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New Drugs: Tigecycline, Ziconotide, and Clofarabine
NEW
DRUGS
New Drugs: Tigecycline, Ziconotide, and Clofarabine Daniel A. Hussar
Antibiotic The extent to which microorganisms have developed resistance to antimicrobial agents to which they were initially susceptible is an ongoing concern. The approval of tigecycline (Tygacil—Wyeth) represents an important step in the development of new antibiotics active against certain bacteria resistant to many of the previously marketed antibiotics. Designated by some as the first of a new class of glycylcycline antibiotics, tigecycline is closely related structurally to minocycline (e.g., Minocin), shares many of the actions and risks of minocycline and other tetracyclines, and may be considered the newest addition to the tetracycline class of antibiotics. However, tigecycline is not apparently affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux, and crossresistance between tigecycline and other antibiotics has not been observed. Tigecycline has a broad spectrum of action that includes numerous gram-positive and -negative aerobic and anaerobic bacteria, some of which (e.g., methicillin-resis636
tant Staphylococcus aureus) have not been demonstrated to be susceptible to other tetracyclines. Its action is usually bacteriostatic. The broad spectrum of action of the new agent permits its use as monotherapy for certain infections for which the use of a combination of antibiotics has previously been necessary. Tigecycline is administered by intravenous infusion and is indicated for the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal infections (cIAI) caused by susceptible strains of the bacteria identified in Table 1. It has also demonstrated activity in vitro against many other organisms including problematic bacteria such as vancomycin-resistant Enterococcus faecalis and E. faecium; however, the clinical effectiveness of tigecycline in the treatment of infections caused by these
bacteria has not yet been demonstrated. In the treatment of cSSSI, tigecycline was compared with a combination regimen of vancomycin and aztreonam (e.g., Azactam) in management of complicated deep soft tissue infections including wound infections, cellulitis, major abscesses, infected ulcers, and burns. The clinical cure rates were 86% and 88%, respectively, and the two regimens were considered to be comparable in their effectiveness. For treatment of cIAI such as appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intraabdominal abscess, perforation of intestine, and peritonitis, tigecycline was compared with imipenem/cilastatin (Primaxin). The clinical cure rates were 86% among patients treated with either of the antibiotics. The treatment of serious infections, which are frequently mixed infections caused by more than one organism, must often be initiated before causative organisms have been identified and their susceptibility determined. Tigecycline may be used as empiric monotherapy before
results of these tests are known, and its broad spectrum of action, which includes bacteria such as staphylococci, streptococci, enterococci, and Bacteroides species, provides effective treatment for many infections that otherwise may have required the use of two or more antibiotics. However, to reduce the development of drug-resistant bacteria, tigecycline should be used only to treat infections that are documented or strongly suspected to be caused by susceptible bacteria. The adverse events most frequently reported with the use of tigecycline are nausea (30%) and vomiting (20%) that are usually mild to moderate in severity and generally occur in the first 1 to 2 days of therapy. Other commonly experienced adverse events include diarrhea (13%), local reactions (9%), infection (8%), fever (7%), and abdominal pain (7%). Because antibiotic-associated colitis has been reported with the use of almost all antibacterial agents, this possibility should be considered in patients who experience diarrhea while being treated with tigecycline. In the clinical studies with
Table 1. Labeled Indications for Tigecycline Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, and Bacteroides fragilis. Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Esherichia coli, Klebsiella oxytoca, K. pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
Journal of the American Pharmacists Association
www.japha.org
September/October 2005
Vol. 45, No. 5
NEW DRUGS
