Active ingredient: Zalcitabine - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

• Anti-HIV Agents
• Antimetabolites
• Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Dosage Forms

• Tablet

Brands / Synonyms

Ddc; Ddcyd; Dideoxycytidine; Hivid; HIVID

Indications

For the treatment of Human immunovirus (HIV) infections.

Pharmacology

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.

Mechanism of Action

Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zalcitabine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

Absorption

>80%

Toxicity

Not Available

Biotrnasformation / Drug Metabolism

Hepatic

Contraindications

HIVID is contraindicated in patients with clinically significant hypersensitivity to zalcitabine or to any of the excipients contained in the tablets.

Drug Interactions

Zidovudine: There is no significant pharmacokinetic interaction between ZDV and zalcitabine which has been confirmed clinically. Zalcitabine also has no significant effect on the intracellular phosphorylation of ZDV, as shown in vitro in peripheral blood mononuclear cells or in two other cell lines (U937 and Molt-4). In the same study it was shown that didanosine and stavudine had no significant effect on the intracellular phosphorylation of zalcitabine in peripheral blood mononuclear cells.

Lamivudine: In vitro studies in peripheral blood mononuclear cells, U937 and Molt-4 cells revealed that lamivudine significantly inhibited zalcitabine phosphorylation in a dose dependent manner. Effects were already seen with doses corresponding to relevant plasma levels in humans, and the intracellular phosphorylation of zalcitabine to its three metabolites (including the active zalcitabine triphosphate metabolite) was significantly inhibited. Zalcitabine inhibited lamivudine phosphorylation at high concentration ratios (10 and 100); however, it is considered to be unlikely that this decrease of phosphorylated lamivudine concentration is of clinical significance, as lamivudine is a more efficient substrate for deoxycytidine kinase than zalcitabine. These in vitro studies suggest that concomitant administration of zalcitabine and lamivudine in humans may result in sub-therapeutic concentrations of active phosphorylated zalcitabine, which may lead to a decreased antiretroviral effect of zalcitabine. It is unknown how the effect seen in these in vitro studies translates into clinical consequences. Concomitant use of zalcitabine and lamivudine is not recommended.

Saquinavir: The combination of HIVID, saquinavir, and ZDV has been studied (as triple combination) in adults. Pharmacokinetic data suggest that absorption, metabolism, and elimination of each of these drugs are unchanged when they are used together.

Drugs Associated With Peripheral Neuropathy: The concomitant use of HIVID with drugs that have the potential to cause peripheral neuropathy should be avoided where possible. Drugs that have been associated with peripheral neuropathy include antiretroviral nucleoside analogues, chloramphenicol, cisplatin, dapsone, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, and vincristine. Concomitant use of HIVID with didanosine is not recommended.

Intravenous Pentamidine: Treatment with HIVID should be interrupted when the use of a drug that has the potential to cause pancreatitis is required. Death due to fulminant pancreatitis possibly related to intravenous pentamidine and HIVID has been reported. If intravenous pentamidine is required to treat Pneumocystis carinii pneumonia, treatment with HIVID should be interrupted.

Amphotericin, Foscarnet, and Aminoglycosides: Drugs such as amphotericin, foscarnet, and aminoglycosides may increase the risk of developing peripheral neuropathy or other HIVID-associated adverse events by interfering with the renal clearance of zalcitabine (thereby raising systemic exposure). Patients who require the use of one of these drugs with HIVID should have frequent clinical and laboratory monitoring with dosage adjustment for any significant change in renal function.

Probenecid or Cimetidine: Concomitant administration of probenecid or cimetidine decreases the elimination of zalcitabine, most likely by inhibition of renal tubular secretion of zalcitabine. Patients receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and the dose of zalcitabine reduced if warranted.

Magnesium/Aluminum-containing Antacid Products: Absorption of zalcitabine is moderately reduced (approximately 25%) when coadministered with magnesium/aluminum-containing antacid products. The clinical significance of this reduction is not known, hence zalcitabine is not recommended to be ingested simultaneously with magnesium/aluminum-containing antacids.

Metoclopramide: Bioavailability is mildly reduced (approximately 10%) when zalcitabine and metoclopramide are coadministered.

Doxorubicin: Doxorubicin caused a decrease in zalcitabine phosphorylation (>50% inhibition of total phosphate formation) in U937/Molt 4 cells. Although there may be decreased zalcitabine activity because of lessened active metabolite formation, the clinical relevance of these in vitro results are not known.