Zalcitabine

Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
CAS Number: 7481-89-2
Brands: HIVID

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  Severe peripheral neuropathy reported.¹ Caution in patients with neuropathy.¹ (See Peripheral Neuropathy under Cautions.)

  
  

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  Pancreatitis reported rarely.¹ If pancreatitis suspected, temporarily interrupt therapy until diagnosis is excluded.¹ (See Pancreatitis under Cautions.)

  
  

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  Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported rarely in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.¹ (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  

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  Hepatic failure and death reported rarely; possibly related to underlying hepatitis B virus (HBV) infection and zalcitabine therapy.¹

  
  

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).^{4 8 9 11 13 14 15 18 23 27 28 29 38 62 85 89}

Uses for Zalcitabine

Treatment of HIV Infection

Treatment of HIV infection in conjunction with other antiretrovirals.^{1 141 169 171}

Zalcitabine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.^{1 141 169}

Dosage

Must be used in conjunction with other antiretrovirals.¹

Modification of zalcitabine dosage may be necessary in patients who develop peripheral neuropathy.¹

Pediatric Patients

Treatment of HIV Infection

Oral

Children <13 years of age†: 0.01 mg/kg every 8 hours under investigation.¹⁴¹ Dosage recommendations not available for neonates and infants.¹⁴¹

Children ≥13 years of age: 0.75 mg every 8 hours.^{1 141}

Adults

Treatment of HIV Infection

Oral

0.75 mg every 8 hours.^{1 169}

If reintroduced following a temporary interruption due to peripheral neuropathy, 0.375 mg every 8 hours.¹

Special Populations

Renal Impairment

Treatment of HIV Infection

Oral

Cl_cr 10–40 mL/minute: 0.75 mg every 12 hours.^{1 169}

Cl_cr <10 mL/minute: 0.75 mg every 24 hours.^{1 169}

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Zalcitabine

Contraindications

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  Known hypersensitivity to zalcitabine.¹

  
  

Warnings/Precautions

Warnings

Clinically important adverse effects reported, some potentially fatal.¹ Patients with decreased CD4⁺ T-cell counts appear to have an increased incidence of adverse effects.¹

Peripheral Neuropathy

Moderate to severe peripheral neuropathy reported; ^{1 65 74 86} occurs more frequently in patients with advanced HIV infection.¹

Zalcitabine-related peripheral neuropathy manifests initially as numbness and burning dysesthesia involving the distal extremities.^{1 2 65 74 82 85 89 102} If drug is not discontinued, sharp shooting pains or severe continuous burning pain may occur and can progress to severe pain requiring opiate analgesics and is potentially irreversible.^{1 65 82 89}

If zalcitabine is discontinued promptly, neuropathy usually is slowly reversible.^{1 29 65 70 74 85 89} Symptoms may initially progress following discontinuation.¹

Use with extreme caution in patients with preexisting peripheral neuropathy; avoid in patients with moderate to severe peripheral neuropathy.¹

Use with caution in individuals at risk of developing peripheral neuropathy, including those with low CD4⁺ T-cell counts (<50 cells/mm³), diabetes, weight loss, and/or those receiving other drugs that have the potential to cause peripheral neuropathy.¹ (See Drugs Associated with Peripheral Neuropathy under Interactions.) Careful monitoring recommended.¹

Discontinue promptly if signs or symptoms of peripheral neuropathy occur (i.e., moderate discomfort from numbness, tingling, burning or pain of the extremities progresses, any related symptoms accompanied by objective findings).¹

Can be reintroduced at a lower dose if all findings have improved to mild symptoms.¹ Permanently discontinue for severe discomfort related to peripheral neuropathy or moderate discomfort that progresses.¹

Pancreatitis

Pancreatitis, sometimes fatal, reported rarely.^{1 86 88}

Closely monitor patients with a history of pancreatitis or known risk factors for pancreatitis.¹

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.^{1 88}

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.^{1 88}

The drug should not be reinitiated until the diagnosis of pancreatitis is excluded and should be discontinued permanently if pancreatitis is diagnosed.^{1 88}

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving zalcitabine.¹ Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.¹ Has been reported in patients with no known risk factors.¹

