4.1. Therapeutic indications

Prialt is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT) analgesia.

4.2. Posology and method of administration

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. (See Section 4.3, 4.4, 4.8 and 5.1).

Posology

Dose initiation

Dosing of ziconotide should be initiated at no more than 2.4 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.

Patients may be titrated in dose increments of ≤ 2.4 μg/day, up to a maximum dose of 21.6 μg/day. The minimal interval between dose increases is 24 hours; the recommended interval, for safety reasons, is 48 hours or more.

The maximum daily dose is 21.6 µg/day (0.9 µg/h).

The median dose at response is approximately 6.0 μg/day and approximately 75% of responsive patients required ≤ 9.6 μg/day in placebo-controlled clinical trials. However, to limit the occurrence of serious adverse reactions, reports from clinical practice indicate that responsive patients may require a smaller daily dose of approximately 3.0 - 4.5 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. Approximately 75% of patients who respond satisfactorily to treatment require a dose of ≤ 9.6 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. As the risk of meningitis secondary to prolonged catheterisation of the intrathecal space is greater with an external catheter infusion system, internal systems are recommended to administer ziconotide for prolonged periods (see section 4.4). An external catheter system should only be used when an internal system cannot be implanted.

When low doses of ziconotide are required, for example when initiating titration, ziconotide must be diluted before use with preservative-free sodium chloride 9 mg/mL (0.9%) solution for injection.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Combination with IT chemotherapy (see section 4.5).

Pre-existing history of psychosis with ziconotide.

History of suicidal attempt or suicidal ideation with ziconotide (see Section 4.2, 4.4 and 4.8).

Infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of cerebrospinal fluid (CSF).

4.4. Special warnings and precautions for use

Patients should undergo a neuropsychiatric evaluation before, after starting and during intrathecal ziconotide, and immediately when any depressive signs or symptoms appear (see Sections 4.3, 4.4 and 4.8).

Caregivers should contact a physician immediately if the patient experiences symptoms of potentially life-threatening adverse event.

Long-term use

Although ziconotide has been studied in long-term, open label efficacy and safety clinical trials, controlled studies of longer than 3 weeks duration have not been conducted (see section 5.1). Possible long-term local toxic effects on the spinal cord have not been excluded and preclinical data in this respect are limited (see section 5.3). 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. Lower catheter tip placement, e.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. Caution should be exercised when ziconotide is administered to patients who are receiving systemic chemotherapy (see section 4.5).

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.

Cognitive and neuropsychiatric adverse reactions

Cognitive and neuropsychiatric adverse reactions, particularly confusion, are common in patients treated with ziconotide. Cognitive impairment typically appears after several weeks of treatment. Episodes of acute psychiatric disturbances, such as hallucinations, paranoid reactions, hostility, aggressiveness, delirium, psychosis and manic reactions have been reported in patients treated with ziconotide. The ziconotide dose should be reduced or discontinued if signs or symptoms of cognitive impairment or neuropsychiatric adverse reactions develop, but other contributing causes should also be considered. The cognitive effects of ziconotide are typically reversible within 1 - 4 weeks after discontinuation of the medicinal product, but may persist in some cases. It is recommended that patients undergo a neuropsychiatric evaluation before and after starting intrathecal ziconotide.

In patients with severe chronic pain there is a higher incidence of suicide and suicide attempts than in the general population. Ziconotide may cause or worsen depression with the risk of suicide in susceptible patients. Patients with a history of suicide-related events prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicidal behaviour, and should receive careful monitoring during treatment. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Patients with a pre-existing history of suicidal attempt with ziconotide should not be given ziconotide again. Ziconotide is contraindicated in patients with a history of suicidal attempt or ideation with ziconotide (section 4.3).

Depression of Central Nervous System (CNS)

Patients have experienced depressed levels of consciousness while receiving ziconotide. The patient usually remains conscious and breathing is not depressed. The event may be self-limited, but ziconotide should be discontinued until the event resolves. The re-introduction of ziconotide is not recommended in these patients. Withdrawal of concomitant CNS depressant medicinal products should also be considered as they may contribute to the reduced level of arousal.

4.5. Interaction with other medicinal products and other forms of interaction

Specific clinical medicinal product interaction studies have not been conducted with ziconotide. However, low plasma ziconotide concentrations, metabolism by ubiquitous peptidases and relatively low plasma protein binding (see section 5.2) make metabolic-based interactions or plasma protein displacement type interactions between ziconotide and other medicinal products unlikely.

No clinical data are available on the interaction between IT chemotherapy and IT ziconotide. Ziconotide is contraindicated in combination with IT chemotherapy (see section 4.3).

Only a small number of patients have received systemic chemotherapy and IT ziconotide. Caution should be exercised when ziconotide is administered to patients who are receiving systemic chemotherapy (see section 4.4).

Medicinal products that affect specific peptidases/proteases would not be expected to impact upon ziconotide plasma exposure. Based on very limited clinical investigations, both angiotensin converting enzyme inhibitors (e.g., benazepril, lisinopril and moexipril) and HIV protease inhibitors (e.g., ritonavir, saquinavir, indinavir), have no readily apparent effect on plasma ziconotide exposure.

