HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`HIVID®
`(zalcitabine)
`TABLETS
`
`WARNING:
`
`THE USE OF HIVID HAS BEEN ASSOCIATED WITH SIGNIFICANT CLINICAL
`ADVERSE REACTIONS, SOME OF WHICH ARE POTENTIALLY FATAL. HIVID
`CAN CAUSE SEVERE PERIPHERAL NEUROPATHY AND BECAUSE OF THIS
`SHOULD BE USED WITH EXTREME CAUTION IN PATIENTS WITH
`PREEXISTING NEUROPATHY. HIVID MAY ALSO RARELY CAUSE
`PANCREATITIS AND PATIENTS WHO DEVELOP ANY SYMPTOMS SUGGESTIVE
`OF PANCREATITIS WHILE USING HIVID SHOULD HAVE THERAPY
`SUSPENDED IMMEDIATELY UNTIL THIS DIAGNOSIS IS EXCLUDED.
`
`LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
`INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
`ANTIRETROVIRAL NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION,
`INCLUDING HIVID (SEE WARNINGS).
`
`IN ADDITION, RARE CASES OF HEPATIC FAILURE AND DEATH CONSIDERED
`POSSIBLY RELATED TO UNDERLYING HEPATITIS B AND HIVID HAVE BEEN
`REPORTED (SEE WARNINGS AND PRECAUTIONS).
`
`DESCRIPTION
`
`HIVID is the Hoffmann-La Roche brand of zalcitabine [formerly called 2',3'-dideoxycytidine
`(ddC)], a synthetic pyrimidine nucleoside analogue active against the human immunodeficiency
`virus (HIV). HIVID is available as film-coated tablets for oral administration in strengths of
`0.375 mg and 0.750 mg. Each tablet also contains the inactive ingredients lactose,
`microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hydroxypropyl
`methylcellulose, polyethylene glycol, and polysorbate 80 along with the following colorant
`system: 0.375 mg tablet — synthetic brown, black, red and yellow iron oxides, and titanium
`dioxide; 0.750 mg tablet — synthetic black iron oxide and titanium dioxide. The chemical name
`for zalcitabine is 4-amino-1-beta-D-2', 3'-dideoxyribofuranosyl-2-(1H)-pyrimidone or 2',3'-
`dideoxycytidine with the molecular formula C9H13N3O3 and a molecular weight of 211.22.
`Zalcitabine has the following structural formula:
`
`1
`
`BMS 2016
`MYLAN v. BMS
`IPR2018-00892
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`Zalcitabine is a white to off-white crystalline powder with an aqueous solubility of 76.4 mg/mL
`at 25°C.
`
`MICROBIOLOGY
`
`Mechanism of Action: Zalcitabine is a synthetic nucleoside analogue of the naturally occurring
`nucleoside deoxycytidine, in which the 3'-hydroxyl group is replaced by hydrogen. Within cells,
`zalcitabine is converted to the active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the
`sequential action of cellular enzymes. Dideoxycytidine 5'-triphosphate inhibits the activity of the
`HIV-reverse transcriptase both by competing for utilization of the natural substrate,
`deoxycytidine 5'-triphosphate (dCTP), and by its incorporation into viral DNA. 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. The active metabolite, ddCTP, is also an inhibitor of cellular DNA polymerase-
`beta and mitochondrial DNA polymerase-gamma and has been reported to be incorporated into
`the DNA of cells in culture.
`
`In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zalcitabine was assessed by
`infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with
`laboratory and clinical isolates of HIV. The IC50 and IC95 values (50% and 95% inhibitory
`concentration) were in the range of 30 to 500 nM and 100 to 1000 nM, respectively (1 nM = 0.21
`ng/mL). Zalcitabine showed antiviral activity in all acute infections; however, activity was
`substantially less in chronically infected cells. In drug combination studies with zidovudine
`(ZDV) or saquinavir, zalcitabine showed additive to synergistic activity in cell culture. The
`relationship between the in vitro susceptibility of HIV to reverse-transcriptase inhibitors and the
`inhibition of HIV replication in humans has not been established.
`
`Drug Resistance: HIV isolates with a reduction in sensitivity to zalcitabine (ddC) have been
`isolated from a small number of patients treated with HIVID by 1 year of therapy. Genetic
`analysis of these isolates showed point mutations (Lys 65 Arg or Asn, Thr 69 Asp, Leu 74 Val,
`Val 75 Thr or Ala, Met 184 Val or Tyr 215 Cys) in the pol gene that encodes for the reverse
`transcriptase. Combination therapy with HIVID and ZDV does not appear to prevent the
`emergence of zidovudine-resistant isolates.