Hepatic failure and death reported rarely; possibly related to underlying HBV infection and zalcitabine therapy.¹

Use with caution in patients with known risk factors for liver disease.¹

Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).¹

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (anaphylactoid reaction, anaphylactic reaction, urticaria without other signs of anaphylaxis) reported.^{1 138}

Major Toxicities

GI Effects

Severe oral ulcers reported.¹

Esophageal ulcers reported infrequently.¹ Consider temporarily discontinuing zalcitabine if esophageal ulcers do not respond to specific treatment for opportunistic pathogens.¹

Cardiac Effects

Cardiomyopathy, CHF, and severe left ventricular hypokinesis reported rarely.^{1 71}

Use with caution in patients with baseline cardiomyopathy or history of CHF.¹

General Precautions

Lymphoma

Lymphoma reported; causative effect not established.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.^a

Specific Populations

Pregnancy

Category C.¹ Antiretroviral Pregnancy Registry at 800-258-4263.¹

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.^{169 175}

Lactation

Not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <13 years of age.^{1 141}

Has been used in children 6 months to 13 years of age† without unusual adverse effects.^{5 31 32 33 34 35 82 139 173 174}

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.^{1 18}

Hepatic Impairment

Caution in patients with preexisting hepatic impairment, increased serum liver enzyme concentrations, or history of alcohol abuse or hepatitis.¹ Temporarily interrupt therapy if clinical or laboratory findings suggestive of pronounced hepatotoxicity occur.¹

Use with caution in patients with known risk factors for liver disease.¹

Renal Impairment

Dosage adjustment needed.¹ Greater risk of toxicity in patients with renal impairment (Cl_cr <55 mL/minute).¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Peripheral neuropathy, abnormal hepatic function, fatigue.¹

Interactions for Zalcitabine

Drugs Associated with Peripheral Neuropathy

Concomitant use with other drugs associated with peripheral neuropathy (e.g., chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold compounds, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, stavudine, vincristine) increases risk of peripheral neuropathy and should be avoided if possible.^{1 2 86}

Specific Drugs

Drug	Interaction	Comments
Abacavir	In vitro evidence of additive or synergistic antiretroviral effects1 26 55 89 127 130
Aminoglycosides	Increased risk of peripheral neuropathy1	Monitor closely; dosage adjustment needed if substantial change in renal function1
Amphotericin B	Increased risk of peripheral neuropathy1	Monitor closely; dosage adjustment needed if substantial change in renal function1
Antacids (magnesium- and aluminum-containing)	Decreased zalcitabine absorption1	Simultaneous ingestion should be avoided1
Didanosine	Increased risk of peripheral neuropathy169 171 172	Concomitant use not recommended169 171 172
Drugs associated with pancreatic toxicity (pentamidine)	Increased risk of pancreatitis1 86	Discontinue didanosine temporarily if parenteral pentamidine used for treatment of Pneumocystis carinii1 88
Doxorubicin	Doxorubicin inhibits intracellular phosphorylation of zalcitabine1	Clinical importance unknown1
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsb
Foscarnet	Increased risk of peripheral neuropathy1	Monitor closely; dosage adjustment needed if substantial change in renal function1
Histamine H2-receptor antagonists (cimetidine)	Increased zalcitabine AUC with cimetidine1	If used with cimetidine, monitor for zalcitabine adverse effects; decrease zalcitabine dosage if necessary1
Lamivudine	May inhibit intracellular phosphorylation of one another1	Concomitant use not recommended1 169
Loperamide	Pharmacokinetic interactions unlikely1
Metoclopramide	Slight decrease (10%) in zalcitabine bioavailability1
Probenecid	Increased zalcitabine AUC1	Monitor for zalcitabine adverse effects; decrease zalcitabine dosage if necessary1
Ribavirin	Ribavirin inhibits intracellular phosphorylation of zalcitabine1	Clinical importance unknown; caution if used concomitantly1
Saquinavir	Pharmacokinetic interactions unlikely1 131 In vitro evidence of additive or synergistic antiretroviral effects1
Stavudine	Additive toxicities (peripheral neuropathy)169 In vitro evidence of additive or synergistic antiretroviral effects1 26 55 89 130	Concomitant use not recommended169
Zidovudine	Pharmacokinetic interactions unlikely1 7 89 In vitro evidence of additive or synergistic antiretroviral effects1 26 55 89 127 130	Concomitant use not recommended in initial regimens because of inferior antiretroviral activity and higher rate of adverse effects compared with other dual NRTI alternatives169