tigecycline, sepsis and septic shock were infrequently reported in patients who were being treated for cIAI secondary to intestinal perforation. Caution should also be exercised with respect to the potential for superinfection caused by nonsusceptible organisms such as fungi. Tigecycline should be used with caution in patients who have experienced a hypersensitivity reaction to any of the tetracycline derivatives. As with the use of the other tetracyclines, tigecycline may cause permanent discoloration of the teeth if it is used during the period of tooth development (i.e., latter half of pregnancy, infancy, and childhood to the age of 8 years). The new drug should also be considered to have the potential to produce other adverse events associated with use of tetracyclines, such as photosensitivity reactions, pseudotumor cerebri, pancreatitis, and antianabolic effects (e.g., azotemia, hypophosphatemia). Because tigecycline may cause harm to the fetus if administered during pregnancy, it is classified in pregnancy category D. Although oral bioavailability of the drug is limited, caution should be exercised if it is administered to a nursing woman. The effectiveness and safety of tigecycline in patients younger than 18 years of age have not been established. Because of its possible effects on the teeth, tigecycline should not be used in children younger than 8 years of age unless other antibiotics are not likely to be effective or are contraindicated. The concurrent use of tigeVol. 45, No. 5
September/October 2005
cycline and warfarin (e.g., Coumadin) has been studied and, although the effects of warfarin on the international normalized ratio were not significantly altered, anticoagulation tests should be monitored if the drugs are used concomitantly. Tigecycline is not extensively metabolized; a glucuronide metabolite and an epimer each account for no more than 10% of the administered dose. The primary route of elimination is biliary excretion (approximately 60%) of unchanged drug and its metabolites. Dosage adjustment is not necessary in patients with renal impairment or in those undergoing hemodialysis. However, a reduction in dosage is recommended in patients with severe hepatic impairment. Tigecycline is administered by intravenous infusion over a period of approximately 30 to 60 minutes. The recommended dosage is an initial dose of 100 mg, followed by 50 mg every 12 hours. In patients with severe hepatic impairment, the initial dose of 100 mg should be followed by a reduced maintenance dose of 25 mg every 12 hours. The usual duration of treatment is 5 to 14 days, with the duration of therapy being determined by the site and severity of the infection and the patient’s progress. Tigecycline is supplied in single-use vials containing 50 mg of the drug as a lyophilized powder for reconstitution. The powder should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and the vial should be gently www.japha.org
swirled until the drug dissolves. Each vial contains a 6% overage and, when reconstituted, 5 mL of solution contains 50 mg of the drug (10 mg/mL). Two vials should be used to provide the loading dose of 100 mg and one vial to provide each maintenance dose. The reconstituted solution should be transferred to 100 mL of solution for intravenous infusion. The intravenous admixture may be stored at room temperature for up to 6 hours or refrigerated for up to 24 hours before administration. The infusion of tigecycline should be administered intravenously through a dedicated line or through a Y-site. The product labeling should be consulted regarding its compatibility with other medications and diluents when administered through a Y-site.
Analgesic Ziconotide (Prialt—Elan) is a new analgesic with a unique mechanism of action and an indication for treatment of severe, chronic pain. It is a synthetic 25-amino acid peptide that is the equivalent of a naturally occurring conopeptide found in the venom of the marine snail, Conus magus. The new agent binds to Ntype calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. It is thought to block these calcium channels on the nerves that transmit pain signals to the brain. Severe chronic pain may result from cancer, accidents, injuries, unsuccessful surgery,
neurologic disorders, acquired immunodeficiency syndrome, and other medical problems, and opioid analgesics such as morphine are the standard treatment. However, tolerance develops to the analgesic action of the opioids, necessitating an increase in dosage that also produces a higher incidence of adverse events (e.g., drowsiness). Unlike the opioids, ziconotide does not cause addiction. It does not bind to opiate receptors, and its actions are not blocked by opioid antagonists. Ziconotide is administered via intrathecal (IT) infusion using a programmable implanted microinfusion device or an external microinfusion device and catheter. It is indicated for the management of severe chronic pain in patients for whom IT therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine. The clinical studies of ziconotide were conducted primarily in patients whose pain was refractory to IT therapy (e.g., morphine). Patients were maintained on the systemic (non-IT) analgesics (including opioids) and adjunctive therapy that they had been using, but the IT therapy was discontinued over a 1- to 3-week period and replaced with IT ziconotide or placebo. The new drug was more effective in relieving pain than placebo. The most important concerns associated with the use of ziconotide have been development of severe psychiatric symptoms and neurologic impairment, and these are
