Ziconotide

12.1 Mechanism of Action Ziconotide binds to N-type calcium channels located on the primary nociceptive (A-δ and C) afferent nerves in the superficial layers (Rexed laminae I and II) of the dorsal horn in the spinal cord. Although the mechanism of action of ziconotide has not been established in humans, results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release from the primary afferent nerve terminals and antinociception.

1 INDICATIONS AND USAGE PRIALT (ziconotide) solution, intrathecal infusion is indicated for the management of severe chronic pain in adult patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. PRIALT (ziconotide) solution, intrathecal infusion is an N-type calcium channel antagonist indicated for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. ( 1 )

2 DOSAGE AND ADMINISTRATION PRIALT is a non-opioid and non-NSAID analgesic agent used for the management of severe and chronic pain. Administer PRIALT intrathecally by or under the direction of a physician experienced in the technique of intrathecal administration and who is familiar with the drug and device labeling. ( 2 ) PRIALT is not for intravenous administration. ( 2.1 ) PRIALT is delivered using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter. ( 2.1 ) PRIALT 25 mcg/mL is used undiluted. The 100 mcg/mL formulation must be used diluted until an appropriate dose has been established. ( 2.1 ) Saline solutions containing preservatives must not be used. ( 2.1 ) Refrigerate but do not freeze all PRIALT solutions after preparation. Begin infusion within 24 hours. ( 2.1 ) Initiate PRIALT at no more than 2.4 mcg/day (0.1 mcg/hr) and titrated to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2–3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hr) by Day 21. ( 2 ) 2.1 General Information PRIALT is intended for administration by or under the direction of a physician experienced in the technique of intrathecal administration and who is familiar with the drug and device labeling. PRIALT is not intended for intravenous administration. PRIALT is intended for intrathecal delivery using the Medtronic SynchroMed ® II and SynchroMed ® III Infusion System [ see Warnings and Precautions ( 5.2 ) ]. Refer to the manufacturer's manual for specific instructions and precautions for programming the microinfusion device and/or refilling the reservoir. PRIALT may be used for therapy undiluted (25 mcg/mL in 20 mL vial) or diluted (100 mcg/mL in 1 or 5 mL vials). The 100 mcg/mL formulation may be administered undiluted once an appropriate dose has been established. Dilute PRIALT with 0.9% Sodium Chloride Injection, USP (preservative free) using aseptic procedures to the desired concentration prior to placement in the microinfusion pump. Saline solutions containing preservatives are not appropriate for intrathecal drug administration and should not be used due to risk of neurotoxicity. Refrigerate but do not freeze all PRIALT solutions after preparation and begin infusion within 24 hours. Inspect vials of PRIALT visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any PRIALT solution with observed particulate matter or discoloration and any unused portion left in the vial. 2.2 Dosing Dose Initiation Initiate dosing with PRIALT via intrathecal device at no more than 2.4 mcg/day (0.1 mcg/hr). Dose Titration Titrate doses by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2 to 3 times per week based on analgesic response and adverse events. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing. The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr). Adjust the dose of intrathecal PRIALT according to the severity of pain, the patient's response to therapy, and the occurrence of adverse reactions. 2.3 Instructions for Use with the Medtronic SynchroMed II and SynchroMed III Infusion System Refer to the manufacturer's manuals for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir, and programming. [ see Warnings and Precautions ( 5.2 ) ] Naïve Pump Priming (i.e., first time use with PRIALT) Use only the undiluted 25 mcg/mL formulation for naïve pump priming. Rinse the internal surfaces of the pump with 2 mL of PRIALT at 25 mcg/mL. Repeat twice for a total of three rinses. Initial Pump Fill Use only the undiluted 25 mcg/mL formulation for the initial pump fill . Fill the naïve pump after priming with the appropriate volume of PRIALT 25 mcg/mL. Begin dosing at a delivery rate no higher than 2.4 mcg/day (0.1 mcg/hr). In a naïve pump, PRIALT is lost due to two factors that do not occur upon subsequent refills: adsorption on internal device surfaces, such as titanium, and by dilution in the residual space of the device. Consequently, the pump reservoir should be refilled with PRIALT within 14 days of the initial fill to ensure appropriate dose administration. Pump Refills For subsequent pump refills, fill the pump at least every 40 days if PRIALT is used diluted. For undiluted PRIALT, fill the pump at least every 84 days. To ensure aseptic transfer of PRIALT into the device, use the Medtronic refill kit. Empty the pump contents prior to refill with PRIALT. If the internal infusion system must be surgically replaced while the person is receiving PRIALT, rinse the replacement pump with PRIALT according to Naïve Pump Priming [ see Dosage and Administration ( 2.

