Elderly Patients
No pharmacokinetic data is available in elderly patients after administration of Lioresal Intrathecal. When a single dose of the oral formulation is administered, data suggest that elderly patients have a slower elimination but a similar systemic exposure to baclofen compared to young adults. However, the extrapolation of these results to multi-dose treatment suggests no significant pharmacokinetics difference between young adults and elderly patients.
Paediatrics
In paediatric patients, respective plasma concentrations are at or below 10 ng/mL.
Hepatic impairment
No pharmacokinetic data is available in patients with hepatic impairment after administration of Lioresal Intrathecal. However, as liver does not play a significant role in the disposition of baclofen it is unlikely that its pharmacokinetics would be altered to a clinically significant level in patients with hepatic impairment.
Renal impairment
No pharmacokinetic data is available in patients with renal impairment after administration of Lioresal Intrathecal. Since baclofen is majorly eliminated unchanged through the kidneys, accumulation of unchanged drug in patients with renal impairment can not be excluded.
5.3 Preclinical safety data
Local tolerance
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. Preclinical studies in animal models have demonstrated that the formation of inflammatory mass is directly related to high dose and/or high concentration of intrathecal opioids and no inflammatory mass is formed with intrathecal baclofen as a sole agent.
Mutagenicity and carcinogenicty
Baclofen was negative for mutagenic and genotoxic potential in tests in bacteria, mammalian cells, yeast, and Chinese hamsters. There was no evidence of a mutagenic potential of baclofen
A 2-year rat study (oral administration) showed that baclofen is not carcinogenic. In the same study a dose-related increase in incidence of ovarian cysts and a less marked increase in enlarged and/or haemorrhagic adrenal glands was observed.
Repeated dose toxicity
Repeated intrathecal administration of baclofen was not associated with the development of inflammatory masses in studies in rats and dogs. No changes to the spinal cord and adjacent tissue and no signs of irritation or inflammation of the spinal cord and surrounding tissues were noted in either species.
Reproduction toxicity
Intrathecal baclofen is unlikely to have adverse effects on fertility or on prenatal or postnatal development based on oral studies in rats and rabbits. Baclofen is not teratogenic in mice, rats, and rabbits at doses at least 125-times the maximum intrathecal mg/kg dose. Lioresal given orally has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses of rats given approximately 500-times the maximum intrathecal dose expressed as a mg/kg dose. This abnormality was not seen in mice or rabbits. Lioresal dosed orally has been shown to cause delayed fetal growth (ossification of bones) at doses that also caused maternal toxicity in rats and rabbits. Baclofen caused widening of the vertebral arch in rat fetuses at a high intraperitoneal dose.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium chloride; water for injections
6.2 Incompatibilities
If alternative baclofen concentrations are required Lioresal Intrathecal may be diluted under aseptic conditions with sterile preservative-free sodium chloride for injections. The ampoules should not be mixed with other solutions for injection or infusion (dextrose has proved to be incompatible due to a chemical reaction with baclofen).
The compatibility of Lioresal Intrathecal with the components of the infusion pump (including the chemical stability of baclofen in the reservoir) and the presence of an in-line bacterial retentive filter should be confirmed with the pump manufacturer prior to use.
6.3 Shelf life
Lioresal® Intrathecal Injection 50micrograms/1ml:  3 years
Lioresal® Intrathecal Infusion 10mg/20ml:  5 years
Lioresal® Intrathecal Infusion 10mg/5ml:  3 years
6.4 Special precautions for storage
Protect from heat (store below 30°C).
Medicines should be kept out of the reach and sight of children.
6.5 Nature and contents of container
Colourless glass ampoules, glass type I, according to Ph. Eur.
6.6 Special precautions for disposal and other handling
Each ampoule is intended for single use only, and any unused solution should be discarded. Ampoules should not be either frozen or autoclaved.
7. Marketing authorisation holder
Novartis Pharmaceuticals UK Limited
Trading as Ciba Laboratories
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
England.
8. Marketing authorisation number(s)
Lioresal® Intrathecal Injection 50micrograms/1ml:  PL 00101/0500
Lioresal® Intrathecal Infusion 10mg/20ml:  PL 00101/0501
Lioresal® Intrathecal Infusion 10mg/5ml:  PL 00101/0502
9. Date of first authorisation/renewal of the authorisation
Lioresal® Intrathecal Injection 50micrograms/1ml:  1 February 2003
Lioresal® Intrathecal Infusion 10mg/20ml: 1 February 2003
Lioresal® Intrathecal Infusion 10mg/5ml: 3 September 2004
10. Date of revision of the text
03 June 2015