Journal of the American Pharmacists Association
637
NEW DRUGS
the subject of a black-box warning in product labeling. Hallucinations (12%), paranoid reactions (3%), hostility (2%), delirium (2%), unresponsiveness/stupor (2%), and psychosis (1%), as well as manic reactions and suicide attempts, have been reported, and use of ziconotide is contraindicated in patients with a history of psychosis. Other central nervous system (CNS) adverse events have been experienced frequently. These include confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), and abnormal thinking (8%). Patients should be cautioned about engaging in potentially hazardous activities such as driving and the added risk associated with concurrent use of other CNS depressant agents. Although most patients treated with ziconotide are also receiving systemic opioids, the concurrent use of ziconotide and IT opioids has not been studied and is not recommended. Serious adverse events with ziconotide occur less frequently when the dosage of the drug is slowly titrated over 21 days rather than more quickly. The most frequently experienced adverse events in a study using a slow titration schedule included dizziness (47%), nausea (41%), asthenia (22%), somnolence (22%), confusion (18%), and headache (15%). Approximately 40% of the patients in the clinical studies had serum creatine kinase (CK) concentrations above the upper limit of normal, although most did not experience related adverse events. 638
However, one case of symptomatic myopathy and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations have been reported. Serum CK concentrations should be monitored periodically (e.g., every other week for the first month and monthly as appropriate thereafter), and patients should promptly report new or worsening muscle pain, soreness, or weakness, with or without darkened urine. The administration of ziconotide by the intrathecal route is associated with a risk of meningitis that may result from the inadvertent contamination of the microinfusion device, as well as through other means. The risk is greater with use of an external device when compared with the use of an internal microinfusion device and surgically implanted catheter. Patients and caregivers must be attentive to signs and symptoms of meningitis such as fever, headache, stiff neck, altered mental status (e.g., lethargy, confusion, disorientation), nausea, and vomiting. Ziconotide is classified in pregnancy category C. It is not known whether the drug is excreted in human milk, and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of ziconotide in pediatric patients have not been established. Once ziconotide is transferred from the cerebrospinal fluid into the systemic circulation, it becomes susceptible to proteolytic cleavage by various peptidases and proteases found in most organs. It is rapidly broken down to pep-
Journal of the American Pharmacists Association
tide fragments and amino acids, and is not likely to interact with other medications via pharmacokinetic mechanisms. Ziconotide is supplied in a single-use 20 mL glass vial containing the drug in a concentration of 25 mcg/mL, and in single-use 1 mL, 2 mL, and 5 mL glass vials containing the drug in a concentration of 100 mcg/mL. The lowerpotency formulation is used undiluted and the higherpotency formulation is diluted with preservative-free 0.9% Sodium Chloride Injection, USP (preservative free). The drug is intended for use only in the Medtronic SynchroMed EL, SynchroMed II Infusion System, and Simms Deltec Cadd Micro External Microinfusion Device and Catheter. Treatment with ziconotide should be initiated at a dosage no greater than 2.4 mcg/day (0.1 mcg/hour) and then titrated to patient response. The dosage may be titrated upward by up to 2.4 mcg/day at intervals of no more than two to three times per week, up to a recommended maximum dosage of 19.2 mcg/day by day 21. The product labeling should be consulted for more detailed information regarding the dosage and administration of the drug.