Zalcitabine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed; peak plasma concentrations achieved in 0.5–2 hours.^{1 37 38 82 84 89} Bioavailability is 70–88% (range: 23–127%).^{1 2 37 38 62 77 82 84 89}

Food

Food may decrease the rate and extent of absorption.^{1 62 89}

Special Populations

Plasma concentrations increased in patients with renal impairment.^{1 89}

Oral bioavailability lower in children than adults; bioavailability is 54% (range: 29–100%) in children.^{1 35}

Distribution

Extent

Not well characterized.¹

Distributed into CSF in low concentrations.^{1 2 37 82 89}

Not known whether zalcitabine crosses the placenta or is distributed into milk.¹

Plasma Protein Binding

<4%.¹

Elimination

Metabolism

Not metabolized substantially in the liver.¹

Intracellularly, zalcitabine is phosphorylated and converted by cellular enzymes to the active metabolite, dideoxycytidine 5′-triphosphate.^{1 23 29 38}

Elimination Route

Principally eliminated in urine as unchanged drug.^{1 2 35 37 38 82 89}

Not known whether removed by hemodialysis or peritoneal dialysis.¹

Half-life

1.2–2 hours (range: 0.5–3 hours).^{1 2 37 82 84}

Children 6 months to 13 years of age: 0.2–1.9 hours.³⁵

Special Populations

Half-life prolonged in patients with renal impairment; half-life of 8.5 hours reported in patients with Cl_cr <55 mL/minute.^{1 89}

Stability

Storage

Oral

Tablets

15–30°C; tightly closed bottles.¹

Actions and SpectrumActions

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  Analog of 2′-deoxycytidine.^{1 13 14 15 18 23 28 29 38 62 89}

  
  


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  Pharmacologically related to other NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.¹

  
  


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  Active in vitro against HIV-1^{30 39 41 43 48 54 79 80 81 89 105} and HIV-2.^{30 41 54 89}

  
  


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  Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).^{1 8 9 13 14 15 18 23 27 28 29 38 79 82 85 89}

  
  


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  Strains of HIV-1 with reduced susceptibility to zalcitabine have been produced in vitro and have emerged during therapy with the drug.^{1 77 123}

  
  


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  Strains of HIV resistant to zalcitabine may be cross-resistant to some other NRTIs.^{30 56 57 58 64 77 89 95 96}

  
  


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  Cross-resistance between zalcitabine and HIV protease inhibitors (PIs) is highly unlikely since the drugs have different target enzymes.¹ Cross-resistance between didanosine and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is considered to be low since the drugs bind at different sites on reverse transcriptase and have different mechanisms of action.¹⁷²

  
  

Advice to Patients

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  Critical nature of compliance with HIV therapy.¹ Importance of using zalcitabine in conjunction with other antiretrovirals—not for monotherapy.¹

  
  


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  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


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  Patients should be advised that peripheral neuropathy is the major toxicity associated with zalcitabine therapy.¹ They should be advised to report early symptoms of peripheral neuropathy (numbness, tingling, burning) to their clinician.¹ Dosage modification may be necessary; importance of following clinician’s instructions regarding dosage adjustment.¹

  
  


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  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.¹

  
  


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  Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

  
  


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  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


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  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Zalcitabine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	0.375 mg	HIVID	Roche
		0.75 mg	HIVID	Roche

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Hivid 0.375MG Tablets (ROCHE): 90/$189.99 or 270/$529.96

Hivid 0.75MG Tablets (ROCHE): 90/$225.99 or 270/$645.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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55. Eron JJ, Johnson VA, Merrill DP et al. Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2′,3′-dideoxycytidine in vitro. Antimicrob Agents Chemother. 1992; 36:1559-62. [IDIS 298971] [PubMed 1324648]

56. Fitzgibbon JE, Howell RM, Haberzettl CA et al. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2′,3′-dideoxycytidine. Antimicrob Agents Chemother. 1992; 36:153-7. [PubMed 1317143]

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