Hivid (Zalcitabine) - Drug Interactions, Contraindications, Overdosage, etc

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 (see WARNINGS).

Amphotericin, Foscarnet, and Aminoglycosides

Drugs such as amphotericin, foscarnet, and aminoglycosides may increase the risk of developing peripheral neuropathy (see WARNINGS: 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 (see CLINICAL PHARMACOLOGY: Drug Interactions).

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.

OVERDOSAGE

Acute Overdosage

Inadvertent pediatric overdoses have occurred with doses up to 1.5 mg/kg HIVID. Pediatric patients had prompt gastric lavage and treatment with activated charcoal and had no sequelae. Mixed overdoses including HIVID and other drugs have led to drowsiness and vomiting (with HIVID or placebo, zidovudine and trimethoprim/sulfamethoxazole [TMP/SMX]), or increased GGT (with 18.75 mg HIVID with zidovudine and lormetazepam) or increased creatine phosphokinase (with HIVID or placebo, zidovudine, fluconazole, dapsone and wine). There is no experience with acute HIVID overdosage at higher doses and sequelae are unknown. There is no known antidote for HIVID overdosage. It is not known whether zalcitabine is dialyzable by peritoneal dialysis or hemodialysis.

Chronic Overdosage

In an initial dose-finding study in which zalcitabine was administered at doses 25 times (0.25 mg/kg every 8 hours) the currently recommended dose, one patient discontinued HIVID after 1½ weeks of treatment subsequent to the development of a rash and fever. In the early Phase 1 studies, all patients receiving zalcitabine at approximately 6 times the current total daily recommended dose experienced peripheral neuropathy by week 10. Eighty percent of patients who received approximately 2 times the current total daily recommended dose experienced peripheral neuropathy by week 12.

CONTRAINDICATIONS

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

REFERENCES

1. 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.
2. Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection . N Engl J Med. 1994;330(10): 657-662.
3. Follansbee S, Drew L, Olson R, et al. The efficacy of zalcitabine (ddC, HIVID) versus zidovudine (ZDV) as monotherapy in ZDV-naive patients with advanced HIV disease; a randomized, double-blind, comparative trial (ACTG 114; N3300). IXth International Conference on AIDS/IV STD World Congress, Berlin, Germany, June 7-11, 1993. Poster PO-B26-2113.
4. Remick S, Follansbee S, Olson R, et al. Safety and tolerance of zalcitabine (ddC, HIVID) in a double-blind comparative trial (ACTG 114; N3300). IXth International Conference on AIDS/IV STD World Congress, Berlin, Germany, June 7-11, 1993. Poster PO-B26-2115.
5. "Dear Doctor" letter, Burroughs Wellcome Co., June 1, 1993.
6. Food and Drug Administration Antiviral Drugs Advisory Committee Meeting, "Mitochondrial Damage Associated with Nucleoside Analogues," Rockville, MD, September 21, 1993.
7. Sanders VM, Elwell MR, Heath JE, et al. Induction of Thymic Lymphoma in Mice Administered the Dideoxynucleoside ddC. Fundamental and Applied Toxicology. 1995;27: 263-269.
8. Irons RD, Le AT, Som DB, et al. 2'3'-Dideoxycytidine-induced Thymic Lymphoma Correlates with Species-specific Suppression of a Subpopulation of Primitive Hematopoietic Progenitor Cells in Mouse but Not Rat or Human Bone Marrow. J Clin Invest. 1995;95: 2777-2782.

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