Antineoplastic Agent More than 3,000 new cases of pediatric acute leukemia are diagnosed in the United States each year. Acute lymphoblastic leukemia (ALL) is the most common form of www.japha.org
pediatric leukemia, and children who do not respond to initial treatment, or who experience a relapse, have a poor prognosis. Clofarabine (Clolar— Genzyme) is the first drug approved for treatment of pediatric ALL in more than a decade. It is a purine nucleoside antimetabolite most similar structurally to cladribine (Leustatin) and fludarabine (Fludara), although the latter two agents are not indicated for the treatment of pediatric ALL. Clofarabine is metabolized intracellularly to its active triphosphate metabolite that inhibits DNA synthesis. Clofarabine is administered by intravenous infusion and is indicated for treatment of pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two prior regimens. It was approved under the provisions of the Food and Drug Administration’s accelerated approval process based on the attainment of a surrogate endpoint (complete response) that is considered predictive of clinical improvement. In the clinical studies the new drug produced a 30% response rate, with 20% of patients experiencing a complete response and 10% a partial response. Most of these patients had received two to four prior regimens, and clofarabine represents an important addition to the group of agents that may be of benefit in the treatment of pediatric ALL. Clofarabine has also been studied in pediatric and adult patients with acute myeloid leukemia (AML), as well as in treatment of other leukemias. However, these are not September/October 2005
Vol. 45, No. 5
NEW DRUGS
labeled indications at the present time. Severe bone marrow suppression—including neutropenia, anemia, and thrombocytopenia—is the most important concern associated with the use of clofarabine, and patients are at increased risk for serious opportunistic infections. Bone marrow suppression is dose dependent and usually reversible. Complete blood counts and platelet counts should be determined at regular intervals during treatment, and more frequently in patients who develop cytopenias. The most frequently experienced adverse events include febrile neutropenia (57%), nausea (75%), vomiting (83%), diarrhea (53%), abdominal pain (36%), headache (46%), fatigue (36%), pyrexia (41%), rigors (38%), hypotension (29%), pruritus (47%), and dermatitis (41%). The use of clofarabine results in a rapid reduction in peripheral leukemia cells, and patients should be monitored
Vol. 45, No. 5
September/October 2005
for signs and symptoms of tumor lysis syndrome, as well as of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS; also called capillary leak syndrome) and organ dysfunction. The continuous administration of intravenous fluids is recommended throughout the 5 days of clofarabine use, and allopurinol (e.g., Zyloprim) should be administered if hyperuricemia is expected. The use of prophylactic steroids (e.g., hydrocortisone 100 mg/m2 on days 1 and 3) may be of value in preventing SIRS. If clinically significant signs or symptoms of SIRS develop, treatment with clofarabine should be immediately discontinued. When the patient’s condition has stabilized, treatment can be reinstituted with a lower dosage. Clinically important elevations in serum aminotransferases (ALT and AST) occurred in approximately
www.japha.org
40% of the patients treated with clofarabine, and 15% of patients experienced hyperbilirubinemia. Hepatic function should be assessed before and during treatment, and concurrent use of known hepatotoxic medications should be avoided. Clofarabine may cause fetal harm if administered during pregnancy, and it is therefore classified in pregnancy category D. Women of childbearing potential should be advised to avoid becoming pregnant while undergoing treatment with the drug. Women who are breastfeeding should discontinue nursing if treatment with clofarabine is to be initiated. Most of a dose of clofarabine is excreted unchanged in the urine. Renal function should be assessed before and during treatment, and other drugs with known renal toxicity should be avoided during the 5-day periods of clofarabine administration. Clofarabine is administered via intravenous infusion over
a period of 2 hours, and the recommended dosage is 52 mg/m2 once a day for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. Clofarabine is supplied in single-use vials that contain 20 mg of the drug in 20 mL of 0.9% sodium chloride injection. The solution should be filtered through a sterile 0.2 micrometer syringe filter and then further diluted with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, before infusion. The resulting admixture may be stored at room temperature but must be used within 24 hours of preparation. Other medications should not be administered through the same intravenous line. Daniel A. Hussar, PhD, is Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pa.
