PRIALT

Treatment with ziconotide should only be undertaken by physicians experienced in intrathecal (IT) administration of medicinal products. Patients should undergo a neuropsychiatric evaluation before, after starting and during intrathecal ziconotide and immediately when any depressive signs or symptoms appear.

1). 4 μg/day and titrated on an individual patient basis according to analgesic response and adverse reactions. Dose titration For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing.

6 μg/day. The minimal interval between dose increases is 24 hours; the recommended interval, for safety reasons, is 48 hours or more. 9 μg/h). 6 μg/day in placebo-controlled clinical trials. 5 μg/day or lower. Adjust the dose of intrathecal ziconotide according to the severity of pain, the patient’s response to therapy, and the occurrence of adverse reactions.

General management of side effects If necessary the dose can be decreased by any amount (including stopping the infusion) for the management of adverse reactions. 6 μg/day. Stopping rule Treatment should be discontinued in case of lack or insufficient efficacy, defined as pain reduction by less than 20% at the maximal tolerated dose.

The benefit/risk should always be evaluated by the physician on an individual basis. Renal impairment Studies have not been conducted in patients with impaired renal function. Caution should be exercised when ziconotide is administered to patients with impaired renal function.

Hepatic impairment Studies have not been conducted in patients with impaired hepatic function. Caution should be exercised when ziconotide is administered to patients with impaired hepatic function. Older patients ≥ 65 years of age Dose adjustment is not required in older adults.

However, it should be taken into account that renal and/or hepatic insufficiency is more common in patients ≥ 65 years of age. Paediatric population The safety and efficacy of ziconotide in children aged 0 to 18 years have not been established.

No data are available. Method of administration Intrathecal use. Ziconotide must be administered as a continuous infusion via an intrathecal catheter, using an external or internally implanted mechanical infusion pump capable of delivering an accurate infusion volume.

Summary of the safety profile The safety of ziconotide administered as a continuous intrathecal infusion has been evaluated in more than 1,400 patients participating in acute and chronic pain clinical trials. The duration of treatment has ranged from one-hour bolus infusion to continuous use for more than 6 years.

The median exposure time was 43 days. 2 μg/day. In clinical trials, 88% of patients experienced adverse reactions. The most common adverse reactions reported in long-term clinical trials were dizziness (42%), nausea (30%), nystagmus (23%), confusional state (25%), gait abnormal (16%), memory impairment (13%), vision blurred (14%), headache (12%), asthenia (13%), vomiting (11%), and somnolence (10%).

Most adverse reactions were mild to moderate in severity and resolved over time. Tabulated list of adverse reactions Unless otherwise noted the table shows the incidence rates of adverse reactions reported in the intrathecal clinical trials with ziconotide (short- and long-term exposure).

Within each frequency grouping undesirable effects are presented in order of decreasing frequency. 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) Not known (cannot be estimated from the available data) System organ class Very common Common Uncommon Not known Infections and infestations sepsis, meningitis Immune system disorders anaphylactic reactiona Metabolism and nutrition disorders appetite decreased, anorexia Psychiatric disorders confusional state anxiety, auditory hallucination, insomnia, agitation, disorientation, hallucination, visual hallucination, depression, paranoia, irritability, depression aggravated, nervousness, affect lability, mental status changes, anxiety aggravated, confusion aggravated delirium, psychotic disorder, suicidal ideation, suicide attempt, thought blocking, abnormal dreams, aggressiveness Nervous system disorders dizziness, nystagmus, memory impairment, dysarthria, amnesia, dysgeusia, tremor, balance impaired, ataxia, aphasia, incoherence, loss of consciousness, coma, stupor, System organ class Very common Common Uncommon Not known headache, somnolence burning sensation, sedation, paraesthesia, hypoaesthesia, disturbance in attention, speech disorder, areflexia, coordination abnormal, dizziness postural, cognitive disorder, hyperaesthesia, hyporeflexia, ageusia, depressed level of consciousness, dysaesthesia, parosmia, mental impairment convulsions, cerebrovascular accident, encephalopathy Eye disorders vision blurred diplopia, visual disturbance, photophobia Ear and labyrinth disorders vertigo, tinnitus Cardiac disorders atrial fibrillation Vascular disorders Orthostatic hypotension, hypotension Respiratory, thoracic and mediastinal disorders dyspnoea respiratory distress Gastrointestin al disorders nausea, vomiting diarrhoea, dry mouth, constipation, nausea aggravated, upper abdominal pain dyspepsia Skin and subcutaneous tissue disorders pruritus, sweating increased rash Musculoskelet al and connective pain in limb, myalgia, muscle spasms, muscle rhabdomyolysis, myositis, back pain, muscle System organ class Very common Common Uncommon Not known tissue disorders cramp, muscle weakness, arthralgia, peripheral swelling twitching, neck pain Renal and urinary disorders urinary retention, urinary hesitation, dysuria, urinary incontinence acute renal failure General disorders and administration site conditions gait abnormal , asthenia fatigue, pyrexia, lethargy, oedema peripheral, rigors, fall, chest pain, feeling cold, pain, feeling jittery, pain exacerbated difficulty in walking Investigations blood creatine phosphokinase increased, weight decreased electrocardiogra m abnormal, aspartate aminotransferas e increased, blood creatine phosphokinase MM increased, body temperature increased a.

8). Caregivers should contact a physician immediately if the patient experiences symptoms of potentially life-threatening adverse event. 1). 3). Therefore, caution is needed during long-term treatment. Risk of infection The administration of medicinal products by the intrathecal (IT) route carries the risk of potentially serious infections, such as meningitis, which may be life threatening.

Meningitis due to the entrance of organisms along the catheter track or inadvertent contamination of the infusion system is a known complication of intrathecal medicinal product administration, especially with external systems. Patients and physicians must be vigilant for typical symptoms and signs of meningitis.

The optimal intrathecal placement of the catheter tip has not been established. g. at the lumbar level, may reduce the incidence of ziconotide-related neurological adverse reactions. Therefore, catheter tip placement should be carefully considered to allow adequate access to spinal nociceptive segments whilst minimising medicinal product concentrations at cerebral levels.

Only a small number of patients have received systemic chemotherapy and IT ziconotide. 5). Elevations in creatine kinase Elevations in creatine kinase, which are usually asymptomatic, are common amongst patients on intrathecal ziconotide.

Progressive elevation of the creatine kinase is uncommon. However, monitoring of creatine kinase is recommended. In the event of progressive elevation, or clinically significant elevation in association with clinical features of myopathy or rhabdomyolysis, discontinuation of ziconotide should be considered.

Hypersensitivity reactions Hypersensitivity reactions, including anaphylaxis, have not been observed during clinical trials and the immunogenicity of ziconotide administered by the IT route appears to be low. However, the potential for severe allergic reactions cannot be excluded and spontaneous reports of anaphylactic reactions have been received.

1. 5). Pre-existing history of psychosis with ziconotide. 8). Infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of cerebrospinal fluid (CSF).