ZERIT- stavudine capsule, gelatin coated
ZERIT- stavudine powder, for solution
E.R. Squibb & Sons, L.L.C.
WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.1)].
Fatal and nonfatal pancreatitis have occurred during therapy when ZERIT was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression
1 INDICATIONS AND USAGE
ZERIT� (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
The interval between doses of ZERIT (stavudine) should be 12 hours. ZERIT may be taken with or without food.
2.1 Recommended Adult Dosage
The recommended adult dosage is based on body weight as follows:
For patients weighing less than 60 kg: 30 mg every 12 hours.
For patients weighing at least 60 kg: 40 mg every 12 hours.
2.2 Recommended Pediatric Dosage
For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
For pediatric patients weighing at least 30 kg: use the recommended adult dosage
DESCRIPTION
ZERIT� is the brand name for stavudine (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for stavudine is 2?,3?-didehydro-3?-deoxythymidine.
Microbiology
Mechanism of Action
Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki =0.0083 to 0.032 �M) and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases ? and ? and markedly reduces the synthesis of mitochondrial DNA.
Antiviral Activity in Cell Culture
The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50 ) ranged from 0.009 to 4 �M against laboratory and clinical isolates of HIV-1. In cell culture, stavudine exhibited additive to antagonistic activity in combination with zidovudine. Stavudine in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9�45 �M concentrations tested, reduced the anti-HIV-1 activity of stavudine by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been established.