Journal of the American Pharmacists Association
639
DRUGS
New Drugs: Tigecycline, Ziconotide, and Clofarabine Daniel A. Hussar
Antibiotic The extent to which microorganisms have developed resistance to antimicrobial agents to which they were initially susceptible is an ongoing concern. The approval of tigecycline (Tygacil—Wyeth) represents an important step in the development of new antibiotics active against certain bacteria resistant to many of the previously marketed antibiotics. Designated by some as the first of a new class of glycylcycline antibiotics, tigecycline is closely related structurally to minocycline (e.g., Minocin), shares many of the actions and risks of minocycline and other tetracyclines, and may be considered the newest addition to the tetracycline class of antibiotics. However, tigecycline is not apparently affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux, and crossresistance between tigecycline and other antibiotics has not been observed. Tigecycline has a broad spectrum of action that includes numerous gram-positive and -negative aerobic and anaerobic bacteria, some of which (e.g., methicillin-resis636
tant Staphylococcus aureus) have not been demonstrated to be susceptible to other tetracyclines. Its action is usually bacteriostatic. The broad spectrum of action of the new agent permits its use as monotherapy for certain infections for which the use of a combination of antibiotics has previously been necessary. Tigecycline is administered by intravenous infusion and is indicated for the treatment of complicated skin and skin structure infections (cSSSI) and complicated intra-abdominal infections (cIAI) caused by susceptible strains of the bacteria identified in Table 1. It has also demonstrated activity in vitro against many other organisms including problematic bacteria such as vancomycin-resistant Enterococcus faecalis and E. faecium; however, the clinical effectiveness of tigecycline in the treatment of infections caused by these
bacteria has not yet been demonstrated. In the treatment of cSSSI, tigecycline was compared with a combination regimen of vancomycin and aztreonam (e.g., Azactam) in management of complicated deep soft tissue infections including wound infections, cellulitis, major abscesses, infected ulcers, and burns. The clinical cure rates were 86% and 88%, respectively, and the two regimens were considered to be comparable in their effectiveness. For treatment of cIAI such as appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intraabdominal abscess, perforation of intestine, and peritonitis, tigecycline was compared with imipenem/cilastatin (Primaxin). The clinical cure rates were 86% among patients treated with either of the antibiotics. The treatment of serious infections, which are frequently mixed infections caused by more than one organism, must often be initiated before causative organisms have been identified and their susceptibility determined. Tigecycline may be used as empiric monotherapy before
results of these tests are known, and its broad spectrum of action, which includes bacteria such as staphylococci, streptococci, enterococci, and Bacteroides species, provides effective treatment for many infections that otherwise may have required the use of two or more antibiotics. However, to reduce the development of drug-resistant bacteria, tigecycline should be used only to treat infections that are documented or strongly suspected to be caused by susceptible bacteria. The adverse events most frequently reported with the use of tigecycline are nausea (30%) and vomiting (20%) that are usually mild to moderate in severity and generally occur in the first 1 to 2 days of therapy. Other commonly experienced adverse events include diarrhea (13%), local reactions (9%), infection (8%), fever (7%), and abdominal pain (7%). Because antibiotic-associated colitis has been reported with the use of almost all antibacterial agents, this possibility should be considered in patients who experience diarrhea while being treated with tigecycline. In the clinical studies with
Table 1. Labeled Indications for Tigecycline Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, and Bacteroides fragilis. Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Esherichia coli, Klebsiella oxytoca, K. pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
Journal of the American Pharmacists Association
www.japha.org
September/October 2005
Vol. 45, No. 5
NEW DRUGS