6 ADVERSE REACTIONS The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state, nystagmus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics at 1-844-344-4035 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates in clinical practice. A total of 1254 adult patients received PRIALT as a continuous infusion in acute and severe chronic pain trials with an exposure of 662 patient-years. The mean duration of treatment was 193 days with 173 patients (14%) treated for at least 1 year. The average final dose was 17.6 mcg/day (0.73 mcg/hr). The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state and nystagmus. Slower titration of PRIALT may result in fewer serious adverse reactions and discontinuation of PRIALT for adverse reactions [ see Clinical Studies ( 14 ) and Dosage and Administration ( 2 ) ]. Adverse reactions during the slow titration placebo-controlled trial that occurred in 5% or greater of patients and more commonly with PRIALT than with placebo are summarized in Table 1 . Table 1. Incidence of Adverse Reactions in Slow Titration Placebo-Controlled Trial by Percent (Events That Occurred in ≥ 5% of Patients and More Commonly with PRIALT than with Placebo) MedDRA System Organ Class MedDRA Preferred term PRIALT N=112 Placebo N=108 Percentage of Patients Any AE 93 82 Ear and Labyrinth Disorders Vertigo 7 0 Eye Disorders Vision Blurred 12 3 Gastrointestinal Disorders Diarrhea 18 15 Nausea 40 29 Vomiting 16 14 General Disorders and Administration Site Conditions Asthenia 18 6 Gait Abnormal 14 2 Pyrexia 5 3 Rigors 7 5 Infections and Infestations Sinusitis 5 2 Metabolism and Nutrition Disorders Anorexia 6 2 Musculoskeletal and Connective Tissue Disorders Muscle Spasms 6 4 Pain in Limb 5 2 Nervous System Disorders Amnesia 8 0 Ataxia 14 1 Dizziness 46 13 Dysarthria 7 0 Dysgeusia 5 5 Headache 13 11 Memory Impairment 7 1 Nystagmus 8 0 Somnolence 17 10 Tremor 7 3 Psychiatric Disorders Anxiety 8 3 Confusional State 15 5 Insomnia 6 9 Renal and Urinary Disorders Urinary Retention 9 0 Skin and Subcutaneous Disorders Pruritis 7 7 Sweating Increased 5 6 Other Adverse Reactions Observed During Clinical Studies of PRIALT The following adverse reactions assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies: EYE DISORDERS: diplopia, visual disturbance GASTROINTESTINAL DISORDERS: abdominal pain, constipation, dry mouth, nausea aggravated GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: fall, fatigue, lethargy, edema peripheral INVESTIGATIONS: blood creatine phosphokinase increased METABOLISM AND NUTRITION DISORDERS: appetite decreased MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: muscle cramp, muscle weakness, myalgia, pain in limb NERVOUS SYSTEM DISORDERS: aphasia, areflexia, balance impaired, burning sensation, coordination abnormal, disturbance in attention, dizziness postural, dysarthria, dysgeusia, hypoaesthesia, mental impairment, paraesthesia, sedation, speech disorder PSYCHIATRIC DISORDERS: agitation, anxiety, cognitive disorder, confusional state, depression, depression aggravated, disorientation, hallucination, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder, nervousness, paranoia RENAL AND URINARY DISORDERS: dysuria, urinary hesitation VASCULAR DISORDERS: hypotension, orthostatic hypotension. The following medically important adverse reactions occurred in less than 2% of patients were assessed by the clinical investigators as related to PRIALT: acute renal failure , atrial fibrillation, cerebrovascular accident, sepsis, meningitis, psychotic disorder, suicidal ideation, respiratory distress , rhabdomyolysis, electrocardiogram abnormal, stupor, loss of consciousness, clonic convulsion and grand mal convulsion. Fatal aspiration pneumonia and suicide attempt were reported in less than 1% of patients. 6.2 Postmarketing Experience The following adverse events have been reported during post-approval use of PRIALT. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hypersensitivity reactions including angioedema, serious skin reactions including bullous dermatitis, skin ulcers, skin exfoliation, and burning skin sensation.

7 DRUG INTERACTIONS Formal PK drug-drug interaction studies have not been performed with PRIALT. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, intrathecal administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Further, as ziconotide is not highly bound in plasma (approximately 50%) and has low plasma exposure following intrathecal administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely. Over 90% of patients treated with intrathecal PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids. The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended. Combination of PRIALT with intrathecal opiates is not recommended. ( 7 ) Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness. ( 5.3 ) The use of PRIALT may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion. ( 7.1 ) 7.1 Interaction with CNS Depressants Almost all patients in the PRIALT clinical trials received concomitant non-intrathecal medication. Most patients received several concomitant drugs, including antidepressants (66%), anxiolytics (52%), antiepileptics (47%), neuroleptics (46%), and sedatives (34%). The use of drugs with CNS-depressant activities may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion [ see Warnings and Precautions ( 5 ) ].