`
`Cross-resistance: The potential for cross-resistance between HIV-reverse transcriptase inhibitors
`and HIV-protease inhibitors is low because of the different enzyme targets involved. The point
`
`2
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`mutation at position 69 appears to be specific to ddC in its selection and effect. Additionally, the
`point mutations at positions 65, 74, 75, and 184 are associated with resistance to didanosine
`(ddI), that at position 75 with resistance to stavudine (d4T), and those at positions 65 (Lys to
`Arg), and 184 (Met to Val) with resistance to lamivudine (3TC). HIV isolates with multidrug
`resistance to ZDV, ddI, ddC, d4T, and 3TC were recovered from a small number of patients
`treated for 1 year with the combination of ZDV, ddI or ddC. The pattern of resistance mutations
`in the combination therapy was different (Ala 62 Val, Val 75 Ile, Phe 77 Leu, Phe 116 Tyr and
`Gln 151 Met) from monotherapy with mutation 151 being most significant for multidrug
`resistance.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics: The pharmacokinetics of zalcitabine has been evaluated in studies in HIV-
`infected patients following 0.01 mg/kg, 0.03 mg/kg, and 1.5 mg oral doses, and a 1.5 mg
`intravenous dose administered as a 1-hour infusion.
`
`Absorption and Bioavailability in Adults: Following oral administration to HIV-infected patients,
`the mean absolute bioavailability of zalcitabine was >80% (30% CV, range 23% to 124%, n=19).
`The absorption rate of a 1.5 mg oral dose of zalcitabine (n=20) was reduced when administered
`with food. This resulted in a 39% decrease in mean maximum plasma concentrations (Cmax) from
`25.2 ng/mL (35% CV, range 11.6 to 37.5 ng/mL) to 15.5 ng/mL (24% CV, range 9.1 to 23.7
`ng/mL), and a twofold increase in time to achieve maximum plasma concentrations from a mean
`of 0.8 hours under fasting conditions to 1.6 hours when the drug was given with food. The extent
`of absorption (as reflected by AUC) was decreased by 14%, from 72 ng·hr/mL (28% CV, range
`43 to 119 ng·hr/mL) to 62 ng·hr/mL (23% CV, range 42 to 91 ng·hr/mL). The clinical relevance
`of these decreases is unknown. Absorption of zalcitabine does not appear to be reduced in
`patients with diarrhea not caused by an identified pathogen.
`
`Distribution in Adults: The steady-state volume of distribution following intravenous
`administration of a 1.5 mg dose of zalcitabine averaged 0.534 (± 0.127) L/kg (24% CV, range
`0.304 to 0.734 L/kg, n=20). Cerebrospinal fluid obtained from 9 patients at 2 to 3.5 hours
`following 0.06 mg/kg or 0.09 mg/kg intravenous infusion showed measurable concentrations of
`zalcitabine. The CSF: plasma concentration ratio ranged from 9% to 37% (mean 20%),
`demonstrating penetration of the drug through the blood-brain barrier. The clinical relevance of
`these ratios has not been evaluated.
`
`Metabolism and Elimination in Adults: Zalcitabine is phosphorylated intracellularly to
`zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of
`zalcitabine triphosphate are too low for quantitation following administration of therapeutic
`doses to humans.
`
`Zalcitabine does not undergo a significant degree of metabolism by the liver. The primary
`metabolite of zalcitabine that has been identified is dideoxyuridine (ddU), which accounts for less
`than 15% of an oral dose in both urine and feces (n=4). Approximately 10% of an orally
`administered radiolabeled dose of zalcitabine appears in the feces (n=10), comprised primarily of
`
`
`
`3
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`unchanged drug and ddU. Renal excretion of unchanged drug appears to be the primary route of
`elimination, accounting for approximately 80% of an intravenous dose and 60% of an orally
`administered dose within 24 hours after dosing (n=19). The mean elimination half-life is 2 hours
`and generally ranges from 1 to 3 hours in individual patients. Total clearance following an
`intravenous dose averaged 285 mL/min (29% CV, range 165 to 447 mL/min, n=20). Renal
`clearance averaged approximately 235 mL/min or about 80% of total clearance (30% CV, range
`129 to 348 mL/min, n=20). Renal clearance exceeds glomerular filtration rate suggesting renal
`tubular secretion contributes to the elimination of zalcitabine by the kidneys.