tigecycline, sepsis and septic shock were infrequently reported in patients who were being treated for cIAI secondary to intestinal perforation. Caution should also be exercised with respect to the potential for superinfection caused by nonsusceptible organisms such as fungi. Tigecycline should be used with caution in patients who have experienced a hypersensitivity reaction to any of the tetracycline derivatives. As with the use of the other tetracyclines, tigecycline may cause permanent discoloration of the teeth if it is used during the period of tooth development (i.e., latter half of pregnancy, infancy, and childhood to the age of 8 years). The new drug should also be considered to have the potential to produce other adverse events associated with use of tetracyclines, such as photosensitivity reactions, pseudotumor cerebri, pancreatitis, and antianabolic effects (e.g., azotemia, hypophosphatemia). Because tigecycline may cause harm to the fetus if administered during pregnancy, it is classified in pregnancy category D. Although oral bioavailability of the drug is limited, caution should be exercised if it is administered to a nursing woman. The effectiveness and safety of tigecycline in patients younger than 18 years of age have not been established. Because of its possible effects on the teeth, tigecycline should not be used in children younger than 8 years of age unless other antibiotics are not likely to be effective or are contraindicated. The concurrent use of tigeVol. 45, No. 5
September/October 2005
cycline and warfarin (e.g., Coumadin) has been studied and, although the effects of warfarin on the international normalized ratio were not significantly altered, anticoagulation tests should be monitored if the drugs are used concomitantly. Tigecycline is not extensively metabolized; a glucuronide metabolite and an epimer each account for no more than 10% of the administered dose. The primary route of elimination is biliary excretion (approximately 60%) of unchanged drug and its metabolites. Dosage adjustment is not necessary in patients with renal impairment or in those undergoing hemodialysis. However, a reduction in dosage is recommended in patients with severe hepatic impairment. Tigecycline is administered by intravenous infusion over a period of approximately 30 to 60 minutes. The recommended dosage is an initial dose of 100 mg, followed by 50 mg every 12 hours. In patients with severe hepatic impairment, the initial dose of 100 mg should be followed by a reduced maintenance dose of 25 mg every 12 hours. The usual duration of treatment is 5 to 14 days, with the duration of therapy being determined by the site and severity of the infection and the patient’s progress. Tigecycline is supplied in single-use vials containing 50 mg of the drug as a lyophilized powder for reconstitution. The powder should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and the vial should be gently www.japha.org
swirled until the drug dissolves. Each vial contains a 6% overage and, when reconstituted, 5 mL of solution contains 50 mg of the drug (10 mg/mL). Two vials should be used to provide the loading dose of 100 mg and one vial to provide each maintenance dose. The reconstituted solution should be transferred to 100 mL of solution for intravenous infusion. The intravenous admixture may be stored at room temperature for up to 6 hours or refrigerated for up to 24 hours before administration. The infusion of tigecycline should be administered intravenously through a dedicated line or through a Y-site. The product labeling should be consulted regarding its compatibility with other medications and diluents when administered through a Y-site.
Analgesic Ziconotide (Prialt—Elan) is a new analgesic with a unique mechanism of action and an indication for treatment of severe, chronic pain. It is a synthetic 25-amino acid peptide that is the equivalent of a naturally occurring conopeptide found in the venom of the marine snail, Conus magus. The new agent binds to Ntype calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. It is thought to block these calcium channels on the nerves that transmit pain signals to the brain. Severe chronic pain may result from cancer, accidents, injuries, unsuccessful surgery,
neurologic disorders, acquired immunodeficiency syndrome, and other medical problems, and opioid analgesics such as morphine are the standard treatment. However, tolerance develops to the analgesic action of the opioids, necessitating an increase in dosage that also produces a higher incidence of adverse events (e.g., drowsiness). Unlike the opioids, ziconotide does not cause addiction. It does not bind to opiate receptors, and its actions are not blocked by opioid antagonists. Ziconotide is administered via intrathecal (IT) infusion using a programmable implanted microinfusion device or an external microinfusion device and catheter. It is indicated for the management of severe chronic pain in patients for whom IT therapy is warranted and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine. The clinical studies of ziconotide were conducted primarily in patients whose pain was refractory to IT therapy (e.g., morphine). Patients were maintained on the systemic (non-IT) analgesics (including opioids) and adjunctive therapy that they had been using, but the IT therapy was discontinued over a 1- to 3-week period and replaced with IT ziconotide or placebo. The new drug was more effective in relieving pain than placebo. The most important concerns associated with the use of ziconotide have been development of severe psychiatric symptoms and neurologic impairment, and these are
