Zalcitabine

Pronunciation

(zal SITE a been)

U.S. Brand Names

Hivid®

Synonyms

ddC; Dideoxycytidine

Generic Available

No

Canadian Brand Names

Hivid®

Use

In combination with at least two other antiretrovirals in the treatment of patients with HIV infection; it is not recommended that zalcitabine be given in combination with didanosine, stavudine, or lamivudine due to overlapping toxicities, virologic interactions, or lack of clinical data

Pregnancy Risk Factor

C

Pregnancy Implications

It is not known if zalcitabine crosses the human placenta. Animal studies have shown zalcitabine to be teratogenic, developmental toxicities were also observed. Cases of lactic acidosis/hepatic steatosis syndrome have been reported in pregnant women receiving nucleoside analogue drugs. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy in women receiving nucleoside analogues. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to zalcitabine or any component of the formulation

Warnings/Precautions

Careful monitoring of pancreatic enzymes and liver function tests in patients with a history of pancreatitis, increased amylase, those on parenteral nutrition or with a history of ethanol abuse; discontinue use immediately if pancreatitis is suspected; lactic acidosis and severe hepatomegaly and failure have rarely occurred with zalcitabine resulting in fatality (stop treatment if lactic acidosis or hepatotoxicity occur); some cases may possibly be related to underlying hepatitis B; use with caution in patients on digitalis, or with CHF, renal failure, or hyperphosphatemia; zalcitabine can cause severe peripheral neuropathy; avoid use, if possible, in patients with pre-existing neuropathy or at risk of developing neuropathy. Risk factors include CD4 counts <50 cells/mm³, diabetes mellitus, weight loss, other drugs known to cause peripheral neuropathy.

Adverse Reactions

>10%:

Central nervous system: Fever (5% to 17%), malaise (2% to 13%)

Neuromuscular & skeletal: Peripheral neuropathy (28%)

1% to 10%:

Central nervous system: Headache (2%), dizziness (1%), fatigue (4%), seizure (1.3%)

Dermatologic: Rash (2% to 11%), pruritus (3% to 5%)

Endocrine & metabolic: Hypoglycemia (2% to 6%), hyponatremia (4%), hyperglycemia (1% to 6%)

Gastrointestinal: Nausea (3%), dysphagia (1% to 4%), anorexia (4%), abdominal pain (3% to 8%), vomiting (1% to 3%), diarrhea (<1% to 10%), weight loss, oral ulcers (3% to 7%), increased amylase (3% to 8%)

Hematologic: Anemia (occurs as early as 2-4 weeks), granulocytopenia (usually after 6-8 weeks)

Hepatic: Abnormal hepatic function (9%), hyperbilirubinemia (2% to 5%)

Neuromuscular & skeletal: Myalgia (1% to 6%), foot pain

Respiratory: Pharyngitis (2%), cough (6%), nasal discharge (4%)

<1% (Limited to important or life-threatening): Atrial fibrillation, chest pain, constipation, edema, epistaxis, heart racing, hepatic failure, hepatitis, hepatomegaly, hypersensitivity (including anaphylaxis), hypertension, hypocalcemia, jaundice, lactic acidosis, myositis, night sweats, pain, palpitation, pancreatitis, redistribution/accumulation of body fat, syncope, tachycardia, weakness

Overdosage/Toxicology

Symptoms of overdose include delayed peripheral neurotoxicity. Treatment is supportive.

Drug Interactions

Antacids: Magnesium/aluminum-containing antacids may reduce zalcitabine absorption.

Doxorubicin: Decreases zalcitabine phosphorylation in vitro; clinical relevance unknown.

Metoclopramide: May reduce zalcitabine absorption.

Nephrotoxic drugs: Amphotericin, foscarnet, cimetidine, probenecid, and aminoglycosides may potentiate the risk of developing peripheral neuropathy or other toxicities associated with zalcitabine by interfering with the renal elimination of zalcitabine.

Neurotoxic drugs: Drugs associated with peripheral neuropathy which should be avoided, if possible; includes chloramphenicol, cisplatin, dapsone, disulfiram, ethionamide, glutethimide, didanosine, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, and vincristine.

Reverse transcriptase inhibitors: It is not recommended that zalcitabine be given in combination with didanosine, stavudine, or lamivudine due to overlapping toxicities, virologic interactions, or lack of clinical data. Lamivudine has also been shown to decrease zalcitabine phosphorylation in vitro.

Ribavirin: Concomitant use of ribavirin and nucleoside analogues may increase the risk of developing lactic acidosis (includes adefovir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine).

Ethanol/Nutrition/Herb Interactions

Food: Food decreases peak plasma concentrations by 39%. Extent and rate of absorption may be decreased with food.

Stability

Tablets should be stored in tightly closed bottles at 59°F to 86°F

Mechanism of Action

Purine nucleoside (cytosine) analog, zalcitabine or 2',3'-dideoxycytidine (ddC) is converted to active metabolite ddCTP; lack the presence of the 3'-hydroxyl group necessary for phosphodiester linkages during DNA replication. As a result viral replication is prematurely terminated. ddCTP acts as a competitor for binding sites on the HIV-RNA dependent DNA polymerase (reverse transcriptase) to further contribute to inhibition of viral replication.