`
`In patients with impaired kidney function, prolonged elimination of zalcitabine may be expected.
`Preliminary results from 7 patients with renal impairment (estimated creatinine clearance <55
`mL/min) indicate that the half-life was prolonged (up to 8.5 hours) in these patients compared to
`those with normal renal function. Maximum plasma concentrations were higher in some patients
`after a single dose (see PRECAUTIONS).
`
`In patients with normal renal function, the pharmacokinetics of zalcitabine was not altered during
`3 times daily multiple dosing (n=9). Accumulation of drug in plasma during this regimen was
`negligible. The drug was <4% bound to plasma proteins, indicating that drug interactions
`involving binding-site displacement are unlikely (see Drug Interactions).
`
`Drug Interactions: Zidovudine: There was no significant pharmacokinetic interaction between
`zidovudine and zalcitabine when single doses of zalcitabine (1.5 mg) and zidovudine (200 mg)
`were coadministered to 12 HIV-positive patients.
`
`Probenecid: Following administration of a single oral 1.5 mg dose of zalcitabine alone during
`probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) to 12
`HIV-positive patients, mean renal clearance decreased from 310 mL/min (28% CV) to 180
`mL/min (22% CV) and AUC increased from 59 ng·hr/mL (27% CV) to 91 ng·hr/mL (22% CV),
`indicating an increase in exposure of approximately 50% to zalcitabine. Mean half-life of
`zalcitabine increased from 1.7 to 2.5 hours (see PRECAUTIONS).
`
`Cimetidine: Administration of a single dose of 1.5 mg zalcitabine with a single dose of 800 mg
`cimetidine to 12 HIV-positive patients resulted in a decrease in renal clearance from 224 mL/min
`(27% CV) to 171 mL/min (39% CV) and an increase in AUC from 75 ng·hr/mL (29% CV) to
`102 ng·hr/mL (35% CV) (see PRECAUTIONS) indicating an increase in exposure of
`approximately 36% to zalcitabine.
`
`Maalox: Concomitant administration of Maalox® TC (30 mL) with single dose of 1.5 mg
`zalcitabine to 12 HIV-positive patients resulted in a decrease in mean Cmax from 25.2 ng/mL (28%
`CV) to 18.4 ng/mL (34% CV) and AUC from 75 ng·hr/mL (29% CV, n=10) to 58 ng·hr/mL (36%
`CV, n=10) indicating a decrease in bioavailability of approximately 25% to zalcitabine (see
`PRECAUTIONS).
`
`
`
`4
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`Metoclopramide: Administration of a single dose of 1.5 mg zalcitabine with 20 mg
`metoclopramide (10 mg 1 hour before and 10 mg 4 hours after zalcitabine dose) to 12 HIV-
`positive patients resulted in a decrease in AUC from 69 ng·hr/mL (16% CV) to 62 ng·hr/mL
`(21% CV) indicating a decrease in bioavailability of approximately 10% (see PRECAUTIONS).
`Loperamide: Administration of a single dose of 1.5 mg zalcitabine during loperamide treatment
`(4 mg 16 hours before zalcitabine, 2 mg at 10 hours and 4 hours before zalcitabine, and 2 mg 2
`hours after the zalcitabine dose) to 12 HIV-positive patients with diarrhea resulted in no
`significant pharmacokinetic interaction between zalcitabine and loperamide.
`
`Pharmacokinetics in Pediatric Patients: For pharmacokinetic properties in pediatric patients,
`see PRECAUTIONS: Pediatric Use. 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.
`
`INDICATIONS AND USAGE
`
`HIVID is indicated in combination with antiretroviral agents for the treatment of HIV infection.
`This indication is based on study results showing a reduction in the rate of disease progression
`(AIDS-defining events or death) in patients with limited prior antiretroviral therapy who were
`treated with the combination of HIVID and zidovudine (see Description of Clinical Studies).
`This indication is also based on a study showing a reduction in both mortality and AIDS-defining
`clinical events for patients who received INVIRASE® (saquinavir mesylate) in combination with
`HIVID compared to patients who received either HIVID or INVIRASE alone.