Journal of the American Pharmacists Association
637
NEW DRUGS
the subject of a black-box warning in product labeling. Hallucinations (12%), paranoid reactions (3%), hostility (2%), delirium (2%), unresponsiveness/stupor (2%), and psychosis (1%), as well as manic reactions and suicide attempts, have been reported, and use of ziconotide is contraindicated in patients with a history of psychosis. Other central nervous system (CNS) adverse events have been experienced frequently. These include confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), and abnormal thinking (8%). Patients should be cautioned about engaging in potentially hazardous activities such as driving and the added risk associated with concurrent use of other CNS depressant agents. Although most patients treated with ziconotide are also receiving systemic opioids, the concurrent use of ziconotide and IT opioids has not been studied and is not recommended. Serious adverse events with ziconotide occur less frequently when the dosage of the drug is slowly titrated over 21 days rather than more quickly. The most frequently experienced adverse events in a study using a slow titration schedule included dizziness (47%), nausea (41%), asthenia (22%), somnolence (22%), confusion (18%), and headache (15%). Approximately 40% of the patients in the clinical studies had serum creatine kinase (CK) concentrations above the upper limit of normal, although most did not experience related adverse events. 638
However, one case of symptomatic myopathy and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations have been reported. Serum CK concentrations should be monitored periodically (e.g., every other week for the first month and monthly as appropriate thereafter), and patients should promptly report new or worsening muscle pain, soreness, or weakness, with or without darkened urine. The administration of ziconotide by the intrathecal route is associated with a risk of meningitis that may result from the inadvertent contamination of the microinfusion device, as well as through other means. The risk is greater with use of an external device when compared with the use of an internal microinfusion device and surgically implanted catheter. Patients and caregivers must be attentive to signs and symptoms of meningitis such as fever, headache, stiff neck, altered mental status (e.g., lethargy, confusion, disorientation), nausea, and vomiting. Ziconotide is classified in pregnancy category C. It is not known whether the drug is excreted in human milk, and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of ziconotide in pediatric patients have not been established. Once ziconotide is transferred from the cerebrospinal fluid into the systemic circulation, it becomes susceptible to proteolytic cleavage by various peptidases and proteases found in most organs. It is rapidly broken down to pep-
Journal of the American Pharmacists Association
tide fragments and amino acids, and is not likely to interact with other medications via pharmacokinetic mechanisms. Ziconotide is supplied in a single-use 20 mL glass vial containing the drug in a concentration of 25 mcg/mL, and in single-use 1 mL, 2 mL, and 5 mL glass vials containing the drug in a concentration of 100 mcg/mL. The lowerpotency formulation is used undiluted and the higherpotency formulation is diluted with preservative-free 0.9% Sodium Chloride Injection, USP (preservative free). The drug is intended for use only in the Medtronic SynchroMed EL, SynchroMed II Infusion System, and Simms Deltec Cadd Micro External Microinfusion Device and Catheter. Treatment with ziconotide should be initiated at a dosage no greater than 2.4 mcg/day (0.1 mcg/hour) and then titrated to patient response. The dosage may be titrated upward by up to 2.4 mcg/day at intervals of no more than two to three times per week, up to a recommended maximum dosage of 19.2 mcg/day by day 21. The product labeling should be consulted for more detailed information regarding the dosage and administration of the drug.
