DESCRIPTION
VIDEX® EC (didanosine) is the brand name for an enteric-coated formulation of didanosine (ddl), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX EC (didanosine) Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain colloidal silicon dioxide, gelatin, sodium lauryl sulfate, and titanium dioxide. The capsules are imprinted with edible inks.
Didanosine is also available as buffered formulations. Please consult the prescribing information for VIDEX (didanosine) Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution for additional information.
The chemical name for didanosine is 2',3'-dideoxyinosine. The structural formula is:
Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25°C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37°C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC (didanosine), an enteric coating is used to protect didanosine from degradation by stomach acid.
MICROBIOLOGY
Mechanism of Action: Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.
In Vitro HIV Susceptibility: The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC50) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established. Drug Resistance: HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established. Cross-resistance: HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established.
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CLINICAL PHARMACOLOGY
Animal Toxicology: Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues. Pharmacokinetics: The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.
Table 1 Pharmacokinetic Parameters for Didanosine in Adults
| Parameter |
Mean ± SD |
n |
|
Oral bioavailability a |
42±12%
|
6
|
Apparent volume
of distributionb |
1.08±0.22 L/kg
|
6
|
|
CSF -plasma ratio b |
21±0.03% c |
5
|
|
Systemic clearance b |
13.0±1.6 mL/min/kg
|
6
|
|
Renal clearance a |
5.5±2.1 mL/min/kg
|
6
|
|
Elimination half-life a |
1.5±0.4 h
|
6
|
Urinary recovery
of didanosine a |
18±8%
|
6
|
|
CSF = cerebrospinal fluid.
|
| a following oral administration of a buffered formulation. |
| b following I.V. administration. |
| c mean ± SE.
|
|
Comparison of Didanosine Formulations --In VIDEX EC (didanosine) the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid.
In healthy volunteers, as well as subjects infected with HIV, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC (didanosine) formulation relative to a buffered tablet formulation. The peak plasma concentration (CMAX of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (TMAX) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC (didanosine). Effect of Food on Absorption of Didanosine --In the presence of food, the CMAX and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty stomach.
SPECIAL POPULATIONS:
Renal Insufficiency --It is recommended that the VIDEX EC dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis.
Table 2 Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation
|
|
Creatinine Clearance (mL/min) |
| Parameter |
>/= 90 (n=12) |
60-90 (n=6) |
30-59 (n=6) |
10-29 (n=3) |
Dialysis
Patients (n=11) |
|
CLcr (mL/min)
|
112±22
|
68±8
|
46±8
|
13±5
|
ND |
|
CL/F (mL/min)
|
2164±638
|
1566±833
|
1023±378
|
628±104
|
543±174
|
|
CLR (mL/min)
|
458±164
|
247±153
|
100±44
|
20±8
|
<10
|
|
T1/2(h)
|
1.42±0.33
|
1.59±0.13
|
1.75±0.43
|
2.0±0.3
|
4.1±1.2
|
|
ND = not determined due to anuria.
|
|
CLcr= creatinine clearance.
|
|
CL/F = apparent oral clearance.
|
|
CLR= renal clearance.
|
|
Pediatric Patients --The pharmacokinetics of didanosine administered as VIDEX EC have not been studied in pediatric patients. Geriatric Patients --Didanosine pharmacokinetics have not been studied in patients over 65 years of age (see PRECAUTIONS: Geriatric Use).
Gender --The effects of gender on didanosine pharmacokinetics have not been studied. Drug Interactions: (See also PRECAUTIONS: Drug Interactions.)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).
VIDEX EC (didanosine) --Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.
