WARNINGS
SIGNIFICANT CLINICAL ADVERSE REACTIONS, SOME OF WHICH ARE POTENTIALLY FATAL, HAVE BEEN REPORTED WITH HIVID. PATIENTS WITH DECREASED CD4 CELL COUNTS APPEAR TO HAVE AN INCREASED INCIDENCE OF ADVERSE EVENTS.
Peripheral Neuropathy
THE MAJOR CLINICAL TOXICITY OF HIVID IS PERIPHERAL NEUROPATHY, WHICH MAY OCCUR IN UP TO 1/3 OF PATIENTS WITH ADVANCED DISEASE TREATED WITH HIVID. The incidence in patients with less-advanced disease is lower.
HIVID-related peripheral neuropathy is a sensorimotor neuropathy characterized initially by numbness and burning dysesthesia involving the distal extremities. These symptoms may be followed by sharp shooting pains or severe continuous burning pain if the drug is not withdrawn. The neuropathy may progress to severe pain requiring narcotic analgesics and is potentially irreversible. In some patients, symptoms of neuropathy may initially progress despite discontinuation of HIVID. With prompt discontinuation of HIVID, the neuropathy is usually slowly reversible.
There are no data regarding the use of HIVID in patients with preexisting peripheral neuropathy since these patients were excluded from clinical trials; therefore, HIVID should be used with extreme caution in these patients. Individuals with moderate or severe peripheral neuropathy, as evidenced by symptoms accompanied by objective findings, are advised to avoid HIVID.
HIVID should be used with caution in patients with a risk of developing peripheral neuropathy: patients with low CD4 cell counts (CD4<50 cells/mm3), diabetes, weight loss and/or patients receiving HIVID concomitantly with drugs that have the potential to cause peripheral neuropathy (see PRECAUTIONS: Drug Interactions). Careful monitoring is strongly recommended for these individuals.
HIVID should be stopped promptly if signs or symptoms of peripheral neuropathy occur, such as when moderate discomfort from numbness, tingling, burning or pain of the extremities progresses, or any related symptoms occur that are accompanied by an objective finding (see DOSAGE AND ADMINISTRATION).
Pancreatitis
PANCREATITIS, WHICH HAS BEEN FATAL IN SOME CASES, HAS BEEN OBSERVED WITH THE ADMINISTRATION OF HIVID. Pancreatitis is an uncommon complication of HIVID occurring in up to 1.1% of patients.
Patients with a history of pancreatitis or known risk factors for the development of pancreatitis should be followed more closely while on HIVID therapy. Of 528 HIVID-treated patients enrolled in an expanded-access safety study (N3544), who had a history of prior pancreatitis or increased amylase, 28 (5.3%) developed pancreatitis and an additional 23 (4.4%) developed asymptomatic elevated serum amylase.
Treatment with HIVID should be stopped immediately if clinical signs or symptoms (nausea, vomiting, abdominal pain) or if abnormalities in laboratory values (hyperamylasemia associated with dysglycemia, rising triglyceride level, decreasing serum calcium) suggestive of pancreatitis should occur. If clinical pancreatitis develops during HIVID administration, it is recommended that HIVID be permanently discontinued. Treatment with HIVID should also be interrupted if treatment with another drug known to cause pancreatitis (eg, intravenous pentamidine) is required (see Drug Interactions ).
Lactic Acidosis/Severe Hepatomegaly With Steatosis and Hepatic Toxicity
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including HIVID and other antiretrovirals.5,6 A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering HIVID to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with HIVID should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
IN ADDITION, RARE CASES OF HEPATIC FAILURE AND DEATH CONSIDERED POSSIBLY RELATED TO UNDERLYING HEPATITIS B AND HIVID HAVE BEEN REPORTED. Treatment with HIVID in patients with preexisting liver disease, liver enzyme abnormalities, a history of ethanol abuse or hepatitis should be approached with caution. Treatment with HIVID should be suspended in any patient who develops clinical or laboratory findings suggestive of pronounced hepatotoxicity. In clinical trials, drug interruption was recommended if liver function tests exceeded >5 times the upper limit of normal.
Other Serious Toxicities
- a) Oral Ulcers: Severe oral ulcers occurred in up to 3% of patients receiving HIVID in CPCRA 002 and ACTG 175; less severe oral ulcerations have occurred at higher frequencies in other clinical trials.