Pharmacodynamics/Kinetics

Absorption: Well, but variable; decreased 39% with food

Distribution: Minimal data available; variable CSF penetration

Protein binding: <4%

Metabolism: Intracellularly to active triphosphorylated agent

Bioavailability: >80%

Half-life elimination: 2.9 hours; Renal impairment: 8.5 hours

Excretion: Urine (>70% as unchanged drug)

Dosage

Oral:

Neonates: Dose unknown

Infants and Children <13 years: Safety and efficacy have not been established; suggested usual dose: 0.01 mg/kg every 8 hours; range: 0.005-0.01 mg/kg every 8 hours

Adolescents and Adults: 0.75 mg 3 times/day

Dosing adjustment in renal impairment: Adults:

Clcr 10-40 mL/minute: 0.75 mg every 12 hours

Clcr<10 mL/minute: 0.75 mg every 24 hours

Moderately dialyzable (20% to 50%)

Monitoring Parameters

Renal function, viral load, liver function tests, CD4 counts, CBC, serum amylase, triglycerides, calcium

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This is not a cure for HIV nor has it been found to reduce transmission of HIV. Take as directed, around-the-clock, preferably on an empty stomach, 1 hour before or 2 hours after meals. Do not take antacids or other medication within 1 hour of taking this medication. May cause headache, dizziness, fatigue (use caution when driving or engaging in potentially hazardous tasks until response to drug is known); nausea, vomiting, lack of appetite, mouth sores (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report muscle weakness or pain; tingling, numbness, or pain in toes or fingers; weakness of extremities; chest pain, palpitations, or rapid heartbeat; swelling of extremities; weight gain or loss >5 lb/week; signs of infection (eg, fever, chills, sore throat, burning urination, fatigue); unusual bleeding (eg, tarry stools, easy bruising, or blood in stool, urine, or mouth); skin rash or irritation. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information

Potential compliance problems, frequency of administration and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Anesthesia and Critical Care Concerns/Other Considerations

Potential compliance problems, frequency of administration and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Oral ulcerations.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Drowsiness is common; may cause dizziness

Mental Health: Effects on Psychiatric Treatment

May cause granulocytopenia; use caution with clozapine; concurrent use with disulfiram can enhance peripheral neuropathy; avoid combination

Dosage Forms

Tablet: 0.375 mg, 0.75 mg

References

Adkins JC, Peters DH, and Faulds D, "Zalcitabine. An Update of Its Pharmacodynamic and Pharmacokinetic Properties and Clinical Efficacy in the Management of HIV Infection,"Drugs, 1997, 53(6):1054-80.

Bakshi SS, Britto P, Capparelli E, et al, "Evaluation of Pharmacokinetics, Safety, Tolerance, and Activity of Combination of Zalcitabine and Zidovudine in Stable, Zidovudine-Treated Pediatric Patients With Human Immunodeficiency Virus Infection. AIDS Clinical Trials Group Protocol 190 Team,"J Infect Dis, 1997, 175(5):1039-50.

Bazunga M, Tran HT, Kertland H, et al, "The Effects of Renal Impairment on the Pharmacokinetics of Zalcitabine,"J Clin Pharmacol, 1998, 38(1):28-33.

Chadwick EG, Nazareno LA, Nieuwenhuis TJ, et al, "Phase I Evaluation of Zalcitabine Administered to Human Immunodeficiency Virus-Infected Children,"J Infect Dis, 1995, 172(6):1475-9.

"Drugs for AIDS and Associated Infections,"Med Lett Drugs Ther, 1993, 35(904):79-86.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," February 5, 2001. Available at: http://www.aidsinfo.nih.gov. Accessed February 14, 2001.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction,"Am J Health Syst Pharm, 1998, 55:2528-33.

Hirsch MS and D'Aquila RT, "Therapy for Human Immunodeficiency Virus Infection,"N Engl J Med, 1993, 328(23):1686-95.

Pizzo PA, Butler K, Balis F, et al, "Dideoxycytidine Alone and in an Alternating Schedule With Zidovudine in Children With Symptomatic Human Immunodeficiency Virus Infection,"J Pediatr, 1990, 117(5):799-808.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

Shelton MJ, O'Donnell AM, and Morse GD, "Zalcitabine,"Ann Pharmacother, 1993, 27(4):480-9.

Skowron G, Bozzette SA, Lim L, et al, "Alternating and Intermittent Regimens of Zidovudine and Dideoxycytidine in Patients With AIDS or AIDS-Related Complex,"Ann Intern Med, 1993, 118(5):321-30.

Spector SA, Blanchard S, Wara DW, et al, "Comparative Trial of Two Dosages of Zalcitabine in Zidovudine-Experienced Children With Advanced Human Immunodeficiency Virus Disease. Pediatric AIDS Clinical Trials Group,"Pediatr Infect Dis J, 1997, 16(6):623-6.

Spector SA, "HIV Therapy Advances. Pediatric Antiretroviral Choices,"AIDS, 1994, 8(Suppl 3):15-8.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," April 15, 1999. Available at: http://www.aidsinfo.nih.gov.

International Brand Names

DDC Biocrom® (AR); DDC Elvetium® (AR); DDC Filaxis® (AR); DDC Martian® (AR); Hivid® (AT, AU, BE, CA, CH, DE, ES, FI, FR, GB, GR, HK, IE, IL, IS, IT, LV, MX, MY, NL, PT, RO, SK, TH, TR, TW, UY, VE, ZA); Inxibir® (AR); Virorich® (AR); Zalcitabin® (BR)