Didanosine Delayed-Release Capsules

Name: Didanosine Delayed-Release Capsules

Indications

VIDEX® EC (didanosine, USP), also known as ddI, in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies].

Clinical pharmacology

Mechanism of Action

Didanosine is an antiviral agent.

Pharmacokinetics

The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (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. In adults, the mean (± standard deviation) oral bioavailability following single oral dosing with a buffered formulation is 42 (±12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (±8)% of the dose. The CSF-plasma ratio following IV administration is 21 (±0.03)%. 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 (less than 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 7: Pharmacokinetic Parameters for Didanosine in HIV-infected Patients

Parametera Pediatrics Adults
20 kg to less than 25 kg
n=10		 25 kg to less than 60 kg
n=17		 At least 60 kg
n=7		 At least 60 kg
n=44
Apparent clearance (L/h) 89.5 ± 21.6 116.2 ± 38.6 196.0 ± 55.8 174.5 ± 69.7
Apparent volume of distribution (L) 98.1 ± 30.2 154.7 ± 55.0 363 ± 137.7 308.3 ± 164.3
Elimination half-life (h) 0.75 ± 0.13 0.92 ± 0.09 1.26 ± 0.19 1.19 ± 0.21
Steady-state AUC (mg•h/L) 2.38 ± 0.66 2.36 ± 0.70 2.25 ± 0.89 2.65 ± 1.07
a The pharmacokinetic parameters (mean ± standard deviation) of didanosine were determined by a population pharmacokinetic model based on combined clinical studies.

Comparison of Didanosine Formulations

In VIDEX EC, 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-1, the AUC is equivalent for didanosine administered as the VIDEX EC 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.

Effect of Food

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 [see DOSAGE AND ADMINISTRATION]. VIDEX EC should be taken on an empty stomach.

Special Populations

Renal Insufficiency: 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 8). 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. [See DOSAGE AND ADMINISTRATION.]

Table 8: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation

Parameter Creatinine Clearance (mL/min) Dialysis Patients n=11
at least 90 n=12 60-90 n=6 30-59 n=6 10-29 n=3
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 less than 10
T½ (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.

Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIVinfected subjects with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See DOSAGE AND ADMINISTRATION.]

Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from 9 clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [see DOSAGE AND ADMINISTRATION].

Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age [see Use In Specific Populations].

Gender: The effects of gender on didanosine pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 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. For clinical recommendations based on drug interaction studies for drugs in bold font, see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS.

Table 9: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values

Drug Didanosine Dosage n % Change of Didanosine Pharmacokinetic Parametersa
AUC of Didanosine (90% CI) Cmax of Didanosine (90% CI)

tenofovirb,c,300 mg once daily with a light meald		 400 mg single dose
fasting 2 hours before tenofovir		 26 ↑48%
(31, 67%)		 ↑48%
(25, 76%)

tenofovirb,c,300 mg once daily with a light meald		 400 mg single dose
with tenofovir and a light meal		 25 ↑60%
(44, 79%)		 ↑64%
(41, 89%)

tenofovirb,c,300 mg once daily with a light meald		 200 mg single dose
with tenofovir and a light meal		 33 ↑16%
(6, 27%)e		 ↓12%
(-25, 3%)e
250 mg single dose
with tenofovir and a light meal		 33 ↔
(-13, 5%)f		 ↓20%
(-32, -7%)f
325 mg single dose
with tenofovir and a light meal		 33 ↑13%
(3, 24%)f		 ↓11%
(- 24,4%)f
methadone, chronic
maintenance dose		 400 mg single dose 15, 16g ↓17%
(-29, -2%)		 ↓ 16%
(-33, 4%)
↑ Indicates increase.
↓Indicates decrease.
↔Indicates no change, or mean increase or decrease of less than 10%.
a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.
c Tenofovir disoproxil fumarate.
d 373 kcalories, 8.2 grams fat.
e Compared with VIDEX EC 250 mg administered alone under fasting conditions.
f Compared with VIDEX EC 400 mg administered alone under fasting conditions.
g Comparisons are made to historical controls (n=148, pooled from 5 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.

Table 10: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values

Drug Didanosine Dosage n % Change of Coadministered Drug Pharmacokinetic Parameters a,b
AUC of Coadministered Drug (90% CI) Cmax of Coadministered Drug (90% CI)
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,c 300 mg once daily with a light meald 400 mg single dose fasting 2 hours before tenofovir 25 ↔ ↔
tenofovir,c 300 mg once daily with a light meald 400 mg single dose with tenofovir and a light meal 25 ↔ ↔
↔Indicates no change, or mean increase or decrease of less than 10%.
a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.
c Tenofovir disoproxil fumarate.
d 373 kcalories, 8.2 grams fat.

Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. 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. For clinical recommendations based on drug interaction studies for drugs in bold font, see DOSAGE AND ADMINISTRATION (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), CONTRAINDICATIONS, and DRUG INTERACTIONS

Table 11: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values

Drug Didanosine Dosage n % Change of Didanosine Pharmacokinetic Parametersa
AUC of Didanosine (95% CI) Cmax of Didanosine (95% CI)
allopurinol, renally impaired, 300 mg/day 200 mg single dose 2 ↑312% ↑232%
healthy volunteer, 300 mg/day for 7 days 400 mg single dose 14 ↑113% ↑69%
ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine 200 mg every 12 hours 12 ↑111% NA
ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine 200 mg every 12 hours for 3 days 8c ↓16% ↓28%
indinavir, 800 mg single dose simultaneous 200 mg single dose 16 ↔ ↔
1 hour before didanosine 200 mg single dose 16 ↓17% (-27, -7%)b ↓13% (-28, 5%)b
ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine 375 mg every 12 hours for 4 days 12c ↔ ↓12%
loperamide, 4 mg every 6 hours for 1 day 300 mg single dose 12c ↔ ↓23%
metoclopramide, 10 mg single dose 300 mg single dose 12c ↔ ↑13%
ranitidine, 150 mg single dose, 2 hours before didanosine 375 mg single dose 12c ↑14% ↑13%
rifabutin, 300 mg or 600 mg/day for 12 days 167 mg or 250 mg every 12 hours for 12 days 11 ↑13%(-1, 27%) ↑17%(-4, 38%)
ritonavir, 600 mg every 12 hours for 4 days 200 mg every 12 hours for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%)
stavudine, 40 mg every 12 hours for 4 days 100 mg every 12 hours for 4 days 10 ↔ ↔
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8c ↔ ↔
trimethoprim, 200 mg single dose 200 mg single dose 8c ↔ ↑17% (-23, 77%)
zidovudine, 200 mg every 8 hours for 3 days 200 mg every 12 hours for 3 days 6c ↔ ↔
↑Indicates increase.
↓Indicates decrease.
↔Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b 90% CI.
c HIV-infected patients.
NA = Not available.

Table 12: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values

Drug Didanosine Dosage n % Change of Coadministered Drug Pharmacokinetic Parametersa
AUC of Coadministered Drug (95% CI) Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose 200 mg every 12 hours for 14 days 6b ↔ ↔
ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine 200 mg every 12 hours 12b ↓21% NA
nelfinavir, 750 mg single dose, 1 hour after didanosine 200 mg single dose 10b ↑12% ↔
ranitidine, 150 mg single dose, 2 hours before didanosine 375 mg single dose 12b ↓16% ↔
ritonavir, 600 mg every 12 hours for 4 days 200 mg every 12 hours for 4 days 12 ↔ ↔
stavudine, 40 mg every 12 hours for 4 days 100 mg every 12 hours for 4 days 10b ↔ ↑17%
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8b ↓11% (-17, -4%) ↓12% (-28, 8%)
trimethoprim, 200 mg single dose 200 mg single dose 8b ↑10% (-9, 34%) ↓22% (-59, 49%)
zidovudine, 200 mg every 8 hours for 3 days 200 mg every 12 hours for 3 days 6b ↓10% (-27, 11%) ↓16.5% (-53, 47%)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients. NA = Not available.

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.

Antiviral Activity in Cell Culture

The 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% (EC50) 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.

Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosinetreated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution 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 cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.

Animal Toxicology and/or Pharmacology

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.

Clinical Studies

Adult Patients

Study AI454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm³ (range 39 to 1105 cells/mm³) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 13, respectively.

Figure 1 : Treatment Response Through Week 48*, AI454-152

Table 13: Outcomes of Randomized Treatment Through Week 48, AI454-152

Outcome Percent of Patients with HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL)
VIDEX EC + stavudine + nelfinavir
n=258		 zidovudine/lamivudinea + nelfinavir
n=253
Responderb,c 55% (33%) 56% (33%)
Virologic failured 22% (45%) 21% (43%)
Death or discontinued due to disease progression 1% (1%) 2% (2%)
Discontinued due to adverse event 6% (6%) 7% (7%)
Discontinued due to other reasonse 16% (16%) 15% (16%)
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.
e Includes lost to follow-up, subject's withdrawal, discontinuation due to physician's decision, never treated, and other reasons.

Pediatric Patients

Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m² every 6 hours), didanosine (120 mg/m² every 12 hours), or zidovudine (120 mg/m² every 6 hours) plus didanosine (90 mg/m² every 12 hours). Patients treated with didanosine or didanosine plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.

Where can i get more information?

Your pharmacist can provide more information about didanosine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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