Antineoplastic Agent More than 3,000 new cases of pediatric acute leukemia are diagnosed in the United States each year. Acute lymphoblastic leukemia (ALL) is the most common form of www.japha.org
pediatric leukemia, and children who do not respond to initial treatment, or who experience a relapse, have a poor prognosis. Clofarabine (Clolar— Genzyme) is the first drug approved for treatment of pediatric ALL in more than a decade. It is a purine nucleoside antimetabolite most similar structurally to cladribine (Leustatin) and fludarabine (Fludara), although the latter two agents are not indicated for the treatment of pediatric ALL. Clofarabine is metabolized intracellularly to its active triphosphate metabolite that inhibits DNA synthesis. Clofarabine is administered by intravenous infusion and is indicated for treatment of pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two prior regimens. It was approved under the provisions of the Food and Drug Administration’s accelerated approval process based on the attainment of a surrogate endpoint (complete response) that is considered predictive of clinical improvement. In the clinical studies the new drug produced a 30% response rate, with 20% of patients experiencing a complete response and 10% a partial response. Most of these patients had received two to four prior regimens, and clofarabine represents an important addition to the group of agents that may be of benefit in the treatment of pediatric ALL. Clofarabine has also been studied in pediatric and adult patients with acute myeloid leukemia (AML), as well as in treatment of other leukemias. However, these are not September/October 2005
Vol. 45, No. 5
NEW DRUGS
labeled indications at the present time. Severe bone marrow suppression—including neutropenia, anemia, and thrombocytopenia—is the most important concern associated with the use of clofarabine, and patients are at increased risk for serious opportunistic infections. Bone marrow suppression is dose dependent and usually reversible. Complete blood counts and platelet counts should be determined at regular intervals during treatment, and more frequently in patients who develop cytopenias. The most frequently experienced adverse events include febrile neutropenia (57%), nausea (75%), vomiting (83%), diarrhea (53%), abdominal pain (36%), headache (46%), fatigue (36%), pyrexia (41%), rigors (38%), hypotension (29%), pruritus (47%), and dermatitis (41%). The use of clofarabine results in a rapid reduction in peripheral leukemia cells, and patients should be monitored
Vol. 45, No. 5
September/October 2005
for signs and symptoms of tumor lysis syndrome, as well as of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS; also called capillary leak syndrome) and organ dysfunction. The continuous administration of intravenous fluids is recommended throughout the 5 days of clofarabine use, and allopurinol (e.g., Zyloprim) should be administered if hyperuricemia is expected. The use of prophylactic steroids (e.g., hydrocortisone 100 mg/m2 on days 1 and 3) may be of value in preventing SIRS. If clinically significant signs or symptoms of SIRS develop, treatment with clofarabine should be immediately discontinued. When the patient’s condition has stabilized, treatment can be reinstituted with a lower dosage. Clinically important elevations in serum aminotransferases (ALT and AST) occurred in approximately
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40% of the patients treated with clofarabine, and 15% of patients experienced hyperbilirubinemia. Hepatic function should be assessed before and during treatment, and concurrent use of known hepatotoxic medications should be avoided. Clofarabine may cause fetal harm if administered during pregnancy, and it is therefore classified in pregnancy category D. Women of childbearing potential should be advised to avoid becoming pregnant while undergoing treatment with the drug. Women who are breastfeeding should discontinue nursing if treatment with clofarabine is to be initiated. Most of a dose of clofarabine is excreted unchanged in the urine. Renal function should be assessed before and during treatment, and other drugs with known renal toxicity should be avoided during the 5-day periods of clofarabine administration. Clofarabine is administered via intravenous infusion over
a period of 2 hours, and the recommended dosage is 52 mg/m2 once a day for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. Clofarabine is supplied in single-use vials that contain 20 mg of the drug in 20 mL of 0.9% sodium chloride injection. The solution should be filtered through a sterile 0.2 micrometer syringe filter and then further diluted with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, before infusion. The resulting admixture may be stored at room temperature but must be used within 24 hours of preparation. Other medications should not be administered through the same intravenous line. Daniel A. Hussar, PhD, is Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pa.
Journal of the American Pharmacists Association
639