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Abrupt Discontinuation Of Antispasmodic Drug Can Lead To Adverse Events Including Death

Novartis recommends physicians and patients pay careful attention to proper programming and monitoring of infusion system

DORVAL, QC -- September 24, 2002 -- Novartis Pharmaceuticals Canada Inc. is warning patients who use the antispasmodic drug Lioresal(*) Intrathecal (baclofen injection), their caregivers and their treating physicians of adverse events that can result from improper programming and monitoring of the infusion system. Lioresal(*) Intrathecal is an injectable medication, prescribed for the management of patients with severe spasticity due to spinal cord injury or multiple sclerosis who are unresponsive to oral baclofen or who experience unacceptable side effects at effective oral doses. Lioresal(*) Intrathecal has been available in Canada since 1994.

The administration of Lioresal(*) Intrathecal involves an infusion system (pump, catheter and reservoir for the medication) which is surgically implanted in the abdomen of the patient, with the catheter providing medication directly to the spinal cord. The pump is programmed to provide the required dose of medication at a specific delivery rate to the patient. The medication is replenished via a needle which is introduced through the skin, and directly into the reservoir. As the infusion system is not visible, patients and physicians know how much medication is left in the reservoir based on the specific patient's dosing regimen, pump alarms that sound when medication is running low and/or via a scanner and computer located at the treating hospital or clinic. When the scanner is passed over the skin of the patient, it identifies the dosage for the patient in question, delivery rate, and the amount of drug left in the reservoir. Scheduled visits between physicians and patients/caregivers are key to ensuring that the medication is refilled, and abrupt discontinuation of the therapy does not occur.

Analysis of safety databases has shown that abrupt discontinuation of Lioresal(*) Intrathecal, regardless of the cause, has resulted in adverse events that include high fever, altered mental states, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis (muscle disintegration), 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. Furthermore, patients and caregivers should be educated on the early symptoms of Lioresal(*) Intrathecal withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries T-6 or above, communication difficulties, history of withdrawal symptoms from oral or injectable baclofen). Caregivers and patients are requested to consult the technical manual of the implantable infusion system for additional post implant clinician and patient information.

In the first nine years of post-marketing experience, 27 cases of withdrawal temporally related to the cessation of Lioresal(*) Intrathecal therapy were reported around the world, and six patients have died related to the cessation of the drug. In Canada, there have been four cases of adverse events. In most cases, symptoms of withdrawal appeared within hours to a few days following interruption of the 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, pruritis (itching), hypotension (low blood pressure), and paresthesias (abnormal touch sensation such as burning or prickling). Some clinical characteristics of the advanced Lioresal(*) Intrathecal withdrawal syndrome may resemble autonomic dysreflexia (syndrome affecting patients with lesions of the spinal cord, characterized by hypertension, slowed heartbeat, excessive sweating, etc.), 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.

Seizures have been reported during overdose and with withdrawal from Lioresal Intrathecal as well as in patients maintained on therapeutic doses of Lioresal(*) Intrathecal. Except for very 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).

Novartis has sent a health care professional letter to Canadian physicians and pharmacists to remind them of this important safety information associated with Lioresal Intrathecal to enable them to optimally counsel patients and caregivers. The Product Monograph for Lioresal(*) Intrathecal will also be expanded to provide additional background information on this adverse event. The current product monograph contains a statement cautioning users and prescribers of the drug of the dangers related to abrupt drug withdrawal.

ABOUT NOVARTIS CANADA
Novartis Pharmaceuticals Canada Inc., a leader in the healthcare field, is committed to the discovery, development and marketing of innovative products to improve the well being of all Canadians. Novartis Pharmaceuticals Canada conducts hundreds of clinical trials across the country seeking new treatments for cardiovascular disease, diabetes, cancer, organ transplantation and glaucoma. In 2001, the Company invested $34 million in research and development. Novartis Pharmaceuticals Canada Inc. employs approximately 650 people in Canada and its headquarters are located in Dorval, Quebec. In addition to Novartis Pharmaceuticals Canada Inc., the Novartis Group in Canada consists of Novartis Animal Health Canada Inc., Novartis Consumer Health Canada Inc., (including Novartis Nutrition Corporation and Gerber (Canada) Inc.) and CIBA Vision Canada Inc. For further information about Novartis Canada, please consult http://www.novartis.ca.

ABOUT NOVARTIS
Novartis AG (NYSE: NVS) is a world leader in healthcare with core businesses in pharmaceuticals, consumer health, generics, eye-care, and animal health. In 2001, the Group's businesses achieved sales of CHF 32.0 billion (USD 19.1 billion) and a net income of CHF 7.0 billion (USD 4.2 billion). The Group invested approximately CHF 4.2 billion (USD 2.5 billion) in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ about 74 000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com.

(*)Lioresal is a registered trademark.


SOURCE: Novartis Pharmaceuticals Canada Inc

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