- b) Esophageal Ulcers: Infrequent cases of esophageal ulcers have also been attributed to HIVID therapy. Interruption of HIVID should be considered in patients whodevelop esophageal ulcers that do not respond to specific treatment for opportunistic pathogens in order to assess a possible relationship to HIVID.
- c) Cardiomyopathy/Congestive Heart Failure: Cardiomyopathy and congestive heart failure in patients with AIDS have been associated with the use of nucleoside analogues. Infrequent cases have been reported in patients receiving HIVID. Treatment with HIVID in patients with baseline cardiomyopathy or history of congestive heart failure should be approached with caution.
- d) Anaphylactoid Reaction: An anaphylactoid reaction was reported in a patient receiving both HIVID and zidovudine. In addition, there have been several reports of hypersensitivity reactions (including anaphylactic reaction or urticaria without other signs of anaphylaxis).
PRECAUTIONS
General
- Renal Impairment: Patients with renal impairment (estimated creatinine clearance <55 mL/min) may be at a greater risk of toxicity from HIVID due to decreased drug clearance. Dosage adjustment is recommended in these patients (see DOSAGE AND ADMINISTRATION).
- Lymphoma: High doses of zalcitabine, administered for 3 months to B6C3F1 mice (resulting in plasma concentrations over 1000 times those seen in patients taking the recommended doses of HIVID) induced an increased incidence of thymic lymphoma.7 Although the pathogenesis of the effect is uncertain, a predisposition to chemically induced thymic lymphoma and high rates of spontaneous lymphoreticular neoplasms have previously been noted in this strain of mice.8
The incidence of lymphomas was reviewed in 13 comparative studies conducted by Roche, the NIAID and the NCI, as well as 7 Roche expanded-access studies that included HIVID. In one study, ACTG 155, a statistically significant increased rate of lymphomas was seen in patients receiving HIVID or combination HIVID and zidovudine compared to zidovudine alone (rates of 0, 1.3, and 2.3 per 100 person years for zidovudine, HIVID, and combination HIVID and zidovudine, respectively; log rank p-value=0.01, pooling HIVID, and combination HIVID and zidovudine vs zidovudine, p-value=0.003). Based on review of the literature, the incidence of lymphomas in HIV-infected patients with advanced disease on zidovudine monotherapy would be expected to be approximately 1 to 2 per 100 person years of follow-up.
None of the other comparative studies evaluated showed a statistically significant difference in rates of lymphomas in patients receiving HIVID. In a large, controlled clinical trial (ACTG 175) HIVID in combination with zidovudine was not associated with an increase in the incidence of lymphoma over that seen with zidovudine monotherapy (6 of 615 and 9 of 619, respectively).
Lymphoma has been identified as a consequence of HIV infection. This most likely represents a consequence of prolonged immunosuppression; however, an association between the occurrence of lymphoma and antiviral therapy cannot be excluded.
- Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Patients receiving HIVID or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infections, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in antiretroviral therapy should be considered in cases of disease progression, either clinical or as demonstrated by viral rebound (increase in HIV RNA after initial decline).
Information for Patients
Patients should be informed that HIVID is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.
Patients should be told that there is currently no data demonstrating that HIVID therapy can reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
Patients should be advised to take HIVID every day as prescribed. Patients should not alter the dose or discontinue therapy without consulting with their physician. If a dose is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.
Patients should be instructed that the major toxicity of HIVID is peripheral neuropathy. Pancreatitis and hepatic toxicity are other serious potentially life-threatening toxicities that have been reported in patients treated with HIVID. Patients should be advised of the early symptoms of these conditions and instructed to promptly report them to their physician. Since the development of peripheral neuropathy appears to be dose-related to HIVID, patients should be advised to follow their physicians' instructions regarding the prescribed dose.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Laboratory Tests
Complete blood counts and clinical chemistry tests should be performed prior to initiating HIVID therapy and at appropriate intervals thereafter. Baseline testing of serum amylase and triglyceride levels should be performed in individuals with a prior history of pancreatitis, increased amylase, those on parenteral nutrition or with a history of ethanol abuse.
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.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
Zalcitabine was administered orally by dietary admixture to CRL:CD-1® (ICR) Br mice at dosages of 3, 83, or 250 mg/kg/day for 2 years. Plasma exposures (as measured by AUC) at these doses were 6-fold to 704-fold greater than the systemic exposure in humans with the therapeutic dose. Zalcitabine was administered orally by dietary admixture to CDF® (F-344)/CrlBR/CdBR rats at dosages of 3, 28, 83, or 250 mg/kg/day. At the highest dose tested, the systemic exposure to zalcitabine was 833 times the systemic exposure in humans with the therapeutic dose.
