Zalcitabine
A dideoxynucleoside compound in which the 3'-hydroxyl group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of 5' to 3' phosphodiester linkages, which are needed for the elongation of DNA chains, thus resulting in the termination of viral DNA growth.
The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chain-terminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy.
Zalcitabine appears less potent than some other nucleoside RTIs, has an inconvenient three-times daily frequency and is associated with serious adverse events. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV), and it has even been removed from pharmacies entirely in some countries.
Mechanism of effect
Peripheral Neuropathy
Moderate to severe peripheral neuropathy reported; occurs more frequently in patients with advanced HIV infection.
If zalcitabine is discontinued promptly, neuropathy usually is slowly reversible. Symptoms may initially progress following discontinuation.
Use with extreme caution in patients with preexisting peripheral neuropathy; avoid in patients with moderate to severe peripheral neuropathy.
Pancreatitis
Pancreatitis, sometimes fatal, reported rarely.
Closely monitor patients with a history of pancreatitis or known risk factors for pancreatitis.
Monitor serum amylase and triglyceride concentrations in patients with a prior history of pancreatitis, increased serum amylase concentrations, or alcohol abuse or in those receiving parenteral nutrition.
Discontinue immediately if clinical signs or symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory tests (hyperamylasemia associated with dysglycemia, rising triglyceride concentration, decreasing serum calcium) suggestive of pancreatitis occur.
Hypersensitivity Reactions
Hypersensitivity reactions (anaphylactic reaction, urticaria without other signs of anaphylaxis) reported
GI Effects
Severe oral ulcers reported.
Esophageal ulcers reported infrequently. Consider temporarily discontinuing zalcitabine if esophageal ulcers do not respond to specific treatment for opportunistic pathogens.
Cardiac Effects
Cardiomyopathy and CHF reported.
Use with caution in patients with history of cardiomyopathy or CHF.
Specific Populations
Pregnancy
Because of lack of data and concerns regarding teratogenicity in animals, experts recommend the drug not be used in pregnant women unless other alternatives are unavailable.
Lactation
Not known whether distributed into human milk.
Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.
Pediatric Use
Safety and efficacy not established in pediatric patients <13 years of age.
Geriatric Use
Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.
Hepatic Impairment
Caution in patients with preexisting hepatic impairment, increased serum liver enzyme concentrations, or history of alcohol abuse or hepatitis. Temporarily interrupt therapy if clinical or laboratory findings suggestive of pronounced hepatotoxicity occur.
Use with caution in patients with known risk factors for liver disease.
Renal Impairment
Dosage adjustment needed. Greater risk of toxicity in patients with renal impairment (Clcr <55 mL/minute).
Pharmacodynamic
Zalcitabine is an analog of 2'-deoxycytidine that is pharmacologically related to but structurally different from other nucleotide reverse transcriptase inhibitors (NRTIs). Zalcitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.
Pharmacokinetics
Absorption: Rapidly absorbed; peak plasma concentrations achieved in 0.5–2 hours. Bioavailability is 70–88%.
Plasma Protein Binding: <4%.
Half-life: 1.2–2 hours.
Metabolism: Not metabolized substantially in the liver.
Intracellularly, zalcitabine is phosphorylated and converted by cellular enzymes to the active metabolite, dideoxycytidine 5′-triphosphate.
Elimination: Principally eliminated in urine as unchanged drug.
Dosage
Pediatric Patients
Treatment of HIV Infection
Oral
Children <13 years of age: 0.01 mg/kg every 8 hours. Dosage recommendations not available for neonates and infants. Children ≥13 years of age: 0.75 mg every 8 hours.
Adults
Treatment of HIV Infection
Oral
0.75 mg every 8 hours.
If reintroduced following a temporary interruption due to peripheral neuropathy, 0.375 mg every 8 hours.
Renal Impairment
Treatment of HIV Infection
Oral
Clcr 10–40 mL/minute: 0.75 mg every 12 hours.
Clcr <10 mL/minute: 0.75 mg every 24 hours.
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Drug contraindications
hypersensitivity to this drugAlerts
Peripheral Neuropathy
Moderate to severe peripheral neuropathy reported; occurs more frequently in patients with advanced HIV infection.
If zalcitabine is discontinued promptly, neuropathy usually is slowly reversible. Symptoms may initially progress following discontinuation.
Use with extreme caution in patients with preexisting peripheral neuropathy; avoid in patients with moderate to severe peripheral neuropathy.
Pancreatitis
Pancreatitis, sometimes fatal, reported rarely.
Closely monitor patients with a history of pancreatitis or known risk factors for pancreatitis.
Monitor serum amylase and triglyceride concentrations in patients with a prior history of pancreatitis, increased serum amylase concentrations, or alcohol abuse or in those receiving parenteral nutrition.
Discontinue immediately if clinical signs or symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory tests (hyperamylasemia associated with dysglycemia, rising triglyceride concentration, decreasing serum calcium) suggestive of pancreatitis occur.
Hypersensitivity Reactions
Hypersensitivity reactions (anaphylactic reaction, urticaria without other signs of anaphylaxis) reported
GI Effects
Severe oral ulcers reported.
Esophageal ulcers reported infrequently. Consider temporarily discontinuing zalcitabine if esophageal ulcers do not respond to specific treatment for opportunistic pathogens.
Cardiac Effects
Cardiomyopathy and CHF reported.
Use with caution in patients with history of cardiomyopathy or CHF.
Specific Populations
Pregnancy
Because of lack of data and concerns regarding teratogenicity in animals, experts recommend the drug not be used in pregnant women unless other alternatives are unavailable.
Lactation
Not known whether distributed into human milk.
Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.
Pediatric Use
Safety and efficacy not established in pediatric patients <13 years of age.
Geriatric Use
Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.
Hepatic Impairment
Caution in patients with preexisting hepatic impairment, increased serum liver enzyme concentrations, or history of alcohol abuse or hepatitis. Temporarily interrupt therapy if clinical or laboratory findings suggestive of pronounced hepatotoxicity occur.
Use with caution in patients with known risk factors for liver disease.
Renal Impairment
Dosage adjustment needed. Greater risk of toxicity in patients with renal impairment (Clcr <55 mL/minute).
Points of recommendation:
Patients should be advised that peripheral neuropathy is the major toxicity associated with zalcitabine therapy. They should be advised to report early symptoms of peripheral neuropathy (numbness, tingling, burning) to their clinician. Dosage modification may be necessary.
Patients should be advised of the early symptoms of pancreatitis (nausea, vomiting, abdominal pain) and hepatic toxicity and that the development of manifestations of these conditions should be reported promptly to their clinician.
Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
Take on empty stomach: 1 hour before or 2 hours after meals.
Points of recommendation
Patients should be advised that peripheral neuropathy is the major toxicity associated with zalcitabine therapy. They should be advised to report early symptoms of peripheral neuropathy (numbness, tingling, burning) to their clinician. Dosage modification may be necessary.
Patients should be advised of the early symptoms of pancreatitis (nausea, vomiting, abdominal pain) and hepatic toxicity and that the development of manifestations of these conditions should be reported promptly to their clinician.
Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
Take on empty stomach: 1 hour before or 2 hours after meals.
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