Table 3
Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on
Didanosine Plasma AUC and CMAX Values a
| Drug |
Didanosine Dosage |
n |
AUC of
Didanosine (90% CI) |
CMAX of
Didanosine (90% CI) |
tenofovir, b
300 mg once daily
with a light meal c |
400 mg single dose fasting
2 h before tenofovir
|
26
|
up 48%
(31, 67%) |
up 48%
(25, 76%) |
tenofovir, b
300 mg once daily
with a light meal c |
400 mg single dose with
tenofovir and a light meal
|
25
|
up 60%
(44, 79%) |
up 64%
(41, 89%) |
tenofovir, b
300 mg once daily
with a light meal c |
200 mg single dose with
tenofovir and a light meal
|
33
|
up 16%
(6, 27%) d |
up 12%
(-25, 3%)
|
|
|
250 mg single dose with
tenofovir and a light meal
|
33
|
<->
(-13, 5%) e |
down 20%
(-32, -7%) e |
|
|
325 mg single dose with
tenofovir and a light meal
|
33
|
up 13%
(3, 24%) e |
down 11%
(-24, 4%) e |
|
up indicates increase.
|
|
down indicates decrease. |
|
<-> indicates no change, or mean increase or decrease of <10%. |
| a All studies conducted in healthy volunteers >/=60 kg with creatinine clearance >/=60 mL/min. |
| b tenofovir disoproxil fumarate. |
| c 373 kcalories, 8.2 grams fat. |
| d Compared with VIDEX EC 250 mg administered alone under fasting conditions. |
| e Compared with VIDEX EC 400 mg administered alone under fasting conditions. |
|
Table 4
Results of Drug Interaction Studies with VIDEX EC (didanosine):
Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values a
| Drug |
Didanosine Dosage |
n |
AUC of
Coadministered Drug |
CMAX of
Coadministered Drug |
ciprofloxacin,
750 mg single dose
|
400 mg single dose
|
16
|
<-> |
<-> |
indinavir,
800 mg single dose
|
400 mg single dose
|
23
|
<-> |
<-> |
ketoconazole,
200 mg single dose
|
400 mg single dose
|
21
|
<-> |
<-> |
tenofovir, b
300 mg once daily
with a light meal c |
400 mg single dose
fasting 2 h before tenofovir
|
25
|
<-> |
<-> |
tenofovir, b
300 mg once daily
with a light meal c |
400 mg single dose
with tenofovir and
a light meal
|
25
|
<-> |
<-> |
|
<-> indicates no change, or mean increase or decrease of <10%. |
| a All studies conducted in healthy volunteers >/=60 kg with creatinine clearance >/=60 mL/min. |
| b tenofovir disoproxil fumarate. |
| c 373 kcalories, 8.2 grams fat. |
|
Didanosine Buffered Formulations --Tables 5 and 6 summarize the effects on AUC and CMAX, with a 90% or 95% Cl when available, following coadministration of buffered formulations of didanosine with a variety of drugs. Except as noted in table footnotes, the results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir).
Table 5
Results of Drug Interaction Studies with Buffered Formulations of Didanosine:
Effects of Coadministered Drug on Didanosine Plasma AUC and CMAX Values
| Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions ) |
| Drug |
Didanosine Dosage |
n |
AUC of
Didanosine (95% CI) |
CMAX of
Didanosine (95% CI) |
allopurinol,
renally impaired,
300 mg/day
|
200 mg single dose
|
2
|
up 312%
|
up 232%
|
healthy volunteer,
300 mg/day
for 7 days
|
400 mg single dose
|
14
|
up 113%
|
up 69%
|
ganciclovir,
1000 mg q8h,
2 h after didanosine
|
200 mg q12h
|
12
|
up 111%
|
NA |
methadone,
chronic maintenance
dose
|
200 mg
single dose
|
16, 10 a |
down 57%
|
down 66%
|
tenofovir, b
300 mg once daily
1 h after didanosine
|
250 c or 400 mg
once daily for 7 days
|
14
|
up 44%
(31, 59%) d |
up 28%
(11, 48%) d |
| No Clinically Significant Interaction Observed |
| Drug |
Didanosine Dosage |
n |