A significant increase in thymic lymphoma in all zalcitabine dose groups and Harderian gland (a gland of the eye of rodents) adenoma in the two highest dose groups was observed in female CD-1 mice after 2 years of dosing. No increase in tumor incidence was observed in rats or male mice treated with zalcitabine. In an independent study, administration of zalcitabine to B6C3F1 mice at a dose of 1000 mg/kg/day for 3 months induced an increased incidence of thymic lymphoma. A high rate of spontaneous lymphoreticular neoplasms have previously been noted in this strain of mice.
Mutagenesis
Zalcitabine was positive in a cell transformationassay and induced chromosomal aberrations in vitro in human peripheral blood lymphocytes. Oral doses of zalcitabine at 2500 and 4500 mg/kg were clastogenic in the mouse micronucleus assay. Zalcitabine showed no evidence of mutagenicity in Ames tests, Chinese hamster lung cell assays and the mouse lymphoma assay. An unscheduled DNA synthesis assay in rat hepatocytes showed that zalcitabine had no effect on DNA repair.
Impairment of Fertility
Fertility and reproductive performance were assessed in rats at plasma concentrations up to 2142 times those achieved with the maximum recommended human dose (MRHD) based on AUC measurements. No adverse effects on rate of conception or general reproductive performance were observed. The highest dose was associated with embryolethality and evidence of teratogenicity. The next lower dose studied (plasma concentrations equivalent to 485 times the MRHD) was associated with a lower frequency of embryotoxicity but no teratogenicity. The fertility of F1 males was significantly reduced at a calculated dose of 2142 (but not 485) times the MRHD (based on AUC measurements) in a teratology study in which rat mothers were dosed on gestation days 7 to 15. No adverse effects were observed on the fertility of parents or F1 generation in the study of fertility and general reproductive performance or in the perinatal and postnatal reproduction study.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Zalcitabine has been shown to be teratogenic in mice at calculated exposure levels of 1365 and 2730 times that of the MRHD (based on AUC measurements). In rats, zalcitabine was teratogenic at a calculated exposure level of 2142 times the MRHD but not at an exposure level of 485 times the MRHD. In a perinatal and postnatal study in the rat, a high incidence of hydrocephalus was observed in the F1 offspring derived from litters of dams treated with 1071 (but not 485) times the MRHD (based on AUC measurements). There are no adequate and well-controlled studies of zalcitabine in pregnant women. HIVID should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fertile women should not receive HIVID unless they are using effective contraception during therapy. If pregnancy occurs, physicians are encouraged to report such cases by calling (800) 526-6367.
Nonteratogenic Effects
Increased embryolethality was observed in pregnant mice at doses 2730 times the MRHD and in pregnant rats above 485 (but not 98) times the MRHD (based on AUC measurements). Average fetal body weight was significantly decreased in mice at doses of 1365 times the MRHD and in rats at 2142 times the MRHD (based on AUC measurements). In a perinatal and postnatal study, the learning and memory of a significant number of F1 offspring were impaired, and they tended to stay hyperactive for a longer period of time. These effects, observed at a calculated exposure level of 1071 (but not 485) times the MRHD (based on AUC measurements), were considered to result from extensive damage to or gross underdevelopment of the brain of these F1 offspring consistent with the finding of hydrocephalus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to HIVID, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether zalcitabine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving antiretroviral medications, including HIVID.
Pediatric Use
Pharmacokinetics in Pediatric Patients
Limited pharmacokinetic data have been reported for 5 HIV-positive pediatric patients using doses of 0.03 and 0.04 mg/kg HIVID administered orally every 6 hours.1 The mean bioavailability of zalcitabine in these pediatric patients was 54% and mean apparent systemic clearance was 150 mL/min/m2. Due to the small number of subjects and different analytical techniques, it is difficult to make comparisons between pediatric and adult data.
Safety and effectiveness of HIVID in HIV-infected pediatric patients younger than 13 years of age have not been established.
Geriatric Use
Clinical studies of HIVID did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. HIVID is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly (see PRECAUTIONS: General: Renal Impairment and DOSAGE AND ADMINISTRATION).
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