`
`Description of Clinical Studies: The use of HIVID in combination with zidovudine is based on
`the clinical results from study ACTG 175. ACTG 175 was a randomized, double-blind,
`controlled trial that compared zidovudine 200 mg three times daily; didanosine 200 mg twice
`daily; zidovudine+didanosine; and zidovudine+HIVID 0.750 mg three times daily. A total of
`2467 HIV-infected adults (mean baseline CD4 count = 352 cells/mm3) with no prior AIDS-
`defining event enrolled with the following demographics: male (82%), Caucasian (70%), mean
`age of 35 years, asymptomatic HIV infection (81%) and prior antiretroviral use (57%, mean
`duration = 89.5 weeks). The overall mean duration of study treatment was 99 weeks. The
`incidence of AIDS-defining events or death is shown in Table 1:
`
`
`
`5
`
`

`

`
`
`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`Table 1. First AIDS-defining Event or Death and Death Only
`by Study Arm and Antiretroviral Experience in ACTG 175
`
`Antiretroviral
`Experience
`
`Event
`
`zidovudine
`
`
`Overall
`
`
`Naive
`
`
`Experienced
`
`
`
`n
`AIDS/Death
`Death Only
`n
`AIDS/Death
`Death Only
`n
`AIDS/Death
`Death Only
`
`
`
`
`
`
`
`
`
`
`
`619
`96 (16%)
`54 (9%)
`269
`32 (12%)
`18 (7%)
`350
`64 (18%)
`36 (10%)
`
`Treatment
`zidovudine +
`zidovudine +
`didanosine
`HIVID
`615
`
`613
` 76 (12%)
`65 (11%)
` 40 (7%)
`31 (5%)
`
`267
`263
` 16 (6%)
`20 (8%)
` 9 (3%)
`11 (4%)
`350
`
`348
`45 (13%)
` 60 (17%)
`20 (6%)
` 31 (9%)
`
`
`
`
`
`
`
`
`
`
`
`didanosine
`
`620
`
` 71 (11%)
` 29 (5%)
`
`268
` 23 (9%)
` 11 (4%)
`
`352
` 48 (14%)
` 18 (5%)
`
`Although no antiretroviral agent should be used as monotherapy, a description of CPCRA 002 is
`included here as it provides a comparison of the safety and efficacy of HIVID compared to ddI.
`CPCRA 002 was a randomized, multicenter, open-label study in which HIVID was compared to
`ddI as treatment for patients with advanced HIV infection (median CD4 cell count = 37
`cells/mm3) who were clinically intolerant to ZDV, or who had met criteria for having disease
`progression while receiving ZDV.2 Patients in this study had a mean of 17.5 months of prior
`ZDV use. The median duration of treatment for both HIVID and ddI was 34 weeks. The results
`demonstrate that HIVID was at least as efficacious as ddI in terms of time to an AIDS-defining
`event or death, while for survival alone the results favored HIVID. However, most of the patients
`(66%) in either group had disease progression over the median 16 months of follow-up. Overall
`rates of study drug intolerance, discontinuation and adverse events were similar for the two
`groups, although the types of events were different.
`
` A
`
` clinical study (N3300/ACTG 114) has demonstrated ZDV to be superior to HIVID as
`monotherapy for advanced HIV disease (CD4 cell count ≤200 cells/mm3) in previously untreated
`patients.3,4 The final analysis of this study indicated that 134 patients (42%) in the HIVID group
`with a median follow-up of 85 weeks and 120 patients (38%) in the ZDV group with a median
`follow-up of 96 weeks died with a relative risk for mortality of ZDV to HIVID of 0.54.
`
`CONTRAINDICATIONS
`
`HIVID is contraindicated in patients with clinically significant hypersensitivity to zalcitabine or to
`any of the excipients contained in the tablets.
`
`
`
`6
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`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.
`
`1. 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).
`
`2. 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
`
`
`
`7
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`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).
`
`3. 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.
`
`4. 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 who develop esophageal
`ulcers that do not respond to specific treatment for opportunistic pathogens in order to assess
`a possible relationship to HIVID.
`
`
`
`8
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`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:
`
`1. 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).
`
`
`2. 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.
`
`
`
`9
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`3. 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.
`
`
`
`10
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`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 cells1.
`
`Lamivudine: In vitro studies2, 3, 4 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.
`
`
`
`
`11
`
`

`

`HIVID® (zalcitabine) Tablets - PACKAGE INSERT
`09/21/2001
`
`
`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.
`
`Carcinogenes