Ziconotide does not interact with opiate receptors. If discontinuing opiates when initiating ziconotide therapy, opiate withdrawal should be gradual. For patients being withdrawn from IT opiates, the IT opiate infusion dose should be gradually tapered over a few weeks and replaced with a pharmacologically equivalent dose of oral opiates. Adding IT ziconotide to stable doses of IT morphine (see section 5.1), is possible but requires special attention, as a high rate of neuropsychiatric adverse reactions (confusion/thinking abnormal, paranoid reactions and hallucinations, and abnormal gait), some of them serious, was observed in Study 202 despite a low dose of ziconotide. Vomiting and anorexia, and peripheral oedema were also observed when IT ziconotide was added to IT morphine. The addition of IT morphine to stable doses of IT ziconotide is better tolerated (pruritus has been reported) (see section 5.1).

An increased incidence of somnolence has been observed when ziconotide is administered concomitantly with systemic baclofen, clonidine, bupivacaine or propofol thus for the time being their simultaneous use is discouraged.

No data are available regarding the concomitant use of partial opioid agonists (e.g. buprenorphine) with ziconotide.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of ziconotide in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Ziconotide is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether ziconotide/metabolites are excreted in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Prialt therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No specific studies with ziconotide in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects in males while reductions in corpora lutea; implantation sites and number of live embryos were observed in females (see section 5.3).

4.7. Effects on ability to drive and use machines

Prialt has moderate influence on the ability to drive and use machines.

Ziconotide may cause confusion, somnolence and other neurological adverse reactions, therefore patients must be advised not to drive or operate machines if affected.

4.8. Undesirable effects

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. The infusion dose rate ranged from 0.03 - 912 μg/day, with a median final dose rate of 7.2 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, headache, somnolence

dysarthria, amnesia, dysgeusia, tremor, balance impaired, ataxia, aphasia, 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

incoherence, loss of consciousness, coma, stupor, 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

Gastrointestinal disorders

nausea, vomiting

diarrhoea, dry mouth, constipation, nausea aggravated, upper abdominal pain

dyspepsia

Skin and subcutaneous tissue disorders

pruritus, sweating increased

rash

Musculoskeletal and connective tissue disorders

pain in limb, myalgia, muscle spasms, muscle cramp, muscle weakness, arthralgia, peripheral swelling

rhabdomyolysis, myositis, back pain, muscle 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

electrocardiogram abnormal, aspartate aminotransferase increased, blood creatine phosphokinase MM increased, body temperature increased

a. From spontaneous reporting

Description of selected adverse reactions

Meningitis

Administration of medicinal products by the intrathecal route carries the risk of potential serious infections, such as meningitis, which may be life threatening. Patients and physicians must be vigilant for typical symptoms and signs of meningitis (see section 4.4).

Elevations of creatine phosphokinase

Elevations in creatine phosphokinase were usually asymptomatic. Monitoring of creatine phosphokinase is recommended. Discontinuation of ziconotide should be considered in the event of progressive or significant elevation of creatine phosphokinase in association with clinical features of myopathy or rhabdomyolysis (see section 4.4).

CNS adverse reactions

Cognitive and neuropsychiatric adverse reactions are common in patients treated with ziconotide. Cognitive impairment typically appears after several weeks of treatment. Episodes of acute psychiatric disturbances, such as hallucinations, paranoid reactions, hostility, aggressiveness, delirium, psychosis and manic reactions have been reported in patients treated with ziconotide. The ziconotide dose should be reduced or discontinued if signs or symptoms of cognitive impairment or neuropsychiatric adverse reactions develop, but other contributing causes should also be considered. The cognitive effects of ziconotide are typically reversible within 1 - 4 weeks after discontinuation of the medicinal product, but may persist in some cases.

The available data do not exclude the possibility of an increased risk of suicide when using ziconotide. Prialt is contra-indicated in patients with a history of suicidal attempt or suicidal ideation with ziconotide (Section 4.3). It is recommended that patients undergo a neuropsychiatric evaluation before and after starting intrathecal ziconotide (see section 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In intravenous infusion studies, healthy male volunteers received ziconotide at doses of up to 70,000 μg/day or 3,200 times the maximum recommended daily intrathecal infusion dose. Postural hypotension was observed in almost all subjects who received high intravenous doses of ziconotide.

The maximum recommended intrathecal dose is 21.6 μg/day. The maximum intended intrathecal dose of ziconotide in clinical trials was 912 μg/day following upward titration over 7 days.

Symptoms

In one clinical study a male cancer patient received an accidental IT ziconotide overdose of 744 μg over a 24-hour period (31 μg/hour) and resumed treatment at the intended dose after experiencing a reduction in Visual Analog Scale of Pain Intensity (VASPI) from 82 to 2.5 mm. In some patients who received intrathecal doses greater than the maximum recommended dose, exaggerated pharmacological effects, e.g., ataxia, nystagmus, dizziness, stupor, depressed level of consciousness, muscle spasms, confusional state, sedation, hypotension, aphasia, speech disorder, nausea and vomiting were observed. There was no indication of respiratory depression. Most patients under observation recovered within 24 hours of withdrawal of the medicinal product.

Management

General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the medicinal product have resolved.