AUC of
Didanosine (95% CI) |
CMAX of
Didanosine (95% CI) |
ciprofloxacin,
750 mg q12h
for 3 days, 2 h
before didanosine
|
200 mg q12h
for 3 days
|
8 e |
down 16%
|
down 28%
|
indinavir,
800 mg single dose
simultaneous
|
200 mg single dose
|
16
|
<-> |
<-> |
|
1 h before didanosine
|
200 mg single dose
|
16
|
down 17% (-27, -7%) d |
down 13% (-28, 5%) d |
ketoconazole, 200 mg/day
for 4 days, 2 h before
didanosine
|
375 mg q12h
for 4 days
|
12 e |
<-> |
down 12%
|
loperamide, 4 mg q6h
for 1 day
|
300 mg single dose
|
12 e |
<-> |
down 23%
|
metoclopramide,
10 mg single dose
|
300 mg single dose
|
12 e |
<-> |
up 13%
|
ranitidine,
150 mg single dose,
2 h before didanosine
|
375 mg single dose
|
12 e |
up 14%
|
up 13%
|
rifabutin,
300 or 600 mg/day
for 12 days
|
167 or 250 mg q12h
for 12 days
|
11
|
up 13% (-1, 27%) |
up 17% (-4, 38%) |
ritonavir, 600 mg q12h
for 4 days
|
200 mg q12h
for 4 days
|
12
|
down 13% (0, 23%) |
down 16% (5, 26%) |
stavudine, 40 mg q12h
for 4 days
|
100 mg q12h
for 4 days
|
10
|
<-> |
<-> |
sulfamethoxazole,
1000 mg single dose
|
200 mg
single dose
|
8 e |
<-> |
<-> |
trimethoprim,
200 mg single dose
|
200 mg
single dose
|
8 e |
<-> |
up 17% (-23, 77%) |
zidovudine, 200 mg q8h
for 3 days
|
200 mg q12h
for 3 days
|
6 e |
<-> |
<-> |
|
up indicates increase.
|
|
down indicates decrease. |
|
<-> indicates no change, or mean increase or decrease of <10%. |
| a Parallel-group design; entries are subjects receiving combination and control regimens, respectively. |
| b tenofovir disoproxil fumarate. |
| c patients <60 kg with creatinine clearance >/=60 mL/min. |
| d 90% CI.
|
| e HIV-infected patients. |
|
NA Not available. |
|
Table 6
Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values
| No Clinically Significant Interaction Observed |
| Drug |
Didanosine Dosage |
n |
AUC of
Coadministered
Drug (95% CI) |
CMAX of
Coadministered
Drug (95% CI) |
dapsone,
100 mg single dose
|
200 mg q12h
for 14 days
|
6 a |
<-> |
<-> |
delavirdine,
400 mg single dose
simultaneous
|
125 or 200 mg q12h
|
12 a |
down 32% b |
down 53% b |
|
1 hr before didanosine
|
125 or 200 mg q12h
|
12 a |
up 20%
|
up 18%
|
ganciclovir,
1000 mg q8h,
2 h after didanosine
|
200 mg q12h
|
12 a |
down 21%
|
NA |
nelfinavir,
750 mg single dose,
1 h after didanosine
|
200 mg
single dose
|
10 a |
up 12%
|
<-> |
ranitidine,
150 mg single dose,
2 h before didanosine
|
375 mg
single dose
|
12 a |
down 16%
|
<-> |
ritonavir, 600 mg q12h
for 4 days
|
200 mg q12h
for 4 days
|
12
|
<-> |
<-> |
stavudine, 40 mg q12h
for 4 days
|
100 mg q12h
for 4 days
|
10 a |
<-> |
up 17%
|
sulfamethoxazole,
1000 mg single dose
|
200 mg
single dose
|
8 a |
down 11% (-17, -4%) |
down 12% (-28, 8%)
|
tenofovir, c
300 mg once daily
1 h after didanosine
|
250 d or 400 mg
once daily for
7 days
|
14
|
<-> |
<-> |
trimethoprim,
200 mg single dose
|
200 mg
single dose
|
8 a |
up 10% (-9, 34%) |
down 22% (-59, 49%) |
zidovudine,
200 mg q8h for 3 days
|
200 mg q12h
for 3 days
|
6 a |
down 10% (-27, 11%) |
down 16.5% (-53, 47%) |
|
up indicates increase.
|
|
down indicates decrease. |
|
<-> indicates no change, or mean increase or decrease of <10%. |
| a HIV-infected patients. |
| b This result is probably related to the buffer and is not expected to occur with VIDEX EC.
|
| c tenofovir disoproxil fumarate. |
| d patients <60 kg with creatinine clearance >/=60 mL min.
|
|
NA Not available. |
|
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